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Sample records for apoptosis involves constitutive

  1. Involvement of Bim in Photofrin-mediated photodynamically induced apoptosis.

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    Wang, Xianwang; He, Xiaobing; Hu, Shujuan; Sun, Anbang; Lu, Chengbiao

    2015-01-01

    Photodynamic therapy (PDT) is a promising noninvasive technique, which has been successfully applied to the treatment of human cancers. Studies have shown that the Bcl-2 family proteins play important roles in PDT-induced apoptosis. However, whether Bcl-2-interacting mediator of cell death (Bim) is involved in photodynamic treatment remains unknown. In this study, we attempt to determine the effect of Bim on Photofrin photodynamic treatment (PPT)-induced apoptosis in human lung adenocarcinoma ASTC-a-1 cells. The translocation of Bim/Bax of the cells were monitored by laser confocal scanning microscope. The levels of Bim protein and activated caspase-3 in cells were detected by western blot assay. Caspase-3 activities were measured by Caspase-3 Fluorogenic Substrate (Ac-DEVD-AFC) analysis. The induction of apoptosis was detected by Hoechst 33258 and PI staining as well as flow cytometry analysis. The effect of Bim on PPT-induced apoptosis was determined by RNAi. BimL translocated to mitochondria in response to PPT, similar to the downstream pro-apoptotic protein Bax activation. PPT increased the level of Bim and activated caspase-3 in cells and that knockdown of Bim by RNAi significantly protected against caspase-3 activity. PPT-induced apoptosis were suppressed in cells transfected with shRNA-Bim. We demonstrated the involvement of Bim in PPT-induced apoptosis in human ASTC-a-1 lung adenocarcinoma cells and suggested that enhancing Bim activity might be a potential strategy for treating human cancers. © 2015 S. Karger AG, Basel.

  2. Apoptosis may involve in prenatally heroin exposed neurobehavioral teratogenicity?

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    Ying, Wang; Jang, Farhan Fateh; Teng, Chen; Tai-Zhen, Han

    2009-12-01

    Heroin abuse during pregnancy is a serious problem worldwide. Among all the illicit drugs, heroin is known as the most commonly abused opioid in the United States and China. Most women addicts are of child-bearing age. Heroin abuse during pregnancy, together with related factors like poor nutrition and inadequate maternal care, has been associated with adverse consequences including developmental delay of the offspring and their neurobehavioral teratogenicity. Researchers have done a lot of work to focus mainly on the variation of neurobehavior and its related factors such as the changes of neurotransmitters, receptors and involvement of the limited brain regions, but no one clearly and comprehensively explain the possible mechanism that may participate in the neurobehavioral teratogenicity induced by prenatal heroin exposure. Studies on animals have shown that heroin is a common neuroteratogen which can produce neurobehavioral defects. There must be some underlying mechanisms in the central nervous system which may take part in these defects. We hypothesized that the alterations in developmental apoptosis during embryogenesis could be one of the possible mechanisms which can cause neurobehavioral teratogenicity in prenatally heroin exposed offspring. Heroin is believed to pass through the placenta and blood-brain barrier much more rapidly than morphine due to the presence of acetyl groups and affects the developing brain. So far, it still remains obscure that whether the apoptosis in a particular brain region induced by heroin exposure in uterus is involved in neurobehavioral teratogenicity. Our hypothesis perhaps provides a more logical and possible explanation of the mechanism responsible for neurobehavioral teratogenicity caused by the prenatal heroin exposure during embryonic development. It can help to develop appropriate experimental animal models to understand the detailed mechanisms involved.

  3. Inhibition of constitutive NF-κB activity induces platelet apoptosis via ER stress.

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    Paul, Manoj; Kemparaju, Kempaiah; Girish, Kesturu S

    2017-12-02

    Platelets are anucleate cells, known for their pivotal roles in hemostasis, inflammation, immunity, and disease progression. Being anuclear, platelets are known to express several transcriptional factors which exert nongenomic functions, including the positive and negative regulation of platelet activation. NF-κB is one such transcriptional factor involved in the regulation of genes for survival, proliferation, inflammation and immunity. Although, the role NF-κB in platelet activation and aggregation is partially known, its function in management of platelet survival and apoptosis remain unexplored. Therefore, two unrelated inhibitors of NF-κB activation, BAY 11-7082 and MLN4924 were used to determine the role of NF-κB in platelets. Inhibition of NF-κB caused decreased SERCA activity and increased cytosolic Ca 2+ level causing ER stress which was determined by the phosphorylation of eIF2-α. Further, there was increased BAX and decreased BCl-2 levels, incidence of mitochondrial membrane potential depolarization, release of cytochrome c into cytosol, caspase activation, PS externalization and cell death in BAY 11-7082 and MLN4924 treated platelets. The obtained results demonstrate the critical role played by NF-κB in Ca 2+ homeostasis and survival of platelets. In addition, the study demonstrates the potential side effects associated with NF-κB inhibitors employed during inflammation and cancer therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Suppression by Ghrelin of Porphyromonas gingivalis-Induced Constitutive Nitric Oxide Synthase S-Nitrosylation and Apoptosis in Salivary Gland Acinar Cells

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    Bronislaw L. Slomiany

    2010-01-01

    Full Text Available Oral mucosal inflammatory responses to periodontopathic bacterium, P. gingivalis, and its key virulence factor, LPS, are characterized by a massive rise in epithelial cell apoptosis and the disturbances in NO signaling pathways. Here, we report that the LPS-induced enhancement in rat sublingual salivary gland acinar cell apoptosis and NO generation was associated with the suppression in constitutive nitric oxide synthase (cNOS activity and a marked increase in the activity of inducible nitric oxide synthase (iNOS. We demonstrate that the detrimental effect of the LPS on cNOS was manifested by the enzyme protein S-nitrosylation, that was susceptible to inhibition by iNOS inhibitor, 1400 W. Further, we show that a peptide hormone, ghrelin, countered the LPS-induced changes in apoptosis and cNOS activity. This effect of ghrelin was reflected in the decrease in cNOS S-nitrosylation and the increase in phosphorylation. Our findings imply that P. gingivalis-induced disturbances in the acinar cell NO signaling pathways result from upregulation in iNOS-derived NO that causes cNOS S-nitrosylation that interferes with its activation through phosphorylation. We also show that ghrelin protection against P. gingivalis-induced disturbances involves cNOS activation associated with a decrease in its S-nitrosylation and the increase in phosphorylation.

  5. Involvement of Prohibitin Upregulation in Abrin-Triggered Apoptosis

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    Yu-Huei Liu

    2012-01-01

    Full Text Available Abrin (ABR, a protein purified from the seeds of Abrus precatorius, induces apoptosis in various types of cancer cells. However, the detailed mechanism remains largely uncharacterized. By using a cDNA microarray platform, we determined that prohibitin (PHB, a tumor suppressor protein, is significantly upregulated in ABR-triggered apoptosis. ABR-induced upregulation of PHB is mediated by the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK pathway, as demonstrated by chemical inhibitors. In addition, ABR significantly induced the expression of Bax as well as the activation of caspase-3 and poly(ADP-ribose polymerase (PARP in Jurkat T cells, whereas the reduction of PHB by specific RNA interference delayed ABR-triggered apoptosis through the proapoptotic genes examined. Moreover, our results also indicated that nuclear translocation of the PHB-p53 complex may play a role in the transcription of Bax. Collectively, our data show that PHB plays a role in ABR-induced apoptosis, which may be helpful for the development of diagnostic or therapeutic agents.

  6. Involvement of apoptosis in host-parasite interactions in the zebra mussel.

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    Laëtitia Minguez

    Full Text Available The question of whether cell death by apoptosis plays a biological function during infection is key to understanding host-parasite interactions. We investigated the involvement of apoptosis in several host-parasite systems, using zebra mussels Dreissena polymorpha as test organisms and their micro- and macroparasites. As a stress response associated with parasitism, heat shock proteins (Hsp can be induced. In this protein family, Hsp70 are known to be apoptosis inhibitors. Mussels were diagnosed for their respective infections by standard histological methods; apoptosis was detected using the TUNEL methods on paraffin sections and Hsp70 by immunohistochemistry on cryosections. Circulating hemocytes were the main cells observed in apoptosis whereas infected tissues displayed no or few apoptotic cells. Parasitism by intracellular bacteria Rickettsiales-like and the trematode Bucephalus polymorphus were associated with the inhibition of apoptosis whereas ciliates Ophryoglena spp. or the trematode Phyllodistomum folium did not involve significant differences in apoptosis. Even if some parasites were able to modulate apoptosis in zebra mussels, we did not see evidence of any involvement of Hsp70 on this mechanism.

  7. Involvement of Apoptosis in Host-Parasite Interactions in the Zebra Mussel

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    Minguez, Laëtitia; Brulé, Nelly; Sohm, Bénédicte; Devin, Simon; Giambérini, Laure

    2013-01-01

    The question of whether cell death by apoptosis plays a biological function during infection is key to understanding host-parasite interactions. We investigated the involvement of apoptosis in several host-parasite systems, using zebra mussels Dreissena polymorpha as test organisms and their micro- and macroparasites. As a stress response associated with parasitism, heat shock proteins (Hsp) can be induced. In this protein family, Hsp70 are known to be apoptosis inhibitors. Mussels were diagnosed for their respective infections by standard histological methods; apoptosis was detected using the TUNEL methods on paraffin sections and Hsp70 by immunohistochemistry on cryosections. Circulating hemocytes were the main cells observed in apoptosis whereas infected tissues displayed no or few apoptotic cells. Parasitism by intracellular bacteria Rickettsiales-like and the trematode Bucephalus polymorphus were associated with the inhibition of apoptosis whereas ciliates Ophryoglena spp. or the trematode Phyllodistomum folium did not involve significant differences in apoptosis. Even if some parasites were able to modulate apoptosis in zebra mussels, we did not see evidence of any involvement of Hsp70 on this mechanism. PMID:23785455

  8. Caspase-12 is involved in stretch-induced apoptosis mediated endoplasmic reticulum stress.

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    Zhang, Qiang; Liu, Jianing; Chen, Shulan; Liu, Jing; Liu, Lijuan; Liu, Guirong; Wang, Fang; Jiang, Wenxin; Zhang, Caixia; Wang, Shuangyu; Yuan, Xiao

    2016-04-01

    It is well recognized that mandibular growth, which is caused by a variety of functional appliances, is considered to be the result of both neuromuscular and skeletal adaptations. Accumulating evidence has demonstrated that apoptosis plays an important role in the adaptation of skeletal muscle function. However, the underlying mechanism of apoptosis that is induced by stretch continues to be incompletely understood. Endoplasmic reticulum stress (ERS), a newly defined signaling pathway, initiates apoptosis. This study seeks to determine if caspase-12 is involved in stretch-induced apoptosis mediated endoplasmic reticulum stress in myoblast and its underlying mechanism. Apoptosis was assessed by Hochest staining, DAPI staining and annexin V binding and PI staining. ER chaperones, such as GRP78, CHOP and caspase-12, were determined by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Furthermore, caspase-12 inhibitor was used to value the mechanism of the caspase-12 pathway. Apoptosis of myoblast, which is subjected to cyclic stretch, was observed in a time-dependent manner. We found that GRP78 mRNA and protein were significantly increased and CHOP and caspase-12 were activated in myoblast that was exposed to cyclic stretch. Caspase-12 inhibition reduced stretch-induced apoptosis, and caspase-12 activated caspase-3 to induce apoptosis. We concluded that caspase-12 played an important role in stretch-induced apoptosis that is associated by endoplasmic reticulum stress by activating caspase-3.

  9. Acetate-induced apoptosis in colorectal carcinoma cells involves lysosomal membrane permeabilization and cathepsin D release.

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    Marques, C; Oliveira, C S F; Alves, S; Chaves, S R; Coutinho, O P; Côrte-Real, M; Preto, A

    2013-02-21

    Colorectal carcinoma (CRC) is one of the most common causes of cancer-related mortality. Short-chain fatty acids secreted by dietary propionibacteria from the intestine, such as acetate, induce apoptosis in CRC cells and may therefore be relevant in CRC prevention and therapy. We previously reported that acetic acid-induced apoptosis in Saccharomyces cerevisiae cells involves partial vacuole permeabilization and release of Pep4p, the yeast cathepsin D (CatD), which has a protective role in this process. In cancer cells, lysosomes have emerged as key players in apoptosis through selective lysosomal membrane permeabilization (LMP) and release of cathepsins. However, the role of CatD in CRC survival is controversial and has not been assessed in response to acetate. We aimed to ascertain whether LMP and CatD are involved in acetate-induced apoptosis in CRC cells. We showed that acetate per se inhibits proliferation and induces apoptosis. More importantly, we uncovered that acetate triggers LMP and CatD release to the cytosol. Pepstatin A (a CatD inhibitor) but not E64d (a cathepsin B and L inhibitor) increased acetate-induced apoptosis of CRC cells, suggesting that CatD has a protective role in this process. Our data indicate that acetate induces LMP and subsequent release of CatD in CRC cells undergoing apoptosis, and suggest exploiting novel strategies using acetate as a prevention/therapeutic agent in CRC, through simultaneous treatment with CatD inhibitors.

  10. Curcumin induces growth-arrest and apoptosis in association with the inhibition of constitutively active JAK-STAT pathway in T cell leukemia

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    Rajasingh, Johnson; Raikwar, Himanshu P.; Muthian, Gladson; Johnson, Caroline; Bright, John J.

    2006-01-01

    Adult T cell leukemia is an aggressive and frequently fatal malignancy that expressess constitutively activated growth-signaling pathways in association with deregulated growth and resistance to apoptosis. Curcumin (diferuloylmethane) is a naturally occurring yellow pigment, isolated from the rhizomes of the plant Curcuma longa that has traditionally been used in the treatment of injury and inflammation. But the effect and mechanism of action of curcumin on T cell leukemia is not known. To investigate the antitumor activity of curcumin in T cell leukemia, we examined its effect on constitutive phosphorylation of JAK and STAT proteins, proliferation, and apoptosis in HTLV-I-transformed T cell lines. HTLV-I-transformed T cell leukemia lines, MT-2, HuT-102, and SLB-1, express constitutively phosphorylated JAK3, TYK2, STAT3, and STAT5 signaling proteins. In vitro treatment with curcumin induced a dose-dependent decrease in JAK and STAT phosphorylation resulting in the induction of growth-arrest and apoptosis in T cell leukemia. The induction of growth-arrest and apoptosis in association with the blockade of constitutively active JAK-STAT pathway suggests this be a mechanism by which curcumin induces antitumor activity in T cell leukemia

  11. Resveratrol suppresses constitutive activation of AKT via generation of ROS and induces apoptosis in diffuse large B cell lymphoma cell lines.

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    Azhar R Hussain

    Full Text Available BACKGROUND: We have recently shown that deregulation PI3-kinase/AKT survival pathway plays an important role in pathogenesis of diffuse large B cell lymphoma (DLBCL. In an attempt to identify newer therapeutic agents, we investigated the role of Resveratrol (trans-3,4', 5-trihydroxystilbene, a naturally occurring polyphenolic compound on a panel of diffuse large B-cell lymphoma (DLBCL cells in causing inhibition of cell viability and inducing apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the action of Resveratrol on DLBCL cells and found that Resveratrol inhibited cell viability and induced apoptosis by inhibition of constitutively activated AKT and its downstream targets via generation of reactive oxygen species (ROS. Simultaneously, Resveratrol treatment of DLBCL cell lines also caused ROS dependent upregulation of DR5; and interestingly, co-treatment of DLBCL with sub-toxic doses of TRAIL and Resveratrol synergistically induced apoptosis via utilizing DR5, on the other hand, gene silencing of DR5 abolished this effect. CONCLUSION/SIGNIFICANCE: Altogether, these data suggest that Resveratrol acts as a suppressor of AKT/PKB pathway leading to apoptosis via generation of ROS and at the same time primes DLBCL cells via up-regulation of DR5 to TRAIL-mediated apoptosis. These data raise the possibility that Resveratrol may have a future therapeutic role in DLBCL and possibly other malignancies with constitutive activation of the AKT/PKB pathway.

  12. Vimentin is involved in peptidylarginine deiminase 2-induced apoptosis of activated Jurkat cells.

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    Hsu, Pei-Chen; Liao, Ya-Fan; Lin, Chin-Li; Lin, Wen-Hao; Liu, Guang-Yaw; Hung, Hui-Chih

    2014-05-01

    Peptidylarginine deiminase type 2 (PADI2) deiminates (or citrullinates) arginine residues in protein to citrulline residues in a Ca2+-dependent manner, and is found in lymphocytes and macrophages. Vimentin is an intermediate filament protein and a well-known substrate of PADI2. Citrullinated vimentin is found in ionomycin-induced macrophage apoptosis. Citrullinated vimentin is the target of anti-Sa antibodies, which are specific to rheumatoid arthritis, and play a critical role in the pathogenesis of the disease. To investigate the role of PADI2 in apoptosis, we generated a Jurkat cell line that overexpressed the PADI2 transgene from a tetracycline-inducible promoter, and used a combination of 12-O-tetradecanoylphorbol-13-acetate and ionomycin to activate Jurkat cells. We found that PADI2 overexpression reduced the cell viability of activated Jurkat cells in1a dose- and time-dependent manner. The PADI2-overexpressed and -activated Jurkat cells presented typical manifestations of apoptosis, and exhibited greater levels of citrullinated proteins, including citrullinated vimentin. Vimentin overexpression rescued a portion of the cells from apoptosis. In conclusion, PADI2 overexpression induces apoptosis in activated Jurkat cells. Vimentin is involved in PADI2-induced apoptosis. Moreover, PADI2-overexpressed Jurkat cells secreted greater levels of vimentin after activation, and expressed more vimentin on their cell surfaces when undergoing apoptosis. Through artificially highlighting PADI2 and vimentin, we demonstrated that PADI2 and vimentin participate in the apoptotic mechanisms of activated T lymphocytes. The secretion and surface expression of vimentin are possible ways of autoantigen presentation to the immune system.

  13. Cathepsin B is involved in the heat shock induced cardiomyocytes apoptosis as well as the anti-apoptosis effect of HSP-70.

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    Hsu, Shu-Fen; Hsu, Chuan-Chih; Cheng, Bor-Chih; Lin, Cheng-Hsien

    2014-11-01

    Cathepsin B is one of the major lysosomal cysteine proteases that plays an important role in apoptosis. Herein, we investigated whether Cathepsin B is involved in cardiomyocyte apoptosis caused by hyperthermic injury (HI) and heat shock protein (HSP)-70 protects these cells from HI-induced apoptosis mediated by Cathepsin. HI was produced in H9C2 cells by putting them in a circulating 43 °C water bath for 120 min, whereas preinduction of HSP-70 was produced in H9C2 cells by mild heat preconditioning (or putting them in 42 °C water bath for 30 min) 8 h before the start of HI. It was found that HI caused both cardiomyocyte apoptosis and increased Cathepsin B activity in H9C2 cells. E-64-c, in addition to reducing Cathepsin B activity, significantly attenuated HI-induced cardiomyocyte apoptosis (evidenced by increased apoptotic cell numbers, increased tuncated Bid (t-Bid), increased cytochrome C, increased caspase-9/-3, and decreased Bcl-2/Bax) in H9C2 cells. In addition, preinduction of HSP-70 by mild heat preconditioning or inhibition of HSP-70 by Tripolide significantly attenuated or exacerbated respectively both the cardiomyocyte apoptosis and increased Cathepsin B activity in H9C2 cells. Furthermore, the beneficial effects of pre-induction of HSP-70 by mild heat production in reducing both cardiomyocyte apoptosis and increased Cathepsin B activity caused by HI can be significantly reduced by Triptolide preconditioning. These results indicate that Cathepsin B is involved in HI-induced cardiomyocyte apoptosis in H9C2 cells and HSP-70 protects these cells from HI-induced cardiomyocyte apoptosis through Cathepsin B pathways.

  14. [FcγRIis involved in lipopolysaccharide-induced apoptosis of PC12 cells].

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    Chen, Yanjie; Liang, Yingxia; Zhang, Yan

    2017-06-01

    Objective To investigate the role of IgG Fc receptorI (FcγRI) in lipopolysaccharide (LPS)-induced apoptosis of the rat PC12 cells. Methods PC12 cells were treated with different concentrations of LPS (50, 125, 250, 500, 1000 μg/mL) for 24 hours and cell viability was analyzed by MTT assay. The appropriate concentration of LPS (500 μg/mL) was chosen for the following experiments. PC12 cells in the logarithmic growth phase were divided randomly into three groups: the control group without LPS, the 500 μg/mL LPS treated group and the 500 μg/mL LPS plus 0.2 μg/mL FcγRI neutralizer group. After24-hour different treatments, the mRNA and protein levels of FcγRIwere detected by quantitative real-time PCR and Western blotting, respectively. The apoptosis rate of PC12 cells was determined by flow cytometry combined with annexinV-FITC/PI double staining. The protein expression levels of caspase-3, Bcl-2 and BAX were measured by immunohistochemistry. Results PC12 cell viability decreased in a LPS dose-dependent manner. Compared to the control group, the protein and mRNA expression of FcγRI were upregulated, the expression levels of caspase-3, Bcl-2 and BAX proteins were elevated, and the apoptosis rate of PC12 cells was raised as well in the LPS treated group. Compared to the LPS treated group, the protein and mRNA levels of FcγRI were significantly lower along with significantly reduced expressions of Caspase-3 and BAX and inhibited cell apoptosis in the FcγRIneutralizer treated group, while Bcl-2 protein expression was upregulated. Conclusion FcγRIis involved in the LPS-induced apoptosis in PC12 cells.

  15. Proteomic analysis of pathways involved in estrogen-induced growth and apoptosis of breast cancer cells.

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    Zhang-Zhi Hu

    Full Text Available Estrogen is a known growth promoter for estrogen receptor (ER-positive breast cancer cells. Paradoxically, in breast cancer cells that have been chronically deprived of estrogen stimulation, re-introduction of the hormone can induce apoptosis.Here, we sought to identify signaling networks that are triggered by estradiol (E2 in isogenic MCF-7 breast cancer cells that undergo apoptosis (MCF-7:5C versus cells that proliferate upon exposure to E2 (MCF-7. The nuclear receptor co-activator AIB1 (Amplified in Breast Cancer-1 is known to be rate-limiting for E2-induced cell survival responses in MCF-7 cells and was found here to also be required for the induction of apoptosis by E2 in the MCF-7:5C cells. Proteins that interact with AIB1 as well as complexes that contain tyrosine phosphorylated proteins were isolated by immunoprecipitation and identified by mass spectrometry (MS at baseline and after a brief exposure to E2 for two hours. Bioinformatic network analyses of the identified protein interactions were then used to analyze E2 signaling pathways that trigger apoptosis versus survival. Comparison of MS data with a computationally-predicted AIB1 interaction network showed that 26 proteins identified in this study are within this network, and are involved in signal transduction, transcription, cell cycle regulation and protein degradation.G-protein-coupled receptors, PI3 kinase, Wnt and Notch signaling pathways were most strongly associated with E2-induced proliferation or apoptosis and are integrated here into a global AIB1 signaling network that controls qualitatively distinct responses to estrogen.

  16. Involvement of cathepsin B in mitochondrial apoptosis by p-phenylenediamine under ambient UV radiation

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    Goyal, Shruti; Amar, Saroj Kumar [Photobiology Division, CSIR – Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow 226001, Uttar Pradesh (India); Academy of Scientific and Innovative Research, CSIR-IITR Campus, Lucknow (India); Dubey, Divya; Pal, Manish Kumar [Photobiology Division, CSIR – Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow 226001, Uttar Pradesh (India); Singh, Jyoti [Photobiology Division, CSIR – Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow 226001, Uttar Pradesh (India); Academy of Scientific and Innovative Research, CSIR-IITR Campus, Lucknow (India); Verma, Ankit; Kushwaha, Hari Narayan [Photobiology Division, CSIR – Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow 226001, Uttar Pradesh (India); Ray, Ratan Singh, E-mail: ratanray.2011@rediffmail.com [Photobiology Division, CSIR – Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow 226001, Uttar Pradesh (India)

    2015-12-30

    Highlights: • Photodegradation and formation of photoproduct. • Involvement of ROS in PPD phototoxicity. • Role of ROS in DNA damage, CPD and micronuclei formation. • PPD induced lysosomal destabilization and release of cathepsin B. • Cleavage of Bid and activation of mitochondrial apoptosis. - Abstract: Paraphenylenediamine (PPD), a derivative of paranitroaniline has been most commonly used as an ingredient of oxidative hair dye and permanent tattoos. We have studied the phototoxic potential of PPD under ambient ultraviolet radiation. PPD is photodegraded and form a novel photoproduct under UV A exposure. PPD shows a concentration dependent decrease in cell viability of human Keratinocyte cells (HaCaT) through MTT and NRU test. Significant intracellular ROS generation was measured by DCFDA assay. It caused an oxidative DNA damage via single stranded DNA breaks, micronuclei and CPD formation. Both lysosome and mitochondria is main target for PPD induced apoptosis which was proved through lysosomal destabilization and release of cathepsin B by immunofluorescence, real time PCR and western blot analysis. Cathepsin B process BID to active tBID which induces the release of cytochrome C from mitochondria. Mitochondrial depolarization was reported through transmission electron microscopy. The cathepsin inhibitor reduced the release of cytochrome C in PPD treated cells. Thus study suggests that PPD leads to apoptosis via the involvement of lysosome and mitochondria both under ambient UV radiation. Therefore, photosensitizing nature of hair dye ingredients should be tested before coming to market as a cosmetic product for the safety of human beings.

  17. Involvement of cathepsin B in mitochondrial apoptosis by p-phenylenediamine under ambient UV radiation

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    Goyal, Shruti; Amar, Saroj Kumar; Dubey, Divya; Pal, Manish Kumar; Singh, Jyoti; Verma, Ankit; Kushwaha, Hari Narayan; Ray, Ratan Singh

    2015-01-01

    Highlights: • Photodegradation and formation of photoproduct. • Involvement of ROS in PPD phototoxicity. • Role of ROS in DNA damage, CPD and micronuclei formation. • PPD induced lysosomal destabilization and release of cathepsin B. • Cleavage of Bid and activation of mitochondrial apoptosis. - Abstract: Paraphenylenediamine (PPD), a derivative of paranitroaniline has been most commonly used as an ingredient of oxidative hair dye and permanent tattoos. We have studied the phototoxic potential of PPD under ambient ultraviolet radiation. PPD is photodegraded and form a novel photoproduct under UV A exposure. PPD shows a concentration dependent decrease in cell viability of human Keratinocyte cells (HaCaT) through MTT and NRU test. Significant intracellular ROS generation was measured by DCFDA assay. It caused an oxidative DNA damage via single stranded DNA breaks, micronuclei and CPD formation. Both lysosome and mitochondria is main target for PPD induced apoptosis which was proved through lysosomal destabilization and release of cathepsin B by immunofluorescence, real time PCR and western blot analysis. Cathepsin B process BID to active tBID which induces the release of cytochrome C from mitochondria. Mitochondrial depolarization was reported through transmission electron microscopy. The cathepsin inhibitor reduced the release of cytochrome C in PPD treated cells. Thus study suggests that PPD leads to apoptosis via the involvement of lysosome and mitochondria both under ambient UV radiation. Therefore, photosensitizing nature of hair dye ingredients should be tested before coming to market as a cosmetic product for the safety of human beings.

  18. Genes involved in immunity and apoptosis are associated with human presbycusis based on microarray analysis.

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    Dong, Yang; Li, Ming; Liu, Puzhao; Song, Haiyan; Zhao, Yuping; Shi, Jianrong

    2014-06-01

    Genes involved in immunity and apoptosis were associated with human presbycusis. CCR3 and GILZ played an important role in the pathogenesis of presbycusis, probably through regulating chemokine receptor, T-cell apoptosis, or T-cell activation pathways. To identify genes associated with human presbycusis and explore the molecular mechanism of presbycusis. Hearing function was tested by pure-tone audiometry. Microarray analysis was performed to identify presbycusis-correlated genes by Illumina Human-6 BeadChip using the peripheral blood samples of subjects. To identify biological process categories and pathways associated with presbycusis-correlated genes, bioinformatics analysis was carried out by Gene Ontology Tree Machine (GOTM) and database for annotation, visualization, and integrated discovery (DAVID). Quantitative RT-PCR (qRT-PCR) was used to validate the microarray data. Microarray analysis identified 469 up-regulated genes and 323 down-regulated genes. Both the dominant biological processes by Gene Ontology (GO) analysis and the enriched pathways by Kyoto encyclopedia of genes and genomes (KEGG) and BIOCARTA showed that genes involved in immunity and apoptosis were associated with presbycusis. In addition, CCR3, GILZ, CXCL10, and CX3CR1 genes showed consistent difference between groups for both the gene chip and qRT-PCR data. The differences of CCR3 and GILZ between presbycusis patients and controls were statistically significant (p < 0.05).

  19. Unlawful occupation of Inner-City Buildings: A Constitutional Analysis of the Rights and Obligations involved

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    Janke Strydom

    2014-11-01

    Full Text Available The unlawful occupation of inner-city buildings in South Africa has led to a number of legal disputes between vulnerable occupiers and individual landowners that highlight the conflict between individuals' constitutional right not to be evicted in an arbitrary manner and property owners' constitutional right not to be deprived of property arbitrarily. The cause of this tension is a shortage of affordable housing options for low-income households in the inner cities, a fact which shows that the state is evidently struggling to give effect to its housing obligation embodied in section 26(1 and (2 of the Constitution. In the majority of cases the courts assume that any interference with private landowners' rights beyond a temporary nature would be unjustifiable, but they do this without undertaking a proper constitutional analysis to determine whether a further limitation of the individual landowner's property rights might be justifiable and non-arbitrary in the circumstances of each case. In general the courts can allow, suspend or refuse the eviction of unlawful occupiers, provided that the order does not amount to an arbitrary deprivation of property. Nevertheless, in some instances the arbitrary deprivation of property is unavoidable, despite the court's best efforts to protect property entitlements. These eviction cases show the limits of the courts' powers both to provide adequate solutions to protect owners' property rights and to give effect to the constitutional housing provision. In the light of three eviction cases, namely Blue Moonlight, Modderklip and Olivia Road, this article explains the role of the court and the local authority, together with the entitlements and social obligations of inner-city landowners within the framework of the property clause, in order to analyse the constitutionality of the courts' decisions and to suggest ways in which the inner-city housing shortage may be addressed more effectively. This article also

  20. Apoptosis induction is involved in UVA-induced autolysis in sea cucumber Stichopus japonicus.

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    Qi, Hang; Fu, Hui; Dong, Xiufang; Feng, Dingding; Li, Nan; Wen, Chengrong; Nakamura, Yoshimasa; Zhu, Beiwei

    2016-05-01

    Autolysis easily happens to sea cucumber (Stichopus japonicus, S. japonicus) for external stimulus like UV exposure causing heavy economic losses. Therefore, it is meaningful to reveal the mechanism of S. japonicas autolysis. In the present study, to examine the involvement of apoptosis induction in UVA-induced autolysis of S. japonicas, we investigated the biochemical events including the DNA fragmentation, caspase-3 activation, mitogen-activated protein kinases (MAPKs) phosphorylation and free radical formation. Substantial morphological changes such as intestine vomiting and dermatolysis were observed in S. japonicus during the incubation after 1-h UVA irradiation (10W/m(2)). The degradation of the structural proteins and enhancement of cathepsin L activity were also detected, suggesting the profound impact of proteolysis caused by the UVA irradiation even for 1h. Furthermore, the DNA fragmentation and specific activity of caspase-3 was increased up to 12h after UVA irradiation. The levels of phosphorylated p38 mitogen activated protein kinase (MAPK) and phosphorylated c-Jun.-N-terminal kinase (JNK) were significantly increased by the UVA irradiation for 1h. An electron spin resonance (ESR) analysis revealed that UVA enhanced the free radical formation in S. japonicas, even through we could not identify the attributed species. These results suggest that UVA-induced autolysis in S. japonicas at least partially involves the oxidative stress-sensitive apoptosis induction pathway. These data present a novel insight into the mechanisms of sea cucumber autolysis induced by external stress. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Several nuclear events during apoptosis depend on caspase-3 activation but do not constitute a common pathway.

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    Lisa Trisciuoglio

    Full Text Available A number of nuclear events occur during apoptosis, including DNA laddering, nuclear lamina breakdown, phosphorylation of histones H2B and histone H2AX, and the tight binding to chromatin of HMGB1 and CAD, the nuclease responsible for DNA laddering. We have performed an epistasis analysis to investigate whether these events cluster together in pathways. We find that all depend directly or indirectly on caspase-3 activation. CAD activation, H2AX phosphorylation and DNA laddering cluster together into a pathway, but all other events appear to be independent of each other downstream of caspase-3, and likely evolved subject to different functional pressures.

  2. TNF/TNFR1 pathway and endoplasmic reticulum stress are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes

    International Nuclear Information System (INIS)

    Zhang, Fu-Tao; Ding, Yi; Shah, Zahir; Xing, Dan; Gao, Yuan; Liu, Dong Ming; Ding, Ming-Xing

    2014-01-01

    Background and purpose: Quinolones cause obvious cartilaginous lesions in juvenile animals by chondrocyte apoptosis, which results in the restriction of their use in pediatric and adolescent patients. Studies showed that chondrocytes can be induced to produce TNFα, and the cisternae of the endoplasmic reticulum in quinolone-treated chondrocytes become dilated. We investigated whether TNF/TNFR 1 pathway and endoplasmic reticulum stress (ERs) are involved in ofloxacin (a typical quinolone)-induced apoptosis of juvenile canine chondrocytes. Experimental approach: Canine juvenile chondrocytes were treated with ofloxacin. Cell survival and apoptosis rates were determined with MTT method and flow cytometry, respectively. The gene expression levels of the related signaling molecules (TNFα, TNFR 1 , TRADD, FADD and caspase-8) in death receptor pathways and main apoptosis-related molecules (calpain, caspase-12, GADD153 and GRP78) in ERs were measured by qRT-PCR. The gene expression of TNFR 1 was suppressed with its siRNA. The protein levels of TNFα, TNFR 1 and caspase-12 were assayed using Western blotting. Key results: The survival rates decreased while apoptosis rates increased after the chondrocytes were treated with ofloxacin. The mRNA levels of the measured apoptosis-related molecules in death receptor pathways and ERs, and the protein levels of TNFα, TNFR 1 and caspase-12 increased after the chondrocytes were exposed to ofloxacin. The downregulated mRNA expressions of TNFR 1 , Caspase-8 and TRADD, and the decreased apoptosis rates of the ofloxacin-treated chondrocytes occurred after TNFR 1 –siRNA interference. Conclusions and implications: Ofloxacin-induced chondrocyte apoptosis in a time- and concentration-dependent fashion. TNF/TNFR 1 pathway and ERs are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes in the early stage. - Highlights: • Chondrocyte apoptosis is induced by ofloxacin in a time- and concentration-dependent manners.

  3. Apoptosis induced by tungsten carbide-cobalt nanoparticles in JB6 cells involves ROS generation through both extrinsic and intrinsic apoptosis pathways.

    Science.gov (United States)

    Zhao, Jinshun; Bowman, Linda; Magaye, Ruth; Leonard, Stephen S; Castranova, Vincent; Ding, Min

    2013-04-01

    In this study, apoptosis and related signaling induced by WC-Co nanoparticles were investigated in JB6 cells and rat lung macrophages. Electron spin resonance (ESR) and fluorescent staining indicated that both WC-Co nanoparticles and fine particles stimulated reactive oxygen species (ROS) generation. Catalase exhibited an inhibitory effect on WC-Co nanoparticle-induced ROS as well as mitochondrial membrane permeability damage. Further study indicated that WC-Co nanoparticles elicited higher cytotoxicity and apoptotic induction than fine particles. Western blot analysis showed activation of proapoptotic factors including Fas, Fas-associated protein with death domain (FADD), caspase 3, 8 and 9, BID and BAX. In addition, both cytochrome c and apoptosis-inducing factor (AIF) were upregulated and released from mitochondria to the cytoplasm. Our findings demonstrate that, on a mass basis, WC-Co nanoparticles exhibit higher cytotoxicity and apoptotic induction than fine particles. Apoptosis induced by WC-Co nanoparticles and fine particles involves both extrinsic and intrinsic apoptosis pathways.

  4. Drosophila muscleblind is involved in troponin T alternative splicing and apoptosis.

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    Marta Vicente-Crespo

    2008-02-01

    Full Text Available Muscleblind-like proteins (MBNL have been involved in a developmental switch in the use of defined cassette exons. Such transition fails in the CTG repeat expansion disease myotonic dystrophy due, in part, to sequestration of MBNL proteins by CUG repeat RNA. Four protein isoforms (MblA-D are coded by the unique Drosophila muscleblind gene.We used evolutionary, genetic and cell culture approaches to study muscleblind (mbl function in flies. The evolutionary study showed that the MblC protein isoform was readily conserved from nematods to Drosophila, which suggests that it performs the most ancestral muscleblind functions. Overexpression of MblC in the fly eye precursors led to an externally rough eye morphology. This phenotype was used in a genetic screen to identify five dominant suppressors and 13 dominant enhancers including Drosophila CUG-BP1 homolog aret, exon junction complex components tsunagi and Aly, and pro-apoptotic genes Traf1 and reaper. We further investigated Muscleblind implication in apoptosis and splicing regulation. We found missplicing of troponin T in muscleblind mutant pupae and confirmed Muscleblind ability to regulate mouse fast skeletal muscle Troponin T (TnnT3 minigene splicing in human HEK cells. MblC overexpression in the wing imaginal disc activated apoptosis in a spatially restricted manner. Bioinformatics analysis identified a conserved FKRP motif, weakly resembling a sumoylation target site, in the MblC-specific sequence. Site-directed mutagenesis of the motif revealed no change in activity of mutant MblC on TnnT3 minigene splicing or aberrant binding to CUG repeat RNA, but altered the ability of the protein to form perinuclear aggregates and enhanced cell death-inducing activity of MblC overexpression.Taken together our genetic approach identify cellular processes influenced by Muscleblind function, whereas in vivo and cell culture experiments define Drosophila troponin T as a new Muscleblind target, reveal a

  5. The dual role of autophagy under hypoxia-involvement of interaction between autophagy and apoptosis.

    Science.gov (United States)

    Li, Mengmeng; Tan, Jin; Miao, Yuyang; Lei, Ping; Zhang, Qiang

    2015-06-01

    Hypoxia is one of severe cellular stress and it is well known to be associated with a worse outcome since a lack of oxygen accelerates the induction of apoptosis. Autophagy, an important and evolutionarily conserved mechanism for maintaining cellular homeostasis, is closely related to the apoptosis caused by hypoxia. Generally autophagy blocks the induction of apoptosis and inhibits the activation of apoptosis-associated caspase which could reduce cellular injury. However, in special cases, autophagy or autophagy-relevant proteins may help to induce apoptosis, which could aggravate cell damage under hypoxia condition. In addition, the activation of apoptosis-related proteins-caspase can also degrade autophagy-related proteins, such as Atg3, Atg4, Beclin1 protein, inhibiting autophagy. Although the relationship between autophagy and apoptosis has been known for rather complex for more than a decade, the underlying regulatory mechanisms have not been clearly understood. This short review discusses and summarizes the dual role of autophagy and the interaction and molecular regulatory mechanisms between autophagy and apoptosis under hypoxia.

  6. Modulations of DNMT1 and HDAC1 are involved in the OTA-induced cytotoxicity and apoptosis in vitro.

    Science.gov (United States)

    Zhou, Yajiao; Gan, Fang; Hou, Lili; Zhou, Xuan; Adam Ibrahim, Yassin Abdulrahim; Huang, Kehe

    2017-12-25

    Ochratoxin A (OTA) as a fungal metabolite is reported to induce cytotoxicity and apoptosis through the mechanism of oxidative stress. Oxidative stress could induce the epigenetic enzymes modifications. However, whether epigenetic enzymes modifications are involved in OTA-induced cytotoxicity and apoptosis has not been reported until now. Therefore, the objectives of this study were to verify OTA-induced cytotoxicity and apoptosis and to investigate the potential role of epigenetic enzymes in OTA-induced cytotoxicity and apoptosis in PK15 cells. The results demonstrated that OTA at 4 μg/ml treatment for 12 h and 24 h induced cytotoxicity and apoptosis as demonstrated by decreasing cell viability, increasing LDH release, Annexin V/PI staining, Bcl-2/Bax mRNA ratio and apoptotic nuclei in PK15 cells. OTA treatment up-regulated ROS production and down-regulated GSH levels. In addition, OTA treatment activated the epigenetics related enzymes DNA methyltransferase 1 (DNMT1) and Histone deacetylase 1 (HDAC1). Adding DNMT1 inhibitor (5-Aza-2dc) or HDAC1 inhibitor (LBH589) depressed the up-regulation of DNMT1 or HDAC1 expression, the decreases of GSH levels and increases of ROS production induced by OTA, respectively. Furthermore, inhibition of DNMT1 or HDAC1 by their inhibitor reversed the decreases of cell viability and increases of LDH activity and apoptosis induced by OTA, respectively. In conclusion, the observed effects indicate that the critical modulation of DNMT1 and HDAC1 is related to OTA-induced cytotoxicity and apoptosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Insights on the involvement of (-)-epigallocatechin gallate in ER stress-mediated apoptosis in age-related macular degeneration.

    Science.gov (United States)

    Karthikeyan, Bose; Harini, Lakshminarasimhan; Krishnakumar, Vaithilingam; Kannan, Velu Rajesh; Sundar, Krishnan; Kathiresan, Thandavarayan

    2017-01-01

    Endoplasmic reticulum (ER) stress-mediated apoptosis is a well-known factor in the pathogenesis of age-related macular degeneration (AMD). ER stress leads to accumulation of misfolded proteins, which in turn activates unfolded protein response (UPR) of the cell for its survival. The prolonged UPR of ER stress promotes cell death; however, the transition between adaptation and ER stress-induced apoptosis has not been clearly understood. Hence, the present study investigates the regulatory effect of (-)-epigallocatechin gallate (EGCG) on ER stress-induced by hydrogen peroxide (H 2 O 2 ) and disturbance of calcium homeostasis by thapsigargin (TG) in mouse retinal pigment epithelial (MRPE) cells. The oxidant molecules influenced MRPE cells showed an increased level of intracellular calcium [Ca 2+ ] i in ER and transferred to mitochondria through ER-mitochondrial tether site then increased ROS production. EGCG restores [Ca 2+ ] i homeostasis by decreasing ROS production through inhibition of prohibitin1 which regulate ER-mitochondrial tether site and inhibit apoptosis. Effect of EGCG on ER stress-mediated apoptosis was elucidated by exploring the UPR signalling pathways. EGCG downregulated GRP78, CHOP, PERK, ERO1α, IRE1α, cleaved PARP, cleaved caspase 3, caspase 12 and upregulated expression of calnexinin MRPE cells. In addition to this, inhibition of apoptosis by EGCG was also confirmed with expression of proteins Akt, PTEN and GSK3β. MRPE cells with EGCG upregulates phosphorylation of Akt at ser473 and phospho ser380 of PTEN, but phosphorylation at ser9 of GSK3β was inhibited. Further, constitutively active (myristoylated) CA-Akt transfected in MRPE cells had an increased Akt activity in EGCG influenced cells. These findings strongly suggest that antioxidant molecules inhibit cell death through the proper balancing of [Ca 2+ ] i and ROS production in order to maintain UPR of ER in MRPE cells. Thus, modulation of UPR signalling may provide a potential target for

  8. NDV-induced apoptosis in absence of Bax; evidence of involvement of apoptotic proteins upstream of mitochondria

    Directory of Open Access Journals (Sweden)

    Molouki Aidin

    2012-08-01

    Full Text Available Abstract Background Recently it was shown that following infection of HeLa cells with Newcastle disease virus (NDV, the matrix (M protein binds to Bax and subsequently the intrinsic pathway of apoptosis is activated. Moreover, there was very little alteration on mRNA and protein levels of Bax and Bcl-2 after infection with NDV. Finding In order to further investigate the role of members of the Bcl-2 family, Bax-knockout and wild-type HCT116 cells were infected with NDV strain AF2240. Although both cells underwent apoptosis through the activation of the intrinsic pathway and the release of cytochrome c from mitochondria, the percentage of dead Bax-knockout cells was significantly lower than wt cells (more than 10% at 48 h post-infection. In a parallel experiment, the effect of NDV on HT29 cells, that are originally Bcl-2-free, was studied. Apoptosis in HT29 cells was associated with Bax redistribution from cytoplasm to mitochondria, similar to that of HeLa and wt HCT116 cells. Conclusion Although the presence of Bax during NDV-induced apoptosis contributes to a faster cell death, it was concluded that other apoptotic protein(s upstream of mitochondria are also involved since cancer cells die whether in the presence or absence of Bax. Therefore, the classic Bax/Bcl-2 ratio may not be a major determinant in NDV-induced apoptosis.

  9. Involvement of VDAC, Bax and Ceramides in the Efflux of AIF from Mitochondria during Curcumin-Induced Apoptosis

    Science.gov (United States)

    Scharstuhl, Alwin; Mutsaers, Henricus A. M.; Pennings, Sebastiaan W. C.; Russel, Frans G. M.; Wagener, Frank A. D. T. G.

    2009-01-01

    Background We previously identified curcumin as a potent inducer of fibroblast apoptosis, which could be used to treat hypertrophic scar formation. Here we investigated the underlying mechanism of this process. Principal Findings Curcumin-induced apoptosis could not be blocked by caspase-inhibitors and we could not detect any caspase-3/7 activity. Curcumin predominantly induced mitochondria-mediated ROS formation and stimulated the expression of the redox-sensitive pro-apoptotic factor p53. Inhibition of the pro-apoptotic signaling enzyme glycogen synthase kinase-3β (GSK-3β) blocked curcumin-induced apoptosis. Apoptosis was associated with high molecular weight DNA damage, a possible indicator of apoptosis-inducing factor (AIF) activity. Indeed, curcumin caused nuclear translocation of AIF, which could be blocked by the antioxidant N-acetyl cysteine. We next investigated how AIF is effluxed from mitochondria in more detail. The permeability transition pore complex (PTPC), of which the voltage-dependent anion channel (VDAC) is a component, could be involved since the VDAC-inhibitor DIDS (4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid) efficiently blocked AIF translocation. However, PTPC is not involved in AIF release since cyclosporine A, a specific inhibitor of the complex did not block apoptosis. Alternatively, the pro-apoptotic protein Bax could have formed mitochondrial channels and interacted with VDAC. Curcumin caused mitochondrial translocation of Bax, which was blocked by DIDS, suggesting a Bax-VDAC interaction. Interestingly, ceramide channels can also release apoptogenic factors from mitochondria and we found that addition of ceramide induced caspase-independent apoptosis. Surprisingly, this process could also be blocked by DIDS, suggesting the concerted action of Bax, VDAC and ceramide in the efflux of AIF from the mitochondrion. Conclusions Curcumin-induced fibroblast apoptosis is totally caspase-independent and relies on the mitochondrial

  10. Disruption of apoptosis pathways involved in zebrafish gonad differentiation by 17α-ethinylestradiol and fadrozole exposures

    International Nuclear Information System (INIS)

    Luzio, Ana; Matos, Manuela; Santos, Dércia; Fontaínhas-Fernandes, António A.; Monteiro, Sandra M.

    2016-01-01

    Highlights: • Apoptosis in females is avoided by anti-apoptotic pathways and in males is essential to the “juvenile ovary” failure. • BIRC5 is central to the regulation of zebrafish spermatogenesis. • EE2 did not change sex ratios, but Fadrozole induced masculinization with a significant increase in male proportion. • The few females identified after exposure to Fadrozole may have avoided sex reversal by increasing anti-apoptotic proteins. • EE2 increased the pro-apoptotic genes/proteins in males, promoting gonad differentiation. - Abstract: Zebrafish (Danio rerio) sex determination seems to involve genetic factors (GSD) but also environmental factors (ESD), such as endocrine disrupting chemicals (EDCs) that are known to mimic endogenous hormones and disrupt gonad differentiation. Apoptosis has also been proposed to play a crucial role in zebrafish gonad differentiation. Nevertheless, the interactions between EDCs and apoptosis have received little attention. Thus, this study aimed to assess if and which apoptotic pathways are involved in zebrafish gonad differentiation and how EDCs may interfere with this process. With these purposes, zebrafish were exposed to 17α-ethinylestradiol (EE 2 , 4 ng/L) and fadrozole (Fad, 50 μg/L) from 2 h to 35 days post-fertilization (dpf). Afterwards, a gene expression analysis by qRT-PCR and a stereological analysis, based on systematic sampling and protein immunohistochemistry, were performed. The death receptors (FAS; TRADD), anti-apoptotic (BCL-2; MDM2), pro-apoptotic (CASP-2 and −6) and cell proliferation (BIRC5/survivin; JUN) genes and proteins were evaluated. In general, apoptosis was inhibited in females through the involvement of anti-apoptotic pathways, while in males apoptosis seemed to be crucial to the failure of the “juvenile ovary” development and the induction of testes transformation. The JUN protein was shown to be necessary in juvenile ovaries, while the BIRC5 protein seemed to be involved in

  11. Disruption of apoptosis pathways involved in zebrafish gonad differentiation by 17α-ethinylestradiol and fadrozole exposures

    Energy Technology Data Exchange (ETDEWEB)

    Luzio, Ana, E-mail: aluzio@utad.pt [Centre for the Research and Technology of Agro-Environmental and Biological Sciences, CITAB, Departamento de Biologia e Ambiente (DeBA), University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Life Sciences and Environment School, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Matos, Manuela [University of Lisbon, Faculty of Sciences, BioISI– Biosystems & Integrative Sciences Institute, Campo Grande, 1749-016 Lisbon (Portugal); Department of Genetics and Biotechnology, Life Sciences and Environment School (ECVA), University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Santos, Dércia [Life Sciences and Environment School, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Fontaínhas-Fernandes, António A.; Monteiro, Sandra M. [Centre for the Research and Technology of Agro-Environmental and Biological Sciences, CITAB, Departamento de Biologia e Ambiente (DeBA), University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Life Sciences and Environment School, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); and others

    2016-08-15

    Highlights: • Apoptosis in females is avoided by anti-apoptotic pathways and in males is essential to the “juvenile ovary” failure. • BIRC5 is central to the regulation of zebrafish spermatogenesis. • EE2 did not change sex ratios, but Fadrozole induced masculinization with a significant increase in male proportion. • The few females identified after exposure to Fadrozole may have avoided sex reversal by increasing anti-apoptotic proteins. • EE2 increased the pro-apoptotic genes/proteins in males, promoting gonad differentiation. - Abstract: Zebrafish (Danio rerio) sex determination seems to involve genetic factors (GSD) but also environmental factors (ESD), such as endocrine disrupting chemicals (EDCs) that are known to mimic endogenous hormones and disrupt gonad differentiation. Apoptosis has also been proposed to play a crucial role in zebrafish gonad differentiation. Nevertheless, the interactions between EDCs and apoptosis have received little attention. Thus, this study aimed to assess if and which apoptotic pathways are involved in zebrafish gonad differentiation and how EDCs may interfere with this process. With these purposes, zebrafish were exposed to 17α-ethinylestradiol (EE{sub 2}, 4 ng/L) and fadrozole (Fad, 50 μg/L) from 2 h to 35 days post-fertilization (dpf). Afterwards, a gene expression analysis by qRT-PCR and a stereological analysis, based on systematic sampling and protein immunohistochemistry, were performed. The death receptors (FAS; TRADD), anti-apoptotic (BCL-2; MDM2), pro-apoptotic (CASP-2 and −6) and cell proliferation (BIRC5/survivin; JUN) genes and proteins were evaluated. In general, apoptosis was inhibited in females through the involvement of anti-apoptotic pathways, while in males apoptosis seemed to be crucial to the failure of the “juvenile ovary” development and the induction of testes transformation. The JUN protein was shown to be necessary in juvenile ovaries, while the BIRC5 protein seemed to be involved

  12. Occipital foramina development involves localised regulation of mesenchyme proliferation and is independent of apoptosis

    Science.gov (United States)

    Akbareian, Sophia E; Pitsillides, Andrew A; Macharia, Raymond G; McGonnell, Imelda M

    2015-01-01

    Cranial foramina are holes within the skull, formed during development, allowing entry and exit of blood vessels and nerves. Once formed they must remain open, due to the vital structures they contain, i.e. optic nerves, jugular vein, carotid artery, and other cranial nerves and blood vessels. Understanding cranial foramina development is essential as cranial malformations lead to the stenosis or complete closure of these structures, resulting in blindness, deafness, facial paralysis, raised intracranial pressure and lethality. Here we focus on describing early events in the formation of the jugular, carotid and hypoglossal cranial foramina that form in the mesoderm-derived, endochondral occipital bones at the base of the embryonic chick skull. Whole-mount skeletal staining of skulls indicates the appearance of these foramina from HH32/D7.5 onwards. Haematoxylin & eosin staining of sections shows that the intimately associated mesenchyme, neighbouring the contents of these cranial foramina, is initially very dense and gradually becomes sparser as development proceeds. Histological examination also revealed that these foramina initially contain relatively large-diameter nerves, which later become refined, and are closely associated with the blood vessel, which they also innervate within the confines of the foramina. Interestingly cranial foramina in the base of the skull contain blood vessels lacking smooth muscle actin, which suggests these blood vessels belong to glomus body structures within the foramina. The blood vessel shape also appears to dictate the overall shape of the resulting foramina. We initially hypothesised that cranial foramina development could involve targeted proliferation and local apoptosis to cause ‘mesenchymal clearing’ and the creation of cavities in a mechanism similar to joint cavitation. We find that this is not the case, and propose that a mechanism reliant upon local nerve/blood vessel-derived restriction of ossification may

  13. Identification of genes regulated by Wnt/β-catenin pathway and involved in apoptosis via microarray analysis

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    Chen Quan

    2006-09-01

    Full Text Available Abstract Background Wnt/β-catenin pathway has critical roles in development and oncogenesis. Although significant progress has been made in understanding the downstream signaling cascade of this pathway, little is known regarding Wnt/β-catenin pathway modification of the cellular apoptosis. Methods To identify potential genes regulated by Wnt/β-catenin pathway and involved in apoptosis, we used a stably integrated, inducible RNA interference (RNAi vector to specific inhibit the expression and the transcriptional activity of β-catenin in HeLa cells. Meanwhile, we designed an oligonucleotide microarray covering 1384 apoptosis-related genes. Using oligonucleotide microarrays, a series of differential expression of genes was identified and further confirmed by RT-PCR. Results Stably integrated inducible RNAi vector could effectively suppress β-catenin expression and the transcriptional activity of β-catenin/TCF. Meanwhile, depletion of β-catenin in this manner made the cells more sensitive to apoptosis. 130 genes involved in some important cell-apoptotic pathways, such as PTEN-PI3K-AKT pathway, NF-κB pathway and p53 pathway, showed significant alteration in their expression level after the knockdown of β-catenin. Conclusion Coupling RNAi knockdown with microarray and RT-PCR analyses proves to be a versatile strategy for identifying genes regulated by Wnt/β-catenin pathway and for a better understanding the role of this pathway in apoptosis. Some of the identified β-catenin/TCF directed or indirected target genes may represent excellent targets to limit tumor growth.

  14. Mechanisms involved in apoptosis of carp leukocytes upon in vitro and in vivo immunostimulation

    NARCIS (Netherlands)

    Kepka, M.; Verburg-van Kemenade, B.M.L.; Homa, J.; Chadzinska, M.K.

    2014-01-01

    During inflammation leukocyte activity must be carefully regulated, as high concentrations and/or prolonged action of pro-inflammatory mediators e.g. reactive oxygen species (ROS) can be detrimental not only for pathogens but also for host tissues. Programmed cell death – apoptosis is a most

  15. Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Bing, E-mail: wangbin69@yahoo.com; Wang, Xin-bao; Chen, Li-yu; Huang, Ling; Dong, Rui-zen

    2013-07-19

    Highlights: •Belinostat activates AMPK in cultured pancreatic cancer cells. •Activation of AMPK is important for belinostat-induced cytotoxic effects. •ROS and TAK1 are involved in belinostat-induced AMPK activation. •AMPK activation mediates mTOR inhibition by belinostat. -- Abstract: Pancreatic cancer accounts for more than 250,000 deaths worldwide each year. Recent studies have shown that belinostat, a novel pan histone deacetylases inhibitor (HDACi) induces apoptosis and growth inhibition in pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In the current study, we found that AMP-activated protein kinase (AMPK) activation was required for belinostat-induced apoptosis and anti-proliferation in PANC-1 pancreatic cancer cells. A significant AMPK activation was induced by belinostat in PANC-1 cells. Inhibition of AMPK by RNAi knockdown or dominant negative (DN) mutation significantly inhibited belinostat-induced apoptosis in PANC-1 cells. Reversely, AMPK activator AICAR and A-769662 exerted strong cytotoxicity in PANC-1 cells. Belinostat promoted reactive oxygen species (ROS) production in PANC-1 cells, increased ROS induced transforming growth factor-β-activating kinase 1 (TAK1)/AMPK association to activate AMPK. Meanwhile, anti-oxidants N-Acetyl-Cysteine (NAC) and MnTBAP as well as TAK1 shRNA knockdown suppressed belinostat-induced AMPK activation and PANC-1 cell apoptosis. In conclusion, we propose that belinostat-induced apoptosis and growth inhibition require the activation of ROS-TAK1-AMPK signaling axis in cultured pancreatic cancer cells.

  16. Arsenic-induced alteration in intracellular calcium homeostasis induces head kidney macrophage apoptosis involving the activation of calpain-2 and ERK in Clarias batrachus

    International Nuclear Information System (INIS)

    Banerjee, Chaitali; Goswami, Ramansu; Datta, Soma; Rajagopal, R.; Mazumder, Shibnath

    2011-01-01

    We had earlier shown that exposure to arsenic (0.50 μM) caused caspase-3 mediated head kidney macrophage (HKM) apoptosis involving the p38-JNK pathway in Clarias batrachus. Here we examined the roles of calcium (Ca 2+ ) and extra-cellular signal-regulated protein kinase (ERK), the other member of MAPK-pathway on arsenic-induced HKM apoptosis. Arsenic-induced HKM apoptosis involved increased expression of ERK and calpain-2. Nifedipine, verapamil and EGTA pre-treatment inhibited the activation of calpain-2, ERK and reduced arsenic-induced HKM apoptosis as evidenced from reduced caspase-3 activity, Annexin V-FITC-propidium iodide and Hoechst 33342 staining. Pre-incubation with ERK inhibitor U 0126 inhibited the activation of calpain-2 and interfered with arsenic-induced HKM apoptosis. Additionally, pre-incubation with calpain-2 inhibitor also interfered with the activation of ERK and inhibited arsenic-induced HKM apoptosis. The NADPH oxidase inhibitor apocynin and diphenyleneiodonium chloride also inhibited ERK activation indicating activation of ERK in arsenic-exposed HKM also depends on signals from NADPH oxidase pathway. Our study demonstrates the critical role of Ca 2+ homeostasis on arsenic-induced HKM apoptosis. We suggest that arsenic-induced alteration in intracellular Ca 2+ levels initiates pro-apoptotic ERK and calpain-2; the two pathways influence each other positively and induce caspase-3 mediated HKM apoptosis. Besides, our study also indicates the role of ROS in the activation of ERK pathway in arsenic-induced HKM apoptosis in C. batrachus. - Highlights: → Altered Ca 2+ homeostasis leads to arsenic-induced HKM apoptosis. → Calpain-2 plays a critical role in the process. → ERK is pro-apoptotic in arsenic-induced HKM apoptosis. → Arsenic-induced HKM apoptosis involves cross talk between calpain-2 and ERK.

  17. MicroRNA-122 down-regulation is involved in phenobarbital-mediated activation of the constitutive androstane receptor.

    Directory of Open Access Journals (Sweden)

    Ryota Shizu

    Full Text Available Constitutive androstane receptor (CAR is a nuclear receptor that regulates the transcription of target genes, including CYP2B and 3A. Phenobarbital activates CAR, at least in part, in an AMP-activated protein kinase (AMPK-dependent manner. However, the precise mechanisms underlying phenobarbital activation of AMPK are still unclear. In the present study, it was demonstrated that phenobarbital administration to mice decreases hepatic miR-122, a liver-enriched microRNA involved in both hepatic differentiation and function. The time-course change in the phenobarbital-mediated down-regulation of miR-122 was inversely correlated with AMPK activation. Phenobarbital decreased primary miR-122 to approximately 25% of the basal level as early as 1 h and suppressed transactivity of mir-122 promoter in HuH-7 cells, suggesting that the down-regulation occurred at the transcriptional level. AMPK activation by metformin or 5-aminoimidazole-4-carboxamide 1-β-D-ribonucleoside had no evident effect on miR-122 levels. An inhibitory RNA specific for miR-122 increased activated AMPK and CAR-mediated trancactivation of the phenobarbital-responsive enhancer module in HepG2 cells. Conversely, the reporter activity induced by the ectopic CAR was almost completely suppressed by co-transfection with the miR-122 mimic RNA. GFP-tagged CAR was expressed in the cytoplasm in addition to the nucleus in the majority of HuH-7 cells in which miR-122 was highly expressed. Co-transfection of the mimic or the inhibitor RNA for miR-122 further increased or decreased, respectively, the number of cells that expressed GFP-CAR in the cytoplasm. Taken together, these results suggest that phenobarbital-mediated down-regulation of miR-122 is an early and important event in the AMPK-dependent CAR activation and transactivation of its target genes.

  18. MicroRNA-122 down-regulation is involved in phenobarbital-mediated activation of the constitutive androstane receptor.

    Science.gov (United States)

    Shizu, Ryota; Shindo, Sawako; Yoshida, Takemi; Numazawa, Satoshi

    2012-01-01

    Constitutive androstane receptor (CAR) is a nuclear receptor that regulates the transcription of target genes, including CYP2B and 3A. Phenobarbital activates CAR, at least in part, in an AMP-activated protein kinase (AMPK)-dependent manner. However, the precise mechanisms underlying phenobarbital activation of AMPK are still unclear. In the present study, it was demonstrated that phenobarbital administration to mice decreases hepatic miR-122, a liver-enriched microRNA involved in both hepatic differentiation and function. The time-course change in the phenobarbital-mediated down-regulation of miR-122 was inversely correlated with AMPK activation. Phenobarbital decreased primary miR-122 to approximately 25% of the basal level as early as 1 h and suppressed transactivity of mir-122 promoter in HuH-7 cells, suggesting that the down-regulation occurred at the transcriptional level. AMPK activation by metformin or 5-aminoimidazole-4-carboxamide 1-β-D-ribonucleoside had no evident effect on miR-122 levels. An inhibitory RNA specific for miR-122 increased activated AMPK and CAR-mediated trancactivation of the phenobarbital-responsive enhancer module in HepG2 cells. Conversely, the reporter activity induced by the ectopic CAR was almost completely suppressed by co-transfection with the miR-122 mimic RNA. GFP-tagged CAR was expressed in the cytoplasm in addition to the nucleus in the majority of HuH-7 cells in which miR-122 was highly expressed. Co-transfection of the mimic or the inhibitor RNA for miR-122 further increased or decreased, respectively, the number of cells that expressed GFP-CAR in the cytoplasm. Taken together, these results suggest that phenobarbital-mediated down-regulation of miR-122 is an early and important event in the AMPK-dependent CAR activation and transactivation of its target genes.

  19. Involvement of apoptosis and calcium accumulation through TRPV1 channels in neurobiology of epilepsy.

    Science.gov (United States)

    Nazıroğlu, M; Övey, İ S

    2015-05-07

    Calcium ion accumulation into the cytosol of the hippocampus and dorsal root ganglion (DRG) are main reasons in etiology of epilepsy. Transient receptor potential vanilloid type 1 (TRPV1) channel is a cation-permeable calcium channel found in the DRG and hippocampus. Although previous studies implicate TRPV1 channels in the generation of epilepsy, suppression of ongoing seizures by TRPV1 antagonists has not yet been investigated. We tested the effects of TRPV1-specific antagonists, capsazepine (CPZ) and 5'-iodoresiniferatoxin (IRTX) on the modulation of calcium accumulation, apoptosis and anticonvulsant properties in the hippocampus and DRG of pentylentetrazol (PTZ) and capsaicin (CAP) administrated rats. Forty rats were divided into five groups as follows; control, PTZ, CAP+PTZ, IRTX, and IRTX+PTZ. Fura-2 and patch-clamp experiments were performed on neurons dissected from treated animals by CAP and CPZ. PTZ and CAP+PTZ administrations increased intracellular free Ca(2+) concentrations, TRPV1 current densities, apoptosis, caspase 3 and 9 values although the values were reduced by IRTX and CPZ treatments. Latency time was extended by application CPZ and IRTX although CAP produced acceleration of epileptic seizures. Taken together, these results support a role for TRPV1 channels in the inhibition of apoptosis, epileptic seizures and calcium accumulation, indicating that TRPV1 inhibition may possibly be a novel target in the DRG and hippocampus for prevention of epileptic seizures and peripheral pain. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Apoptosis of supraoptic AVP neurons is involved in the development of central diabetes insipidus after hypophysectomy in rats

    Directory of Open Access Journals (Sweden)

    Huang Lijin

    2008-06-01

    Full Text Available Abstract Background It has been reported that various types of axonal injury of hypothalamo-neurohypophyseal tract can result in degeneration of the magnocellular neurons (MCNs in hypothalamus and development of central diabetes insipidus (CDI. However, the mechanism of the degeneration and death of MCNs after hypophysectomy in vivo is still unclear. This present study was aimed to disclose it and to figure out the dynamic change of central diabetes insipidus after hypophysectomy. Results The analysis on the dynamic change of daily water consumption (DWC, daily urine volume(DUV, specific gravity of urine(USG and plasma vasopressin concentration showed that the change pattern of them was triphasic and neuron counting showed that the degeneration of vasopressin neurons began at 10 d, aggravated at 20 d and then stabilized at 30 d after hypophysectomy. There was marked upregulation of cleaved Caspase-3 expression of vasopressin neurons in hypophysectomy rats. A "ladder" pattern of migration of DNA internucleosomal fragments was detected and apoptotic ultrastructure was found in these neurons. There was time correlation among the occurrence of diabetes insipidus, the changes of plasma vasopressin concentration and the degeneration of vasopressin neurons after hypophysectomy. Conclusion This study firstly demonstrated that apoptosis was involved in degeneration of supraoptic vasopressin neurons after hypophysectomy in vivo and development of CDI. Our study on time course and correlations among water metabolism, degeneration and apoptosis of vasopressin neurons suggested that there should be an efficient therapeutic window in which irreversible CDI might be prevented by anti-apoptosis.

  1. Involvement of TR3/Nur77 translocation to the endoplasmic reticulum in ER stress-induced apoptosis

    International Nuclear Information System (INIS)

    Liang Bin; Song Xuhong; Liu Gefei; Li Rui; Xie Jianping; Xiao Lifeng; Du Mudan; Zhang Qiaoxia; Xu Xiaoyuan; Gan Xueqiong; Huang Dongyang

    2007-01-01

    Nuclear orphan receptor TR3/Nur77/NGFI-B is a novel apoptotic effector protein that initiates apoptosis largely by translocating from the nucleus to the mitochondria, causing the release of cytochrome c. However, it is possible that TR3 translocates to other organelles. The present study was designed to determine the intracellular localization of TR3 following CD437-induced nucleocytoplasmic translocation and the mechanisms involved in TR3-induced apoptosis. In human neuroblastoma SK-N-SH cells and human esophageal squamous carcinoma EC109 and EC9706 cells, 5 μM CD437 induced translocation of TR3 to the endoplasmic reticulum (ER). This distribution was confirmed by immunofluorescence analysis, subcellular fractionation analysis and coimmunoprecipitation analysis. The translocated TR3 interacted with ER-targeting Bcl-2; initiated an early release of Ca 2+ from ER; resulted in ER stress and induced apoptosis through ER-specific caspase-4 activation, together with induction of mitochondrial stress and subsequent activation of caspase-9. Our results identified a novel distribution of TR3 in the ER and defined two parallel mitochondrial- and ER-based pathways that ultimately result in apoptotic cell death

  2. Cathepsin L is involved in cathepsin D processing and regulation of apoptosis in A549 human lung epithelial cells.

    Science.gov (United States)

    Wille, Aline; Gerber, Annegret; Heimburg, Anke; Reisenauer, Anita; Peters, Christoph; Saftig, Paul; Reinheckel, Thomas; Welte, Tobias; Bühling, Frank

    2004-07-01

    Cathepsins are implicated in a multitude of physiological and pathophysiological processes. The aim of the present study was to investigate the function of cathepsin L (catL) in the proteolytic network of human lung epithelial cells and its role in the regulation of apoptosis. We found that catL-deficient A549 cells as well as lung tissue extracts of catL(-/-) mice express increased amounts of single-chain cathepsin D (catD). Degradation experiments indicate that catL specifically degrades the single-chain isoform of catD. Furthermore, we found that catL-deficient cells showed increased sensitivity to apoptosis. Finally, we demonstrate that the inhibition of catD activity by pepstatin A decreased the number of apoptotic cells in catL-deficient A549 cells after anti-Fas treatment. In conclusion, catL is involved in catD processing and the accumulation of catD isoforms in catL-deficient cells is associated with increased rates of spontaneous and anti-Fas-induced apoptosis.

  3. GADD45α is involved in the apoptosis of lymphocytes induced by riboflavin and ultraviolet light.

    Science.gov (United States)

    Yang, Peng; Wen, Huiqin; Zhong, Tao; Hu, Hailiang; Zhu, Bangqiang; Xia, Kang; Xu, Mo; Bian, Maohong

    2017-03-01

    Riboflavin plus ultraviolet (UV) pathogen reduction technology (RF-PRT) is an effective method for inactivating the residual white blood cells (WBCs) in blood components. The RF-PRT system for platelets is known to activate many signaling pathways, including p38 and NF-κB. Nevertheless, proteomic studies in WBCs after riboflavin plus UV treatment requires further analysis. ABO/D-matched lymphocytes were pooled, split, and treated with RF-PRT or UV light or left untreated. After treatment, cell apoptosis was measured. In addition, cell proliferation and the cycle distribution were evaluated upon stimulation with phytohemagglutinin. The changes in the protein expression levels of growth arrest and DNA damage-inducible (GADD)45α, p38, and c-Jun N-terminal kinase (JNK) were determined by Western blotting. The effect of GADD45α, p38, and JNK on apoptosis was assessed. RF-PRT significantly inhibited proliferation and induced G1 arrest in lymphocytes. Furthermore, the percentage of apoptotic cells was increased in RF-PRT-treated lymphocytes compared to UV-treated cells or untreated cells, associated with the up regulation of GADD45α expression. Consistent with these observations, the inhibition of GADD45α expression partially counteracted the effects of riboflavin plus UV treatment. The p38 and JNK signaling pathways were activated by GADD45α in RF-PRT-treated lymphocytes. These data revealed that RF-PRT effectively inhibited proliferation and induced apoptosis of lymphocytes by promoting GADD45α expression, which subsequently activates p38 and JNK signaling pathways. © 2016 AABB.

  4. Mechanisms involved in enhancement of apoptosis by radiation or hyperthermia in combination with sodium butyrate

    International Nuclear Information System (INIS)

    Wei, Z.L.; Zhao, Q.L.; Hassan, M.A.; Kondo, Takashi

    2010-01-01

    Sodium butyrate is a four-carbon fatty acid and natural component of the colonic milieu. Butyrate has been shown to induce apoptosis in numerous types of cancer cells, and received much attention as a potential chemopreventive agent for colorectal cancer. However, during initial clinical trials, its efficacy was limited. X-irradiation or hyperthermia as an adjuvant significantly enhanced the cell growth arrest, alteration of the cell cycle, and cell death caused by butyrate. The balance between anti-apoptotic and pro-apoptotic Bcl-2 family proteins was lost and a mitochondrial pathway was activated. In this review, the interactions of butyrate with X-irradiation and hyperthermia are discussed. (author)

  5. Endosomes and lysosomes are involved in early steps of Tl(III)-mediated apoptosis in rat pheochromocytoma (PC12) cells.

    Science.gov (United States)

    Hanzel, Cecilia E; Almeira Gubiani, María F; Verstraeten, Sandra V

    2012-11-01

    The mechanisms that mediate thallium (Tl) toxicity are still not completely understood. The exposure of rat pheochromocytoma (PC12) cells to Tl(I) or Tl(III) activates both mitochondrial (Tl(I) and Tl(III)) and extrinsic (Tl(III)) pathways of apoptosis. In this work we evaluated the hypothesis that the effects of Tl(III) may be mediated by the damage to lysosomes, where it might be incorporated following the route of iron uptake. PC12 cells exposed for 3 h to 100 μM Tl(III) presented marked endosomal acidification, effect that was absent when cells were incubated in a serum-free medium and that was fully recovered when the latter was supplemented with transferrin. After 6 h of incubation the colocalization of cathepsins D and B with the lysosomal marker Lamp-1 was decreased together with an increase in the total activity of the enzymes. A permanent damage to lysosomes after 18 h of exposure was evidenced from the impairment of acridine orange uptake. Cathepsin D caused the cleavage of pro-apoptotic protein BID that is involved in the activation of the intrinsic pathway of apoptosis. Supporting that, BID cleavage and the activation of caspase 3 by Tl(III) were fully prevented when cells were preincubated with cathepsin D inhibitor (pepstatin A) and only partially prevented when cathepsin B inhibitor (E64d) was used. None of these inhibitors affected BID cleavage or caspase 3 activation in Tl(I)-treated cells. Together, experimental results support the role of Tl(III) uptake by the acidic cell compartments and their involvement in the early steps of Tl(III)-mediated PC12 cells apoptosis.

  6. Ginkgo biloba exocarp extracts induces apoptosis in Lewis lung cancer cells involving MAPK signaling pathways.

    Science.gov (United States)

    Cao, Chenjie; Su, Ya; Han, Dongdong; Gao, Yanqi; Zhang, Menghua; Chen, Huasheng; Xu, Aihua

    2017-02-23

    A fruit of Ginkgo biloba L. is known as Ginkgo nuts. It is an edible traditional Chinese medicine, and could be used for the treatment of cancer thousands of years ago in China. The extracts prepared from the exocarp of Ginkgo biloba (Ginkgo biloba exocarp extracts, GBEE) has the effects of anti-cancer, immune promotion, anti-aging and etc. To study the effects of GBEE inducing apoptosis in Lewis lung cancer (LLC) cells and the role of Mitogen-activated protein kinase(MAPK) signaling pathways in it. The LLC solid tumor model was established in C57BL/6J mice. The tumor-bearing mice were randomly divided into 5 groups. A normal control group without tumor cells was established additionally. There were 10 mice in each group, and they were dosed 24h after inoculation. The GBEE (50, 100, 200mg/kg b.w.) groups were dosed by intragastric gavage (i.g.). The mice in positive control group were intraperitoneal (i.p.) injected with cyclophosphamide (CPA) at a dose of 20mg/kg (b.w.). The model control group and the normal control group were both given normal saline (NS) by i.g.. All the groups were dosed at a volume of 0.1mL/10g (b.w.), once a day for 18d. The day after the last administration, the transplanted tumors was stripped and weighed, and the inhibition rate was calculated. In vitro experiments, MTT method was applied to detect the effects of GBEE on LLC cells and primary cultured mouse lung cells. Annexin V-FITC/PI method was used to detect the apoptosis rate of LLC cells. Rhodamine 123 method was used to detect the Mitochondrial transmembrane potential (MTP). Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the levels of Fas mRNA. Western Blot was used to detect the expression of Bax, Bcl-2, Cyt C, cleaved Caspase-3 and MAPK proteins in the corresponding parts of LLC cells. GBEE (50-200mg/kg) inhibited the growth of LLC transplanted tumors with a dose-effect relationship. GBEE (5-160µg/mL) inhibited the proliferation of LLC

  7. Atmospheric-pressure plasma jet induces apoptosis involving mitochondria via generation of free radicals.

    Directory of Open Access Journals (Sweden)

    Hak Jun Ahn

    Full Text Available The plasma jet has been proposed as a novel therapeutic method for anticancer treatment. However, its biological effects and mechanism of action remain elusive. Here, we investigated its cell death effects and underlying molecular mechanisms, using air and N₂ plasma jets from a micro nozzle array. Treatment with air or N₂ plasma jets caused apoptotic death in human cervical cancer HeLa cells, simultaneously with depolarization of mitochondrial membrane potential. In addition, the plasma jets were able to generate reactive oxygen species (ROS, which function as surrogate apoptotic signals by targeting the mitochondrial membrane potential. Antioxidants or caspase inhibitors ameliorated the apoptotic cell death induced by the air and N₂ plasma jets, suggesting that the plasma jet may generate ROS as a proapoptotic cue, thus initiating mitochondria-mediated apoptosis. Taken together, our data suggest the potential employment of plasma jets as a novel therapy for cancer.

  8. Involvement of BAFF and APRIL in Resistance to Apoptosis of Acute Myeloid Leukemia.

    Science.gov (United States)

    Bolkun, Lukasz; Grubczak, Kamil; Schneider, Gabriela; Zembko, Paula; Radzikowska, Urszula; Singh, Paulina; Kloczko, Janusz; Ratajczak, Mariusz Z; Moniuszko, Marcin; Eljaszewicz, Andrzej

    2016-01-01

    B-cell activation factor of the TNF family (BAFF), and a proliferation-inducing ligand (APRIL), two members of the tumour necrosis factor (TNF) superfamily, beyond playing a significant role in normal B-cell development, promote survival and proliferation of malignant B cells. Both ligands interact with 3 receptors: BAFF-R, specific to BAFF, and TACI and BCMA which are shared by both BAFF and APRIL. Here we wished to investigate the potential role of these proteins in resistance of acute myeloid leukaemia (AML) blasts to apoptosis. We found that the levels of both mRNA and proteins of APRIL, BAFF and their receptors were expressed in leukaemic cells of 24 newly diagnosed, untreated AML patients. We also demonstrated that patients who did not further respond to induction therapy (NR) presented with significantly higher baseline APRIL and BAFF expression on AML blasts as compared to these subjects who, after induction, achieved complete remission (CR) following induction therapy. Moreover, we observed striking differences in baseline levels of BCMA between CR and NR patients as we did not find detectable expression of this receptor in the latter group of patients. Interestingly, we found that AML blasts collected at baseline from NR patients cultured in presence of exogenous BAFF and APRIL were significantly more resistant to spontaneous or drug-induced apoptosis as compared with cells derived from CR patients. Altogether, our data confirm that BAFF and APRIL signaling play important role in AML pathogenesis and susceptibility to cytotoxic therapy while measuring of BCMA expression on AML cells can become a novel prognostic factor for chemotherapy response.

  9. The novel Indole-3-formaldehyde (2-AITFEI-3-F) is involved in processes of apoptosis induction?

    Science.gov (United States)

    Karimabad, Mojgan Noroozi; Mahmoodi, Mehdi; Jafarzadeh, Abdollah; Darehkordi, Ali; Hajizadeh, Mohammad Reza; Khorramdelazad, Hossein; Falahati-Pour, Soudeh Khanamani; Hassanshahi, Gholamhossein

    2017-07-15

    Balancing between Bax and Bcl-2 plays critical roles in both proliferation and self-renewal activation of cancer cells. Indole-3-formaldehyde derivatives limit the growth and facilitate cell death in different cell systems. In this study, we introduced a novel indole derivative (2-AITFEI-3-F) with tendency to facilitate apoptosis in NB4 line in comparison to basal Indole-3-formaldehyde (I3F). The NB4 cells were cultured in RPMI1640 medium contained 2-AITFEI-3-F and I3F (15.12-1000μg/mL) for 24, 48 and 72h. Inhibition of cell proliferation was assessed by trypan blue staining technique and MTT assay. The fold changes of Bax/Bcl-2 expression against β-actin were determined by real-time-PCR technique. Western blotting analysis was also applied for evaluating the expression of Bax and Bcl2 at protein level. Data were analyzed by student t and repeated measure tests. Differences were considered significant if (P<0.01). There was a significant difference in cell viability, when various concentrations of 2-AITFEI-3-F (but similar to I3F) were used for 24, 48 and 72h in comparison to I3F regarding the cellular viability (P<0.05). Real time PCR and Western blotting analysis indicated that the gene and protein expression level of Bcl-2 down-regulated while Bax was up-regulated in compare to untreated control cells and cells treated with I3F (P<0.01). According to these findings, the novel indole derivative 2-AITFEI-3-F probably triggered apoptosis of NB4 cells by modulating Bax/Bcl-2 ratio. Furthermore, the 2-AITFEI-3-F had markedly displayed anti-cancer activity than I3F. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Xue, Tao; Luo, Peihua; Zhu, Hong; Zhao, Yuqin [Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 (China); Wu, Honghai; Gai, Renhua; Wu, Youping [Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058 (China); Yang, Bo [Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 (China); Yang, Xiaochun, E-mail: yangxiaochun@zju.edu.cn [Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 (China); Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058 (China); He, Qiaojun, E-mail: qiaojunhe@zju.edu.cn [Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 (China); Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058 (China)

    2012-06-15

    Dasatinib, a multitargeted inhibitor of BCR–ABL and SRC kinases, exhibits antitumor activity and extends the survival of patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). However, some patients suffer from hepatotoxicity, which occurs through an unknown mechanism. In the present study, we found that Dasatinib could induce hepatotoxicity both in vitro and in vivo. Dasatinib reduced the cell viability of rat primary hepatocytes, induced the release of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) in vitro, and triggered the ballooning degeneration of hepatocytes in Sprague–Dawley rats in vivo. Apoptotic markers (chromatin condensation, cleaved caspase-3 and cleaved PARP) were detected to indicate that the injury induced by Dasatinib in hepatocytes in vitro was mediated by apoptosis. This result was further validated in vivo using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Here we found that Dasatinib dramatically increased the level of reactive oxygen species (ROS) in hepatocytes, reduced the intracellular glutathione (GSH) content, attenuated the activity of superoxide dismutase (SOD), generated malondialdehyde (MDA), a product of lipid peroxidation, decreased the mitochondrial membrane potential, and activated nuclear factor erythroid 2-related factor 2 (Nrf2) and mitogen-activated protein kinases (MAPK) related to oxidative stress and survival. These results confirm that oxidative stress plays a pivotal role in Dasatinib-mediated hepatotoxicity. N-acetylcysteine (NAC), a typical antioxidant, can scavenge free radicals, attenuate oxidative stress, and protect hepatocytes against Dasatinib-induced injury. Thus, relieving oxidative stress is a viable strategy for reducing Dasatinib-induced hepatotoxicity. -- Highlights: ►Dasatinib shows potential hepatotoxicity both in vitro and in vivo. ►Apoptosis plays a vital role in Dasatinib

  11. Involvement of the Extrinsic and Intrinsic Pathways in Ultraviolet B-Induced Apoptosis of Corneal Epithelial Cells

    Science.gov (United States)

    Ubels, John L.; Glupker, Courtney D.; Schotanus, Mark P.; Haarsma, Loren D.

    2015-01-01

    The goal of this study was to elucidate the pathway by which UVB initiates efflux of K+ and subsequently apoptosis in human corneal limbal epithelial (HCLE) cells. The initial focus of the study was on the extrinsic pathway involving Fas. HCLE cells transfected with Fas siRNA were exposed to 80–150 mJ/cm2 UVB and incubated in culture medium with 5.5 mM K+. Knock down of Fas resulted in limited reduction in UVB-induced caspase-8 and -3 activity. Patch-clamp recordings showed no difference in UVB-induced normalized K+ currents between Fas transfected and control cells. Knockdown of caspase-8 had no effect on the activation of caspase-3 following UVB exposure, while a caspase-8 inhibitor completely eliminated UVB activation of caspase-3. This suggests that caspase-8 is a robust enzyme, able to activate caspase-3 via residual caspase-8 present after knockdown, and that caspase-8 is directly involved in the UVB activation of caspase-3. Inhibition of caspase-9 significantly decreased the activation of caspases-8 and -3 in response to UVB. Knockdown of Apaf-1, required for activation of caspase-9, resulted in a significant reduction in UVB-induced activation of caspases-9, -8, and -3. Knockdown of Apaf-1 also inhibited intrinsic and UVB-induced levels of apoptosis, as determined by DNA fragmentation measured by TUNEL assay. In UVB exposed cultures treated with caspase-3 inhibitor, the percentage of apoptotic cells was reduced to control levels, confirming the necessity of caspase-3 activation in DNA fragmentation. The lack of effect of Fas knockdown on K+ channel activation, as well as the limited effect on activation of caspases-8 and -3, strongly suggest that Fas and the extrinsic pathway is not of primary importance in the initiation of apoptosis in response to UVB in HCLE cells. Inhibition of caspase-8 and -3 activation following inhibition of caspase-9, as well as reduction in activation of caspases-9, -8, and -3 and DNA fragmentation in response to Apaf-1

  12. NF-kappaB is involved in SHetA2 circumvention of TNF-alpha resistance, but not induction of intrinsic apoptosis.

    Science.gov (United States)

    Chengedza, Shylet; Benbrook, Doris Mangiaracina

    2010-03-01

    Treatment of cancer with tumor necrosis factor-alpha (TNF-alpha) is hindered by resistance and toxicity. The flexible heteroarotinoid, SHetA2, sensitizes resistant ovarian cancer cells to TNF-alpha-induced extrinsic apoptosis, and also induces intrinsic apoptosis as a single agent. This study tested the hypothesis that nuclear factor-kappaB (NF-kappaB) is involved in SHetA2-regulated intrinsic and extrinsic apoptosis. SHetA2 inhibited basal and TNF-alpha-induced or hydrogen peroxide-induced NF-kappaB activity through counter-regulation of upstream kinase (IkappaB kinase) activity, inhibitor protein (IkappaB-alpha) phosphorylation, and p-65 NF-kappaB subunit nuclear translocation, but independently of reactive oxygen species generation. Ectopic over-expression of p-65, or treatment with TNF-alpha receptor 1 (TNFR1) small interfering RNA or a caspase-8 inhibitor, each attenuated synergistic apoptosis by SHetA2 and TNF-alpha, but did not affect intrinsic apoptosis caused by SHetA2. In conclusion, NF-kappaB repression is involved in SHetA2 circumvention of resistance to TNF-alpha-induced extrinsic apoptosis, but not in SHetA2 induction of intrinsic apoptosis.

  13. Serotonin inhibits apoptosis of pulmonary artery smooth muscle cells through 5-HT2A receptors involved in the pulmonary artery remodeling of pulmonary artery hypertension.

    Science.gov (United States)

    Liu, Ya; Tian, Hongyan; Yan, Xiaoli; Fan, Fenling; Wang, Wenping; Han, Junli

    2013-03-01

    Decreased pulmonary artery smooth muscle cell (PASMC) apoptosis play a key role in pulmonary artery remodeling during pulmonary artery hypertension (PAH), but the mechanisms involved are unclear. Serotonin (5-HT) inhibits apoptosis in many pathologic processes by activating the 5-HT2A receptor. Therefore, we hypothesized that 5-HT may be the promoter of decreased apoptosis in PAH through the 5-HT2A receptor. We found that inhibition of the 5-HT2A receptor prevented the increase in pulmonary artery pressure and pulmonary artery remodeling in rats stimulated by monocrotaline. This effect was accompanied by increased apoptosis in the pulmonary artery. Cultured PASMCs stimulated with 5-HT showed a decrease in apoptosis with increased phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), pyruvate dehydrogenase kinase (PDK), and mitochondrial transmembrane potential. These effects were markedly prevented by a 5-HT2A receptor inhibitor, an ERK1/2 activation inhibitor peptide I, or a PDK inhibitor. In conclusion, 5-HT inhibited PASMC apoptosis by activating the 5-HT2A receptor through the pERK1/2 and PDK pathways.5-HT decreasing apoptosis through 5-HT2A receptor is involved, at least in part, in pulmonary artery remolding.

  14. Scutellaria barbate extract induces apoptosis of hepatoma H22 cells via the mitochondrial pathway involving caspase-3.

    Science.gov (United States)

    Dai, Zhi-Jun; Wang, Xi-Jing; Li, Zong-Fang; Ji, Zong-Zheng; Ren, Hong-Tao; Tang, Wei; Liu, Xiao-Xu; Kang, Hua-Feng; Guan, Hai-Tao; Song, Ling-Qin

    2008-12-28

    To study the growth inhibitory and apoptotic effects of Scutellaria barbata D.Don (S. barbata) and to determine the underlying mechanism of its antitumor activity in mouse liver cancer cell line H22. Proliferation of H22 cells was examined by MTT assay. Cellular morphology of PC-2 cells was observed under fluorescence microscope and transmission electron microscope (EM). Mitochondrial transmembrane potential was determined under laser scanning confocal microscope (LSCM) with rhodamine 123 staining. Flow cytometry was performed to analyze the cell cycle of H22 cells with propidium iodide staining. Protein level of cytochrome C and caspase-3 was measured by semi-quantitive RT-PCR and Western blot analysis. Activity of caspase-3 enzyme was measured by spectrofluorometry. MTT assay showed that extracts from S. barbata (ESB) could inhibit the proliferation of H22 cells in a time-dependent manner. Among the various phases of cell cycle, the percentage of cells in S phase was significantly decreased, while the percentage of cells in G(1) phase was increased. Flow cytometry assay also showed that ESB had a positive effect on apoptosis. Typical apoptotic morphologies such as condensation and fragmentation of nuclei and blebbing membrane of apoptotic cells could be observed under transmission electron microscope and fluorescence microscope. To further investige the molecular mechanism behind ESB-induced apoptosis, ESB-treated cells rapidly lost their mitochondrial transmembrane potential, released mitochondrial cytochrome C into cytosol, and induced caspase-3 activity in a dose-dependent manner. ESB can effectively inhibit the proliferation and induce apoptosis of H22 cells involving loss of mitochondrial transmembrane potential, release of cytochrome C, and activation of caspase-3.

  15. TNF/TNFR{sub 1} pathway and endoplasmic reticulum stress are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Fu-Tao; Ding, Yi; Shah, Zahir; Xing, Dan; Gao, Yuan; Liu, Dong Ming; Ding, Ming-Xing, E-mail: dmx@mail.hzau.edu.cn

    2014-04-15

    Background and purpose: Quinolones cause obvious cartilaginous lesions in juvenile animals by chondrocyte apoptosis, which results in the restriction of their use in pediatric and adolescent patients. Studies showed that chondrocytes can be induced to produce TNFα, and the cisternae of the endoplasmic reticulum in quinolone-treated chondrocytes become dilated. We investigated whether TNF/TNFR{sub 1} pathway and endoplasmic reticulum stress (ERs) are involved in ofloxacin (a typical quinolone)-induced apoptosis of juvenile canine chondrocytes. Experimental approach: Canine juvenile chondrocytes were treated with ofloxacin. Cell survival and apoptosis rates were determined with MTT method and flow cytometry, respectively. The gene expression levels of the related signaling molecules (TNFα, TNFR{sub 1}, TRADD, FADD and caspase-8) in death receptor pathways and main apoptosis-related molecules (calpain, caspase-12, GADD153 and GRP78) in ERs were measured by qRT-PCR. The gene expression of TNFR{sub 1} was suppressed with its siRNA. The protein levels of TNFα, TNFR{sub 1} and caspase-12 were assayed using Western blotting. Key results: The survival rates decreased while apoptosis rates increased after the chondrocytes were treated with ofloxacin. The mRNA levels of the measured apoptosis-related molecules in death receptor pathways and ERs, and the protein levels of TNFα, TNFR{sub 1} and caspase-12 increased after the chondrocytes were exposed to ofloxacin. The downregulated mRNA expressions of TNFR{sub 1}, Caspase-8 and TRADD, and the decreased apoptosis rates of the ofloxacin-treated chondrocytes occurred after TNFR{sub 1}–siRNA interference. Conclusions and implications: Ofloxacin-induced chondrocyte apoptosis in a time- and concentration-dependent fashion. TNF/TNFR{sub 1} pathway and ERs are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes in the early stage. - Highlights: • Chondrocyte apoptosis is induced by ofloxacin in a time- and

  16. The role of Pten/Akt signaling pathway involved in BPA-induced apoptosis of rat Sertoli cells.

    Science.gov (United States)

    Wang, Chengmin; Fu, Wenjuan; Quan, Chao; Yan, Maosheng; Liu, Changjiang; Qi, Suqin; Yang, Kedi

    2015-07-01

    Bisphenol-A (BPA), one of endocrine-disrupting chemicals, is a male reproductive toxicant. Previous studies have revealed the direct cytotoxicity of BPA in many cultured cells, such as mitotic aneuploidy in embryonic cells and somatic cells, and apoptosis in neurons and testicular Sertoli cells. To understand the action of BPA and assess its risk, the Pten/Akt pathway was investigated in cultured Sertoli cells to elucidate the mechanism of the reproductive effects of BPA. The results showed that over 50 μM BPA treatment could decrease the viability of Sertoli cells and cause more apoptosis. In addition, BPA could induce the increase in mRNA levels of Pten and Akt. The protein level of Pten was increased; however, the protein levels of phospho-Akt and procaspase-3 were decreased after BPA exposure. Taken together, observed results suggested that the Pten/Akt pathway might be involved in the apoptotic effects of BPA on Sertoli cells. © 2014 Wiley Periodicals, Inc.

  17. Constitutively active Arabidopsis MAP Kinase 3 triggers defense responses involving salicylic acid and SUMM2 resistance protein

    KAUST Repository

    Genot, Baptiste

    2017-04-12

    Mitogen-activated protein kinases (MAPKs) are important regulators of plant immunity. Most of the knowledge about the function of these pathways is derived from loss-of-function approaches. Using a gain-of-function approach, we investigated the responses controlled by a constitutively active (CA) MPK3 in Arabidopsis thaliana. CA-MPK3 plants are dwarfed and display a massive de-repression of defense genes associated with spontaneous cell death as well as accumulation of reactive oxygen species (ROS), phytoalexins and the stress-related hormones ethylene and salicylic acid (SA). Remarkably CA-MPK3/sid2 and CA-MPK3/ein2-50 lines which are impaired in SA synthesis and ethylene signaling, respectively, retain most of the CA-MPK3-associated phenotypes, indicating that constitutive activity of MPK3 can bypass SA and ethylene signaling to activate defense responses. A comparative analysis of the molecular phenotypes of CA-MPK3 and mpk4 autoimmunity suggested convergence between the MPK3 and MPK4-guarding modules. In support of this model, CA-MPK3 crosses with summ1 and summ2, two known suppressors of mpk4, resulted in a partial reversion of the CA-MPK3 phenotypes. Overall, our data unravel a novel mechanism by which the MAPK signaling network contributes to a robust defense response system.

  18. Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma.

    Science.gov (United States)

    Yang, Hongyan; Xie, Yan; Yang, Dongyu; Ren, Decheng

    2017-04-11

    Reactive oxygen species (ROS) play important roles in follicular development and survival. Granulosa cell death is associated with increased ROS, but the mechanism of granulosa cell death induced by ROS is not clear. In order to define the molecular link between ROS and granulosa cell death, COV434, human granulosa tumor cells, were treated with H2O2. Compared to control cells, H2O2 induced granulosa cell death in a dose- and time-dependent manner. H2O2 induced an increase in Bax, Bak and Puma, and a decrease in anti-apoptotic molecules such as Bcl-2, Bcl-xL and Mcl-1. Both knockdown of Puma and overexpression of Bcl-xL could inhibit H2O2-induced granulosa cell death. These results suggest that suppression of Puma and overexpression of anti-apoptotic Bcl-2 family members could improve granulosa cell survival. To explore the mechanisms responsible for these findings, ROS in granulosa cells treatment with H2O2 were measured. The results showed that ROS was increased in a H2O2 dose- and time-dependent manner at the earlier time point. In addition, H2O2 induced an increase in Nrf2 and phosphorylation of JNK and p53. SP600125, an inhibitor of JNK, inhibits H2O2-induced phosphorylation of JNK and p53, and granulosa cell death. Antioxidant N-acetylcysteine (NAC) dose-dependently prevents H2O2-induced granulosa cell death. Furthermore, NAC also prevents phosphorylation of JNK and p53 induced by H2O2. Taken together, these data suggest that H2O2 regulates cell death in granulosa cells via the ROS-JNK-p53 pathway. These findings provide an improved understanding of the mechanisms underlying granulosa cell apoptosis, which could potentially be useful for future clinical applications.

  19. Effects of a novel β-lapachone derivative on Trypanosoma cruzi: Parasite death involving apoptosis, autophagy and necrosis.

    Science.gov (United States)

    Dos Anjos, Danielle Oliveira; Sobral Alves, Eliomara Sousa; Gonçalves, Vinicius Tomaz; Fontes, Sheila Suarez; Nogueira, Mateus Lima; Suarez-Fontes, Ana Márcia; Neves da Costa, João Batista; Rios-Santos, Fabricio; Vannier-Santos, Marcos André

    2016-12-01

    Natural products comprise valuable sources for new antiparasitic drugs. Here we tested the effects of a novel β-lapachone derivative on Trypanosoma cruzi parasite survival and proliferation and used microscopy and cytometry techniques to approach the mechanism(s) underlying parasite death. The selectivity index determination indicate that the compound trypanocidal activity was over ten-fold more cytotoxic to epimastigotes than to macrophages or splenocytes. Scanning electron microscopy analysis revealed that the R72 β-lapachone derivative affected the T. cruzi morphology and surface topography. General plasma membrane waving and blebbing particularly on the cytostome region were observed in the R72-treated parasites. Transmission electron microscopy observations confirmed the surface damage at the cytostome opening vicinity. We also observed ultrastructural evidence of the autophagic mechanism termed macroautophagy. Some of the autophagosomes involved large portions of the parasite cytoplasm and their fusion/confluence may lead to necrotic parasite death. The remarkably enhanced frequency of autophagy triggering was confirmed by quantitating monodansylcadaverine labeling. Some cells displayed evidence of chromatin pycnosis and nuclear fragmentation were detected. This latter phenomenon was also indicated by DAPI staining of R72-treated cells. The apoptotis induction was suggested to take place in circa one-third of the parasites assessed by annexin V labeling measured by flow cytometry. TUNEL staining corroborated the apoptosis induction. Propidium iodide labeling indicate that at least 10% of the R72-treated parasites suffered necrosis within 24 h. The present data indicate that the β-lapachone derivative R72 selectively triggers T. cruzi cell death, involving both apoptosis and autophagy-induced necrosis. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Effects of a novel β–lapachone derivative on Trypanosoma cruzi: Parasite death involving apoptosis, autophagy and necrosis

    Directory of Open Access Journals (Sweden)

    Danielle Oliveira dos Anjos

    2016-12-01

    Full Text Available Natural products comprise valuable sources for new antiparasitic drugs. Here we tested the effects of a novel β–lapachone derivative on Trypanosoma cruzi parasite survival and proliferation and used microscopy and cytometry techniques to approach the mechanism(s underlying parasite death. The selectivity index determination indicate that the compound trypanocidal activity was over ten-fold more cytotoxic to epimastigotes than to macrophages or splenocytes. Scanning electron microscopy analysis revealed that the R72 β–lapachone derivative affected the T. cruzi morphology and surface topography. General plasma membrane waving and blebbing particularly on the cytostome region were observed in the R72-treated parasites. Transmission electron microscopy observations confirmed the surface damage at the cytostome opening vicinity. We also observed ultrastructural evidence of the autophagic mechanism termed macroautophagy. Some of the autophagosomes involved large portions of the parasite cytoplasm and their fusion/confluence may lead to necrotic parasite death. The remarkably enhanced frequency of autophagy triggering was confirmed by quantitating monodansylcadaverine labeling. Some cells displayed evidence of chromatin pycnosis and nuclear fragmentation were detected. This latter phenomenon was also indicated by DAPI staining of R72-treated cells. The apoptotis induction was suggested to take place in circa one-third of the parasites assessed by annexin V labeling measured by flow cytometry. TUNEL staining corroborated the apoptosis induction. Propidium iodide labeling indicate that at least 10% of the R72-treated parasites suffered necrosis within 24 h. The present data indicate that the β–lapachone derivative R72 selectively triggers T. cruzi cell death, involving both apoptosis and autophagy-induced necrosis.

  1. Cyclic Compressive Stress Regulates Apoptosis in Rat Osteoblasts: Involvement of PI3K/Akt and JNK MAPK Signaling Pathways.

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    Fanglong Song

    Full Text Available It is widely accepted that physiological mechanical stimulation suppresses apoptosis and induces synthesis of extracellular matrix by osteoblasts; however, the effect of stress overloading on osteoblasts has not been fully illustrated. In the present study, we investigated the effect of cyclic compressive stress on rat osteoblasts apoptosis, using a novel liquid drop method to generate mechanical stress on osteoblast monolayers. After treatment with different levels of mechanical stress, apoptosis of osteoblasts and activations of mitogen-activated protein kinases (MAPKs and PI3-kinase (PI3K/Akt signaling pathways were investigated. Osteoblasts apoptosis was observed after treated with specific inhibitors prior to mechanical stimulation. Protein levels of Bax/Bcl-2/caspase-3 signaling were determined using western blot with or without inhibitors of PI3K/Akt and phosphorylation of c-jun N-terminal kinase (JNK MAPK. Results showed that mechanical stimulation led to osteoblasts apoptosis in a dose-dependent manner and a remarkable activation of MAPKs and PI3K/Akt signaling pathways. Activation of PI3K/Akt protected against apoptosis, whereas JNK MAPK increased apoptosis via regulation of Bax/Bcl-2/caspase-3 activation. In summary, the PI3K/Akt and JNK MAPK signaling pathways played opposing roles in osteoblasts apoptosis, resulting in inhibition of apoptosis upon small-magnitude stress and increased apoptosis upon large-magnitude stress.

  2. H2AX phosphorylation regulated by p38 is involved in Bim expression and apoptosis in chronic myelogenous leukemia cells induced by imatinib.

    Science.gov (United States)

    Dong, Yaqiong; Xiong, Min; Duan, Lianning; Liu, Ze; Niu, Tianhui; Luo, Yuan; Wu, Xinpin; Xu, Chengshan; Lu, Chengrong

    2014-08-01

    Increasing evidence suggests that histone H2AX plays a critical role in regulation of tumor cell apoptosis and acts as a novel human tumor suppressor protein. However, the action of H2AX in chronic myelogenous leukemia (CML) cells is unknown. The detailed mechanism and epigenetic regulation by H2AX remain elusive in cancer cells. Here, we report that H2AX was involved in apoptosis of CML cells. Overexpression of H2AX increased apoptotic sensitivity of CML cells (K562) induced by imatinib. However, overexpression of Ser139-mutated H2AX (blocking phosphorylation) decreased sensitivity of K562 cells to apoptosis. Similarly, knockdown of H2AX made K562 cells resistant to apoptotic induction. These results revealed that the function of H2AX involved in apoptosis is strictly related to its phosphorylation (Ser139). Our data further indicated that imatinib may stimulate mitogen-activated protein kinase (MAPK) family member p38, and H2AX phosphorylation followed a similar time course, suggesting a parallel response. H2AX phosphorylation can be blocked by p38 siRNA or its inhibitor. These data demonstrated that H2AX phosphorylation was regulated by p38 MAPK pathway in K562 cells. However, the p38 MAPK downstream, mitogen- and stress-activated protein kinase-1 and -2, which phosphorylated histone H3, were not required for H2AX phosphorylation during apoptosis. Finally, we provided epigenetic evidence that H2AX phosphorylation regulated apoptosis-related gene Bim expression. Blocking of H2AX phosphorylation inhibited Bim gene expression. Taken together, these data demonstrated that H2AX phosphorylation regulated by p38 is involved in Bim expression and apoptosis in CML cells induced by imatinib.

  3. Borax-induced apoptosis in HepG2 cells involves p53, Bcl-2, and Bax.

    Science.gov (United States)

    Wei, Y; Yuan, F J; Zhou, W B; Wu, L; Chen, L; Wang, J J; Zhang, Y S

    2016-06-21

    Borax, a boron compound and a salt of boric acid, is known to inhibit the growth of tumor cells. HepG2 cells have been shown to be clearly susceptible to the anti-proliferative effects of borax. However, the specific mechanisms regulating this effect are poorly understood. This study aimed to investigate the pathways underlying the growth inhibition induced by borax in HepG2 cells. The effects of borax on HepG2 cell viability were characterized using MTT. Apoptosis was also verified by annexin V/propidium iodide staining. JC-1 dye and western blotting techniques were used to measure mitochondrial membrane potential and p53, Bax, and Bcl-2 protein expression, respectively. Relevant mRNA levels were measured by qRT-PCR. Borax inhibited the proliferation of HepG2 cells in a time- and dose-dependent manner in vitro. The apoptotic process triggered by borax involved the upregulation of p53 and Bax and the downregulation of Bcl-2, which was confirmed by a change in the mitochondrial membrane potential. These results elucidate a borax-induced apoptotic pathway in HepG2 cells that involves the upregulation of p53 and Bax and the downregulation of Bcl-2.

  4. A mechanism of male germ cell apoptosis induced by bisphenol-A and nonylphenol involving ADAM17 and p38 MAPK activation.

    Directory of Open Access Journals (Sweden)

    Paulina Urriola-Muñoz

    Full Text Available Germ cell apoptosis regulation is pivotal in order to maintain proper daily sperm production. Several reports have shown that endocrine disruptors such as Bisphenol-A (BPA and Nonylphenol (NP induce germ cell apoptosis along with a decrease in sperm production. Given their ubiquitous distribution in plastic products used by humans it is important to clarify their mechanism of action. TACE/ADAM17 is a widely distributed extracellular metalloprotease and participates in the physiological apoptosis of germ cells during spermatogenesis. The aims of this work were: 1 to determine whether BPA and NP induce ADAM17 activation; and 2 to study whether ADAM17 and/or ADAM10 are involved in germ cell apoptosis induced by BPA and NP in the pubertal rat testis. A single dose of BPA or NP (50 mg/kg induces germ cell apoptosis in 21-day-old male rats, which was prevented by a pharmacological inhibitor of ADAM17, but not by an inhibitor of ADAM10. In vitro, we showed that BPA and NP, at similar concentrations to those found in human samples, induce the shedding of exogenous and endogenous (TNF-α ADAM17 substrates in primary rat Sertoli cell cultures and TM4 cell line. In addition, pharmacological inhibitors of metalloproteases and genetic silencing of ADAM17 prevent the shedding induced in vitro by BPA and NP. Finally, we showed that in vivo BPA and NP induced early activation (phosphorylation of p38 MAPK and translocation of ADAM17 to the cell surface. Interestingly, the inhibition of p38 MAPK prevents germ cell apoptosis and translocation of ADAM17 to the cell surface. These results show for the first time that xenoestrogens can induce activation of ADAM17 at concentrations similar to those found in human samples, suggesting a mechanism by which they could imbalance para/juxtacrine cell-to-cell-communication and induce germ cell apoptosis.

  5. The ROS/NF-κB/NR4A2 pathway is involved in H2O2 induced apoptosis of resident cardiac stem cells via autophagy.

    Science.gov (United States)

    Shi, Xingxing; Li, Wenjing; Liu, Honghong; Yin, Deling; Zhao, Jing

    2017-09-29

    Cardiac stem cells (CSCs)-based therapy provides a promising avenue for the management of ischemic heart diseases. However, engrafted CSCs are subjected to acute cell apoptosis in the ischemic microenvironment. Here, stem cell antigen 1 positive (Sca-1 + ) CSCs proved to own therapy potential were cultured and treated with H 2 O 2 to mimic the ischemia situation. As autophagy inhibitor, 3-methyladenine (3MA), inhibited H 2 O 2 -induced CSCs apoptosis, thus we demonstrated that H 2 O 2 induced autophagy-dependent apoptosis in CSCs, and continued to find key proteins responsible for the crosstalk between autophagy and apoptosis. Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2), increased upon cardiomyocyte injury with unknown functions in CSCs, was increased by H 2 O 2 . NR4A2 siRNA attenuated H 2 O 2 induced autophagy and apoptosis in CSCs, which suggested an important role of NR4A2 in CSCs survival in ischemia conditions. Reactive oxygen species (ROS) and NF-κB (P65) subunit were both increased by H 2 O 2 . Either the ROS scavenger, N-acetyl-l-cysteine (NAC) or NF-κB signaling inhibitor, bay11-7082 could attenuate H 2 O 2 -induced autophagy and apoptosis in CSCs, which suggested they were involved in this process. Furthermore, NAC inhibited NF-κB activities, while bay11-7082 inhibited NR4A2 expression, which revealed a ROS/NF-κB/NR4A2 pathway responsible for H 2 O 2 -induced autophagy and apoptosis in CSCs. Our study supports a new clue enhancing the survival rate of CSCs in the infarcted myocardium for cell therapy in ischemic cardiomyopathy.

  6. Constitutional jurisprudence

    OpenAIRE

    Katju, Markandey

    2011-01-01

    Justice Markandey Katja (Judge, Supreme Court of India) explains and illustrates the concept of 'constitutional jurisprudence' - as a kind of philosphy of constitutional law, seeking to explain in general terms ideas such as: What is a constitution? What is its purpose? What is its position in the legal system of the country?

  7. Resistance to ursolic acid-induced apoptosis through involvement of melanogenesis and COX-2/PGE2 pathways in human M4Beu melanoma cancer cells

    International Nuclear Information System (INIS)

    Hassan, Lama; Pinon, Aline; Limami, Youness; Seeman, Josiane; Fidanzi-Dugas, Chloe; Martin, Frederique; Badran, Bassam; Simon, Alain; Liagre, Bertrand

    2016-01-01

    Melanoma is one of the most aggressive forms of cancer with a continuously growing incidence worldwide and is usually resistant to chemotherapy agents, which is due in part to a strong resistance to apoptosis. Previously, we had showed that B16-F0 murine melanoma cells undergoing apoptosis are able to delay their own death induced by ursolic acid (UA), a natural pentacyclic triterpenoid compound. We had demonstrated that tyrosinase and TRP-1 up-regulation in apoptotic cells and the subsequent production of melanin were implicated in an apoptosis resistance mechanism. Several resistance mechanisms to apoptosis have been characterized in melanoma such as hyperactivation of DNA repair mechanisms, drug efflux systems, and reinforcement of survival signals (PI3K/Akt, NF-κB and Raf/MAPK pathways). Otherwise, other mechanisms of apoptosis resistance involving different proteins, such as cyclooxygenase-2 (COX-2), have been described in many cancer types. By using a strategy of specific inhibition of each ways, we suggested that there was an interaction between melanogenesis and COX-2/PGE 2 pathway. This was characterized by analyzing the COX-2 expression and activity, the expression of tyrosinase and melanin production. Furthermore, we showed that anti-proliferative and proapoptotic effects of UA were mediated through modulation of multiple signaling pathways including Akt and ERK-1/2 proteins. Our study not only uncovers underlying molecular mechanisms of UA action in human melanoma cancer cells but also suggest its great potential as an adjuvant in treatment and cancer prevention.

  8. Resistance to ursolic acid-induced apoptosis through involvement of melanogenesis and COX-2/PGE{sub 2} pathways in human M4Beu melanoma cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Hassan, Lama; Pinon, Aline [Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges (France); Limami, Youness [Laboratoire National de Référence (LNR), Université Mohammed VI des Sciences de la Santé, Casablanca (Morocco); Seeman, Josiane; Fidanzi-Dugas, Chloe; Martin, Frederique [Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges (France); Badran, Bassam [Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences, Lebanese University, Beirut (Lebanon); Simon, Alain [Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges (France); Liagre, Bertrand, E-mail: bertrand.liagre@unilim.fr [Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges (France)

    2016-07-01

    Melanoma is one of the most aggressive forms of cancer with a continuously growing incidence worldwide and is usually resistant to chemotherapy agents, which is due in part to a strong resistance to apoptosis. Previously, we had showed that B16-F0 murine melanoma cells undergoing apoptosis are able to delay their own death induced by ursolic acid (UA), a natural pentacyclic triterpenoid compound. We had demonstrated that tyrosinase and TRP-1 up-regulation in apoptotic cells and the subsequent production of melanin were implicated in an apoptosis resistance mechanism. Several resistance mechanisms to apoptosis have been characterized in melanoma such as hyperactivation of DNA repair mechanisms, drug efflux systems, and reinforcement of survival signals (PI3K/Akt, NF-κB and Raf/MAPK pathways). Otherwise, other mechanisms of apoptosis resistance involving different proteins, such as cyclooxygenase-2 (COX-2), have been described in many cancer types. By using a strategy of specific inhibition of each ways, we suggested that there was an interaction between melanogenesis and COX-2/PGE{sub 2} pathway. This was characterized by analyzing the COX-2 expression and activity, the expression of tyrosinase and melanin production. Furthermore, we showed that anti-proliferative and proapoptotic effects of UA were mediated through modulation of multiple signaling pathways including Akt and ERK-1/2 proteins. Our study not only uncovers underlying molecular mechanisms of UA action in human melanoma cancer cells but also suggest its great potential as an adjuvant in treatment and cancer prevention.

  9. NF-κB inhibition is involved in tobacco smoke-induced apoptosis in the lungs of rats

    International Nuclear Information System (INIS)

    Zhong Caiyun; Zhou Yamei; Pinkerton, Kent E.

    2008-01-01

    Apoptosis is a vital mechanism for the regulation of cell turnover and plays a critical role in tissue homeostasis and development of many disease processes. Previous studies have demonstrated the apoptotic effect of tobacco smoke; however, the molecular mechanisms by which tobacco smoke triggers apoptosis remain unclear. In the present study we investigated the effects of tobacco smoke on the induction of apoptosis in the lungs of rats and modulation of nuclear factor-kappa B (NF-κB) in this process. Exposure of rats to 80 mg/m 3 tobacco smoke significantly induced apoptosis in the lungs. Tobacco smoke resulted in inhibition of NF-κB activity, noted by suppression of inhibitor of κB (IκB) kinase (IKK), accumulation of IκBα, decrease of NF-κB DNA binding activity, and downregulation of NF-κB-dependent anti-apoptotic proteins, including Bcl-2, Bcl-xl, and inhibitors of apoptosis. Initiator caspases for the death receptor pathway (caspase 8) and the mitochondrial pathway (caspase 9) as well as effector caspase 3 were activated following tobacco smoke exposure. Tobacco smoke exposure did not alter the levels of p53 and Bax proteins. These findings suggest the role of NF-κB pathway in tobacco smoke-induced apoptosis

  10. Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic-Ischemic Brain Damage in Neonatal Rats.

    Directory of Open Access Journals (Sweden)

    Deyuan Li

    Full Text Available c-Jun N-terminal kinase (JNK plays a key role in the regulation of neuronal apoptosis. Previous studies have revealed that forkhead transcription factor (FOXO3a is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the JNK/FOXO3a pathway is involved in neuronal apoptosis in the developing rat brain after hypoxia-ischemia (HI. In this study, we generated an HI model using postnatal day 7 rats. Fluorescence immunolabeling and Western blot assays were used to detect the distribution and expression of total and phosphorylated JNK and FOXO3a and the pro-apoptotic proteins Bim and CC3. We found that JNK phosphorylation was accompanied by FOXO3a dephosphorylation, which induced FOXO3a translocation into the nucleus, resulting in the upregulation of levels of Bim and CC3 proteins. Furthermore, we found that JNK inhibition by AS601245, a specific JNK inhibitor, significantly increased FOXO3a phosphorylation, which attenuated FOXO3a translocation into the nucleus after HI. Moreover, JNK inhibition downregulated levels of Bim and CC3 proteins, attenuated neuronal apoptosis and reduced brain infarct volume in the developing rat brain. Our findings suggest that the JNK/FOXO3a/Bim pathway is involved in neuronal apoptosis in the developing rat brain after HI. Agents targeting JNK may offer promise for rescuing neurons from HI-induced damage.

  11. Selenium antagonizes cadmium-induced apoptosis in chicken spleen but not involving Nrf2-regulated antioxidant response.

    Science.gov (United States)

    Chen, Menghao; Li, Xiaojing; Fan, Ruifeng; Cao, Changyu; Yao, Haidong; Xu, Shiwen

    2017-11-01

    The nuclear transcription factor NF-E2-related factor 2 (Nrf2) binds to antioxidant response elements (AREs) and is involved in the regulation of genes participated in defending cells against oxidative damage, which have been confirmed in animal models. Selenium (Se), known as an important element in the regulation of antioxidant activity, can antagonize Cadmium (Cd) toxicity in birds. However, the role of Nrf2 in selenium-cadmium interaction has not been reported in birds. To further explore the mechanism of selenium attenuating spleen toxicity induced by cadmium in chickens, cadmium chloride (CdCl 2 , 150mg/kg) and sodium selenite (Na 2 SeO 3 , 2mg/kg) were co-administrated or individually administered in the diet of chickens for 90 days. The results showed that Cd exposure increased the level of hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) and decreased the antioxidant enzyme activities, including superoxide dismutase (SOD), glutathione peroxidase (Gpx), total antioxidative capacity (T-AOC), catalase (CAT). Cd exposure increased obviously nuclear accumulation of Nrf2, and the expression of Nrf2 downstream heme oxygenase-1 (HO-1) and NAD(P)H: quinine oxidoreductase 1 (NQO1), reduced the expression of Kelch-like ECH-associated protein (keap1), Gpx-1 and thioredoxin reductase-1 (TrxR1). In addition, Cd induced the increase of bak, caspase9, p53, Cyt c mRNA levels, increased bax/bcl-2 ratio, increased caspase3 mRNA and protein levels. Selenium treatment reduced the accumulation of Cd in the spleen, attenuates Cd-induced Nrf2 nuclear accumulation, enhanced antioxidant enzyme activities, ameliorated Cd-induced oxidative stress and apoptosis in the spleen. In summary, our results demonstrate that Se ameliorated spleen toxicity induced by cadmium by modulating the antioxidant system, independently of Nrf2-regulated antioxidant response pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Authoritarian Constitutionalism

    OpenAIRE

    Tushnet, Mark V.

    2015-01-01

    Legal scholars and political theorists interested in constitutionalism as a normative concept tend to dichotomize the subject. There is liberal constitutionalism of the sort familiar in the modern West, with core commitments to human rights and self-governance implemented by means of varying institutional devices, and there is authoritarianism, rejecting human rights entirely and governed by unconstrained power-holders. This Article explores the possibility of forms of constitutionalism other...

  13. In vivo and in vitro assessment of pathways involved in contrast media-induced renal cells apoptosis.

    Science.gov (United States)

    Quintavalle, C; Brenca, M; De Micco, F; Fiore, D; Romano, S; Romano, M F; Apone, F; Bianco, A; Zabatta, M A; Troncone, G; Briguori, C; Condorelli, G

    2011-05-12

    Contrast-induced nephropathy accounts for >10% of all causes of hospital-acquired renal failure, causes a prolonged in-hospital stay and represents a powerful predictor of poor early and late outcome. Mechanisms of contrast-induced nephropathy are not completely understood. In vitro data suggests that contrast media (CM) induces a direct toxic effect on renal tubular cells through the activation of the intrinsic apoptotic pathway. It is unclear whether this effect has a role in the clinical setting. In this work, we evaluated the effects of CM both in vivo and in vitro. By analyzing urine samples obtained from patients who experienced contrast-induced acute kidney injury (CI-AKI), we verified, by western blot and immunohistochemistry, that CM induces tubular renal cells apoptosis. Furthermore, in cultured cells, CM caused a dose-response increase in reactive oxygen species (ROS) production, which triggered Jun N-terminal kinases (JNK1/2) and p38 stress kinases marked activation and thus apoptosis. Inhibition of JNK1/2 and p38 by different approaches (i.e. pharmacological antagonists and transfection of kinase-death mutants of the upstream p38 and JNK kinases) prevented CM-induced apoptosis. Interestingly, N-acetylcysteine inhibited ROS production, and thus stress kinases and apoptosis activation. Therefore, we conclude that CM-induced tubular renal cells apoptosis represents a key mechanism of CI-AKI.

  14. In vivo and in vitro assessment of pathways involved in contrast media-induced renal cells apoptosis

    Science.gov (United States)

    Quintavalle, C; Brenca, M; De Micco, F; Fiore, D; Romano, S; Romano, M F; Apone, F; Bianco, A; Zabatta, M A; Troncone, G; Briguori, C; Condorelli, G

    2011-01-01

    Contrast-induced nephropathy accounts for >10% of all causes of hospital-acquired renal failure, causes a prolonged in-hospital stay and represents a powerful predictor of poor early and late outcome. Mechanisms of contrast-induced nephropathy are not completely understood. In vitro data suggests that contrast media (CM) induces a direct toxic effect on renal tubular cells through the activation of the intrinsic apoptotic pathway. It is unclear whether this effect has a role in the clinical setting. In this work, we evaluated the effects of CM both in vivo and in vitro. By analyzing urine samples obtained from patients who experienced contrast-induced acute kidney injury (CI-AKI), we verified, by western blot and immunohistochemistry, that CM induces tubular renal cells apoptosis. Furthermore, in cultured cells, CM caused a dose–response increase in reactive oxygen species (ROS) production, which triggered Jun N-terminal kinases (JNK1/2) and p38 stress kinases marked activation and thus apoptosis. Inhibition of JNK1/2 and p38 by different approaches (i.e. pharmacological antagonists and transfection of kinase-death mutants of the upstream p38 and JNK kinases) prevented CM-induced apoptosis. Interestingly, N-acetylcysteine inhibited ROS production, and thus stress kinases and apoptosis activation. Therefore, we conclude that CM-induced tubular renal cells apoptosis represents a key mechanism of CI-AKI. PMID:21562587

  15. The Strica Homolog AaCASPS16 Is Involved in Apoptosis in the Yellow Fever Vector, Aedes albopictus.

    Directory of Open Access Journals (Sweden)

    Kun Meng

    Full Text Available Caspases are a family of cysteine proteases playing essential roles during apoptosis. Seven caspases identified in Drosophila were Dronc, Dredd, Strica, Dcp-1, Decay, Drice and Damm. Among them, Strica is an insect-specific caspase containing a long serine- and threonine- rich prodomain, of which function is not yet well studied. Here we identified a homolog of strica from Aedes albopictus, named as Aacasps16. Aacasps16 encoded a protein containing a putative serine- and threonine-rich prodomain and a well conserved caspase catalytic domain. AaCASPS16 shared high identity with dipteran insects Strica homologs. Alignment showed that the closest relative of AaCASPS16 was Aedes aegypti AeCASPS16. The expression profiles of Aacasps16 during developmental and adult stages were analyzed. Purified recombinant AaCASPS16 exhibited the highest caspase activity to WEHD, which is the substrate preferred by human caspase-9. AaCASPS16 induced apoptosis when over-expressed in C6/36 cells. AaCASPS16 was processed during apoptosis induced by actinomycin D and ultraviolet irradiation treatment, whereas partial silencing of Aacasps16 reduced actinomycin D- and ultraviolet irradiation-triggered apoptosis in C6/36 cells. Taken together, our study identified AaCASPS16 as a novel apoptotic caspase in Aedes albopictus.

  16. The Strica Homolog AaCASPS16 Is Involved in Apoptosis in the Yellow Fever Vector, Aedes albopictus.

    Science.gov (United States)

    Meng, Kun; Li, Xiaomei; Wang, Shengya; Zhong, Chunyan; Yang, Zhouning; Feng, Lingyan; Liu, Qingzhen

    2016-01-01

    Caspases are a family of cysteine proteases playing essential roles during apoptosis. Seven caspases identified in Drosophila were Dronc, Dredd, Strica, Dcp-1, Decay, Drice and Damm. Among them, Strica is an insect-specific caspase containing a long serine- and threonine- rich prodomain, of which function is not yet well studied. Here we identified a homolog of strica from Aedes albopictus, named as Aacasps16. Aacasps16 encoded a protein containing a putative serine- and threonine-rich prodomain and a well conserved caspase catalytic domain. AaCASPS16 shared high identity with dipteran insects Strica homologs. Alignment showed that the closest relative of AaCASPS16 was Aedes aegypti AeCASPS16. The expression profiles of Aacasps16 during developmental and adult stages were analyzed. Purified recombinant AaCASPS16 exhibited the highest caspase activity to WEHD, which is the substrate preferred by human caspase-9. AaCASPS16 induced apoptosis when over-expressed in C6/36 cells. AaCASPS16 was processed during apoptosis induced by actinomycin D and ultraviolet irradiation treatment, whereas partial silencing of Aacasps16 reduced actinomycin D- and ultraviolet irradiation-triggered apoptosis in C6/36 cells. Taken together, our study identified AaCASPS16 as a novel apoptotic caspase in Aedes albopictus.

  17. CONSTITUTION AND CONSTITUTIONALISM CONTEMPORARY ISSUE

    Directory of Open Access Journals (Sweden)

    Marius ANDREESCU

    2017-05-01

    Full Text Available In a democratic society, the judicial legitimacy of the state and its power, of its institutions, but also the social and political grounds are generated and determined by the Constitution, defined as expressively as possible as being: “The fundamental political and judicial settlement of a people” (I. Deleanu. The supremacy of the Constitution has as main effect the conformity of the entire system of law with the constitutional norms. Guaranteeing the compliance with this principle, essential for the state of law, is first of all an attribution of the Constitutional Court, but also an obligation of the legislative power to receive, through the adopted normative acts, in content and in form, the constitutional norms. Altering the fundamental law of a state represents a political and judicial act extremely complex with major meanings and implications for the socio-political and national systems, but also for each individual. This is why such measure should be very well justified, to answer certain socio-political and legal needs well shaped and mainly to match the principles and rules specific to a democratic constitutional and state system, by insuring its stability and functionality. These are a few aspects of the Romanian contemporary constitutionalism that this study shall critically analyse in order to differentiate between the constitutional ideal and reality.

  18. Fas- and Mitochondria-Mediated Signaling Pathway Involved in Osteoblast Apoptosis Induced by AlCl3.

    Science.gov (United States)

    Xu, Feibo; Ren, Limin; Song, Miao; Shao, Bing; Han, Yanfei; Cao, Zheng; Li, Yanfei

    2017-10-12

    Aluminum (Al) is known to induce apoptosis of osteoblasts (OBs). However, the mechanism is not yet established. To investigate the apoptotic mechanism of OBs induced by aluminum trichloride (AlCl 3 ), the primary OBs from the craniums of fetal Wistar rats were exposed to 0 mg/mL (control group, CG), 0.06 mg/mL (low-dose group, LG), 0.12 mg/mL (mid-dose group, MG), and 0.24 mg/mL (high-dose group, HG) AlCl 3 for 24 h, respectively. We observed that AlCl 3 induced OB apoptosis with the appearance of apoptotic morphology and increase of apoptosis rate. Additionally, AlCl 3 treatment activated mitochondrial-mediated signaling pathway, accompanied by mitochondrial membrane potential (ΔΨm) depolarization, release of cytochrome c from the mitochondria to the cytoplasm, as well as survival signal-related factor caspase-9 and caspase-3 activation. AlCl 3 exposure also activated Fas/Fas ligand signaling pathway, presented as Fas, Fas ligand, and Fas-associated death domain expression enhancement and caspase-8 activation, as well as the hydrolysis of Bid to truncated Bid, suggesting that the Fas-mediated signaling pathway might aggravate mitochondria-mediated OB apoptosis through hydrolyzing Bid. Furthermore, AlCl 3 exposure inhibited Bcl-2 protein expression and increased the expressions of Bax, Bak, and Bim in varying degrees. These results indicated that AlCl 3 exposure induced OB apoptosis through activating Fas- and mitochondria-mediated signaling pathway and disrupted B-cell lymphoma-2 family proteins.

  19. Andrographolide enhances 5-fluorouracil-induced apoptosis via caspase-8-dependent mitochondrial pathway involving p53 participation in hepatocellular carcinoma (SMMC-7721) cells.

    Science.gov (United States)

    Yang, Lu; Wu, Dingfang; Luo, Kewang; Wu, Shihua; Wu, Ping

    2009-04-18

    Despite recent significant advances in the treatment of human carcinoma (HCC), the results of chemotherapy to date remain unsatisfactory. 5-Fluorouracil (5-FU) still represents the cornerstone of treatment of carcinoma, and resistance to the actions of 5-FU is a major obstacle to successful chemotherapy. More effective treatment strategies may involve combinations of agents with activity against HCC. Andrographolide (ANDRO), a natural bicyclic diterpenoid lactone isolated from Andrographis paniculata, has been shown to suppress the growth of HCC cells and trigger apoptosis in vitro. To assess the suitability of ANDRO as a chemotherapeutic agent in HCC, its cytotoxic effects have been evaluated both as a single agent and in combination with 5-FU. ANDRO potentiates the cytotoxic effect of 5-FU in HCC cell line SMMC-7721 through apoptosis. ANDRO alone induces SMMC-7721 apoptosis with p53 expression, Bax conformation and caspase-3,8,9 activation. Surprisingly, the addition of ANDRO to 5-FU induces synergistic apoptosis, which could be corroborated to the increased caspase-8, p53 activity and the significant changes of Bax conformation in these cells, resulting in increased losses of mitochondrial membrane potential, increased release of cytochrome c, and activation of caspase-9 and caspase-3. Suppression of caspase-8 with the specific inhibitor z-IETD-fmk abrogates largely ANDRO/5-FU biological activity by preventing mitochondrial membrane potential disappearance, caspase-3,9 activation and subsequent apoptosis. The results suggest that ANDRO may be effective in combination with 5-FU for the treatment of HCC cells SMMC-7721.

  20. Opposed arsenite-mediated regulation of p53-survivin is involved in neoplastic transformation, DNA damage, or apoptosis in human keratinocytes

    International Nuclear Information System (INIS)

    Li, Yuan; Jiang, Rongrong; Zhao, Yue; Xu, Yuan; Ling, Min; Pang, Ying; Shen, Lu; Zhou, Yun; Zhang, Jianping; Zhou, Jianwei; Wang, Xinru; Liu, Qizhan

    2012-01-01

    Highlights: ► Different concentrations of arsenite cause biphasic effects in HaCaT cells. ► p53-survivin signal pathway plays a role in arsenite-induced biphasic effects. ► ERKs inactivate p53, but improve survivin expression by NF-κB/mot-2. ► JNKs block survivin expression by preventing p53 from mdm2-mediated degradation. ► ERKs and JNKs play roles in arsenite-induced biphasic effects. -- Abstract: Biphasic dose–response relationship induced by environmental agents is often characterized with the effect of low-dose stimulation and high dose inhibition. Some studies showed that arsenite may induce cell proliferation and apoptosis via biphasic dose–response relationship in human cells; however, mechanisms underlying this phenomenon are not well understood. Our present study shows that, for human keratinocytes (HaCaT) cells, a low concentration of arsenite activates extracellular signal-regulated kinases (ERKs), which leads to up-regulation of nuclear factor κB (NF-κB) binding to DNA and to elevated, NF-κB-dependent expression of mot-2 (a p53 inhibitor) and survivin (an inhibitor of apoptosis). Activation of p53 is blocked, and neoplastic transformation is enhanced. Inhibition of ERKs reduces cell proliferation and neoplastic transformation. In contrast, a high concentration of arsenite activates c-Jun N-terminal kinases (JNKs), positive regulators of p53, by binding to p53 and preventing its murine double minute 2 (mdm2)-mediated degradation. The elevated levels of p53 lead to repair of DNA damage and apoptosis. Inhibition of JNKs increases DNA damage but decreases apoptosis. By identifying a mechanism whereby ERKs and JNKs-mediated regulation of the p53-survivin signal pathway is involved in the biphasic effects of arsenite on human keratinocytes, our data expand understanding of arsenite-induced cell proliferation, neoplastic transformation, DNA damage, and apoptosis.

  1. Fucoidan extract induces apoptosis in MCF-7 cells via a mechanism involving the ROS-dependent JNK activation and mitochondria-mediated pathways.

    Directory of Open Access Journals (Sweden)

    Zhongyuan Zhang

    Full Text Available BACKGROUND: Fucoidan extract (FE, an enzymatically digested compound with a low molecular weight, is extracted from brown seaweed. As a natural compound with various actions, FE is attractive, especially in Asian countries, for improving the therapeutic efficacy and safety of cancer treatment. The present study was carried out to investigate the anti-tumor properties of FE in human carcinoma cells and further examine the underlying mechanisms of its activities. METHODOLOGY/PRINCIPAL FINDING: FE inhibits the growth of MCF-7, MDA-MB-231, HeLa, and HT1080 cells. FE-mediated apoptosis in MCF-7 cancer cells is accompanied by DNA fragmentation, nuclear condensation, and phosphatidylserine exposure. FE induces mitochondrial membrane permeabilization (MMP through loss of mitochondrial membrane potential (ΔΨm and regulation of the expression of Bcl-2 family members. Release of apoptosis-inducing factor (AIF and cytochrome c precedes MMP. AIF release causes DNA fragmentation, the final stage of apoptosis, via a caspase-independent mitochondrial pathway. Additionally, FE was found to induce phosphorylation of c-Jun N-terminal kinase (JNK, p38, and extracellular signal-regulated kinase (ERK 1/2, and apoptosis was found to be attenuated by inhibition of JNK. Furthermore, FE-mediated apoptosis was found to involve the generation of reactive oxygen species (ROS, which are responsible for the decrease of ΔΨm and phosphorylation of JNK, p38, and ERK1/2 kinases. CONCLUSIONS/SIGNIFICANCE: These data suggest that FE activates a caspase-independent apoptotic pathway in MCF-7 cancer cells through activation of ROS-mediated MAP kinases and regulation of the Bcl-2 family protein-mediated mitochondrial pathway. They also provide evidence that FE deserves further investigation as a natural anticancer and cancer preventive agent.

  2. Roe Protein Hydrolysates of Giant Grouper (Epinephelus lanceolatus Inhibit Cell Proliferation of Oral Cancer Cells Involving Apoptosis and Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Jing-Iong Yang

    2016-01-01

    Full Text Available Roe protein hydrolysates were reported to have antioxidant property but the anticancer effects were less addressed, especially for oral cancer. In this study, we firstly used the ultrafiltrated roe hydrolysates (URH derived from giant grouper (Epinephelus lanceolatus to evaluate the impact of URH on proliferation against oral cancer cells. We found that URH dose-responsively reduced cell viability of two oral cancer cells (Ca9-22 and CAL 27 in terms of ATP assay. Using flow cytometry, URH-induced apoptosis of Ca9-22 cells was validated by morphological features of apoptosis, sub-G1 accumulation, and annexin V staining in dose-responsive manners. URH also induced oxidative stress in Ca9-22 cells in terms of reactive oxygen species (ROS/superoxide generations and mitochondrial depolarization. Taken together, these data suggest that URH is a potential natural product for antioral cancer therapy.

  3. Autophagy and gap junctional intercellular communication inhibition are involved in cadmium-induced apoptosis in rat liver cells

    Energy Technology Data Exchange (ETDEWEB)

    Zou, Hui [College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, 225009 (China); Zhuo, Liling [College of Life Science, Zaozhuang University, Zaozhuang, Shandong, 277160 (China); Han, Tao; Hu, Di; Yang, Xiaokang; Wang, Yi; Yuan, Yan; Gu, Jianhong; Bian, Jianchun; Liu, Xuezhong [College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, 225009 (China); Liu, Zongping, E-mail: liuzongping@yzu.edu.cn [College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, 225009 (China)

    2015-04-17

    Cadmium (Cd) is known to induce hepatotoxicity, yet the underlying mechanism of how this occurs is not fully understood. In this study, Cd-induced apoptosis was demonstrated in rat liver cells (BRL 3A) with apoptotic nuclear morphological changes and a decrease in cell index (CI) in a time- and concentration-dependent manner. The role of gap junctional intercellular communication (GJIC) and autophagy in Cd-induced apoptosis was investigated. Cd significantly induced GJIC inhibition as well as downregulation of connexin 43 (Cx43). The prototypical gap junction blocker carbenoxolone disodium (CBX) exacerbated the Cd-induced decrease in CI. Cd treatment was also found to cause autophagy, with an increase in mRNA expression of autophagy-related genes Atg-5, Atg-7, Beclin-1, and microtubule-associated protein light chain 3 (LC3) conversion from cytosolic LC3-I to membrane-bound LC3-II. The autophagic inducer rapamycin (RAP) prevented the Cd-induced CI decrease, while the autophagic inhibitor chloroquine (CQ) caused a further reduction in CI. In addition, CBX promoted Cd-induced autophagy, as well as changes in expression of Atg-5, Atg-7, Beclin-1 and LC3. CQ was found to block the Cd-induced decrease in Cx43 and GJIC inhibition, whereas RAP had opposite effect. These results demonstrate that autophagy plays a protective role during Cd-induced apoptosis in BRL 3A cells during 6 h of experiment, while autophagy exacerbates Cd-induced GJIC inhibition which has a negative effect on cellular fate. - Highlights: • GJIC and autophagy is crucial for biological processes. • Cd exposure causes GJIC inhibition and autophagy increase in BRL 3A cells. • Autophagy protects Cd induced BRL 3A cells apoptosis at an early stage. • Autophagy exacerbates Cd-induced GJIC inhibition. • GJIC plays an important role in autophagy induced cell death or survival.

  4. Involvement of apoptosis and autophagy in the death of RPMI 8226 multiple myeloma cells by two enantiomeric sigma receptor ligands.

    Science.gov (United States)

    Korpis, Katharina; Weber, Frauke; Brune, Stefanie; Wünsch, Bernhard; Bednarski, Patrick J

    2014-01-01

    Over-expression of σ receptors by many tumor cell lines makes ligands for these receptors attractive as potential chemotherapeutic drugs. Enantiomeric piperazines (S)-4 and (R)-4 were prepared as potential σ-receptor ligands in a chiral pool synthesis starting from (S)- and (R)-aspartate. Both compounds showed high affinities for the σ₁ and σ₂ receptors. In the human multiple myeloma cell line RPMI 8226, a line expressing high levels of σ receptors, both compounds inhibited cell proliferation with IC₅₀ values in the low μM range. No chiral differentiation between either the σ receptor binding affinity or the cytotoxicity of the two enantiomers was observed. Both compounds induced apoptosis, which was evidenced by nuclear condensation, binding of annexin-V to phosphatidylserine in the outer leaf of the cell membrane, cleavage products of poly(ADP-ribose) polymerase-1 (PARP-1) and caspase-8 as well as the expression of bcl₂ family members bax, bad and bid. However, apoptosis appeared to be caspase independent. Increased levels of the phosphorylated form of the microtubule associated protein light chain 3-II (LC3-II), an autophagosome marker, gave evidence that both compounds induced autophagy. However, further data (e.g., treatment with wortmannin) indicate that autophagy is incomplete and not cytoprotective. Lipid peroxidation (LPO) was observed in RPMI 8226 cells treated with the two compounds, and the lipid antioxidant α-tocopherol attenuated LPO. Interestingly, α-tocopherol reduced significantly both apoptosis and autophagy induced by the compounds. These results provide evidence that, by initiating LPO and changes in mitochondrial membrane potential, both compounds induce apoptosis and autophagy in RPMI 8226 cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Subcellular mechanisms involved in apoptosis induced by aminoglycoside antibiotics: Insights on p53, proteasome and endoplasmic reticulum

    International Nuclear Information System (INIS)

    Denamur, Sophie; Boland, Lidvine; Beyaert, Maxime; Verstraeten, Sandrine L.; Fillet, Marianne; Tulkens, Paul M.; Bontemps, Françoise; Mingeot-Leclercq, Marie-Paule

    2016-01-01

    Gentamicin, an aminoglycoside used to treat severe bacterial infections, may cause acute renal failure. In the renal cell line LLC-PK1, gentamicin accumulates in lysosomes, induces alterations of their permeability, and triggers the mitochondrial pathway of apoptosis via activation of caspase-9 and -3 and changes in Bcl-2 family proteins. Early ROS production in lysosomes has been associated with gentamicin induced lysosomal membrane permeabilization. In order to better understand the multiple interconnected pathways of gentamicin-induced apoptosis and ensuing renal cell toxicity, we investigated the effect of gentamicin on p53 and p21 levels. We also studied the potential effect of gentamicin on proteasome by measuring the chymotrypsin-, trypsin- and caspase-like activities, and on endoplasmic reticulum by determining phopho-eIF2α, caspase-12 activation and GRP78 and 94. We observed an increase in p53 levels, which was dependent on ROS production. Accumulation of p53 resulted in accumulation of p21 and of phospho-eIF2α. These effects could be related to an impairment of proteasome as we demonstrated an inhibition of trypsin-and caspase-like activities. Moderate endoplasmic reticulum stress could also participate to cellular toxicity induced by gentamicin, with activation of caspase-12 without change in GRP74 and GRP98. All together, these data provide new mechanistic insights into the apoptosis induced by aminoglycoside antibiotics on renal cell lines. - Highlights: • Gentamicin induces apoptosis through p53 pathway. • Gentamicin inhibits proteosomal activity. • Gentamicin activates caspase-12.

  6. Deficiency of ataxia telangiectasia mutated kinase modulates cardiac remodeling following myocardial infarction: involvement in fibrosis and apoptosis.

    Directory of Open Access Journals (Sweden)

    Cerrone R Foster

    Full Text Available Ataxia telangiectasia mutated kinase (ATM is a cell cycle checkpoint protein activated in response to DNA damage. We recently reported that ATM plays a protective role in myocardial remodeling following β-adrenergic receptor stimulation. Here we investigated the role of ATM in cardiac remodeling using myocardial infarction (MI as a model.Left ventricular (LV structure, function, apoptosis, fibrosis, and protein levels of apoptosis- and fibrosis-related proteins were examined in wild-type (WT and ATM heterozygous knockout (hKO mice 7 days post-MI. Infarct sizes were similar in both MI groups. However, infarct thickness was higher in hKO-MI group. Two dimensional M-mode echocardiography revealed decreased percent fractional shortening (%FS and ejection fraction (EF in both MI groups when compared to their respective sham groups. However, the decrease in %FS and EF was significantly greater in WT-MI vs hKO-MI. LV end systolic and diastolic diameters were greater in WT-MI vs hKO-MI. Fibrosis, apoptosis, and α-smooth muscle actin staining was significantly higher in hKO-MI vs WT-MI. MMP-2 protein levels and activity were increased to a similar extent in the infarct regions of both groups. MMP-9 protein levels were increased in the non-infarct region of WT-MI vs WT-sham. MMP-9 protein levels and activity were significantly lower in the infarct region of WT vs hKO. TIMP-2 protein levels similarly increased in both MI groups, whereas TIMP-4 protein levels were significantly lower in the infarct region of hKO group. Phosphorylation of p53 protein was higher, while protein levels of manganese superoxide dismutase were significantly lower in the infarct region of hKO vs WT. In vitro, inhibition of ATM using KU-55933 increased oxidative stress and apoptosis in cardiac myocytes.

  7. Caspase-10 Is the Key Initiator Caspase Involved in Tributyltin-Mediated Apoptosis in Human Immune Cells

    Directory of Open Access Journals (Sweden)

    Harald F. Krug

    2012-01-01

    Full Text Available Tributyltin (TBT is one of the most toxic compounds produced by man and distributed in the environment. A multitude of toxic activities have been described, for example, immunotoxic, neurotoxic, and endocrine disruptive effects. Moreover, it has been shown for many cell types that they undergo apoptosis after treatment with TBT and the cell death of immune cells could be the molecular background of its immunotoxic effect. As low as 200 nM up to 1 μM of TBT induces all signs of apoptosis in Jurkat T cells within 1 to 24 hrs of treatment. When compared to Fas-ligand control stimulation, the same sequence of events occurs: membrane blebbing, phosphatidylserine externalisation, the activation of the “death-inducing signalling complex,” and the following sequence of cleavage processes. In genetically modified caspase-8-deficient Jurkat cells, the apoptotic effects are only slightly reduced, whereas, in FADD-negative Jurkat cells, the TBT effect is significantly diminished. We could show that caspase-10 is recruited by the TRAIL-R2 receptor and apoptosis is totally prevented when caspase-10 is specifically inhibited in all three cell lines.

  8. Oroxylin A induced apoptosis of human hepatocellular carcinoma cell line HepG2 was involved in its antitumor activity

    International Nuclear Information System (INIS)

    Hu Yang; Yang Yong; You Qidong; Liu Wei; Gu Hongyan; Zhao Li; Zhang Kun; Wang Wei; Wang Xiaotang; Guo Qinglong

    2006-01-01

    We previously reported that wogonin, a flavonoid compound, was a potent apoptosis inducer of human hepatoma SMMC-7721 cells and murine sarcoma S180 cells. In the present study, the effect of oroxylin A, one wogonin structurally related flavonoid isolated from Scutellariae radix, on human hepatocellular carcinoma cell line HepG2 was examined and molecular mechanisms were also investigated. Oroxylin A inhibited HepG2 cell proliferation in a concentration- and time-dependent manner measured by MTT-assay. Treatment with an apoptosis-inducing concentration of oroxylin A caused typical morphological changes and apoptotic blebbing in HepG2 cells. DNA fragmentation assay was used to examine later apoptosis induced by oroxylin A. FACScan analysis revealed a dramatic increase in the number of apoptotic and G 2 /M phase arrest cells after oroxylin A treatment. The pro-apoptotic activity of oroxylin A was attributed to its ability to modulate the concerted expression of Bcl-2, Bax, and pro-caspase-3 proteins. The expression of Bcl-2 protein and pro-caspase-3 protein was dramatically decreased after treatment with oroxylin A. These results demonstrated that oroxylin A could effectively induce programmed cell death and suggested that it could be a promising antitumor drug

  9. Hydrogen peroxide produced during gamma-glutamyl transpeptidase activity is involved in prevention of apoptosis and maintainance of proliferation in U937 cells.

    Science.gov (United States)

    del Bello, B; Paolicchi, A; Comporti, M; Pompella, A; Maellaro, E

    1999-01-01

    It has been reported in several cell lines that exposure to low levels of reactive oxygen species can exert a stimulatory effect on their proliferation. We have previously shown that mild oxidative conditions can also counteract apoptotic stimuli. A constitutive cellular production of low levels of superoxide and hydrogen peroxide originates from various sources; among these, gamma-glutamyl transpeptidase (GGT), the plasma membrane-bound activity in charge of metabolizing extracellular reduced glutathione, has recently been included. Since the inhibition of GGT is a sufficient stimulus for the induction of apoptosis in selected cell lines, we investigated whether this effect might result from the suppression of the mentioned GGT-dependent prooxidant reactions, on the theory that the latter may represent a basal antiapoptotic and proliferative signal for the cell. Experiments showed that: 1) GGT activity in U937 monoblastoid cells is associated with the production of low levels of hydrogen peroxide, and two independent GGT inhibitors cause a dose-dependent decrease of such GGT-dependent production of H2O2; 2) GGT inhibition with acivicin results in cell growth arrest, and induces cell death and DNA fragmentation with the ladder appearance of apoptosis; 3) treatment of cells with catalase--and even more with Trolox C--is able to decrease their proliferative rate; 4) GGT inhibition (with suppression of H2O2 production) results in a down-regulation of poly(ADP-ribose) polimerase (PARP) activity, which precedes the proteolytic cleavage of PARP molecule, such as that typically induced by caspases. The reported data suggest that the low H2O2 levels originating as a by-product during GGT activity are able to act as sort of a 'life signal' in U937 cells, insofar as they can maintain cell proliferation and protect against apoptosis, possibly through an up-regulation of PARP activity.

  10. Long-term blue light exposure induces RGC-5 cell death in vitro: involvement of mitochondria-dependent apoptosis, oxidative stress, and MAPK signaling pathways.

    Science.gov (United States)

    Huang, Chen; Zhang, Pei; Wang, Wei; Xu, Yongsheng; Wang, Minshu; Chen, Xiaoyong; Dong, Xuran

    2014-06-01

    The mechanism of blue light-induced retinal ganglion cell (RGC) injury is poorly understood. In this study, we established a patented light-emitting diode-based system to study the effects of long-term blue light exposure under culture conditions on RGC-5 cells. Long-term blue light exposure significantly reduced cell viability in a time-dependent manner and induced apoptosis and necrosis in RGC-5 cells. Long-term blue light exposure marked an increase in the expression of Bax and active Caspase-3 (p17), which was accompanied by Bcl-2 down-regulation, and displayed features of the mitochondria-dependent apoptosis pathway. Blue light exposure also increased the generation of reactive oxygen species (ROS), and was a strong inducer of ROS-sensitive protein nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression. Moreover, blue light exposure constitutively activated p38 mitogen-activated protein kinases and c-Jun NH2-terminal kinase (JNK), as well as induced the phosphorylation of extracellular signal-regulated kinase in the early phase, in blue light-exposed RGC-5 cells. The protein expression of c-jun and c-fos was further enhanced after RGC-5 cells were exposed to blue light. Taken together, these findings indicated that blue light induced RGC-5 cell line death in dependence upon exposure duration. The potential mechanisms for this phenomenon might be via activated mitochondria-dependent apoptosis, increased ROS production and protein expressions of Nrf2 and HO-1, and activated JNK/p38 MAPK signaling pathways.

  11. Constitutive Models

    DEFF Research Database (Denmark)

    Sales-Cruz, Mauricio; Piccolo, Chiara; Heitzig, Martina

    2011-01-01

    This chapter presents various types of constitutive models and their applications. There are 3 aspects dealt with in this chapter, namely: creation and solution of property models, the application of parameter estimation and finally application examples of constitutive models. A systematic...... procedure is introduced for the analysis and solution of property models. Models that capture and represent the temperature dependent behaviour of physical properties are introduced, as well as equation of state models (EOS) such as the SRK EOS. Modelling of liquid phase activity coefficients are also...

  12. Review on the Potential Therapeutic Roles of Nigella sativa in the Treatment of Patients with Cancer: Involvement of Apoptosis

    Directory of Open Access Journals (Sweden)

    Hamid Mollazadeh

    2017-09-01

    Full Text Available Nigella sativa (N. sativa, family Ranunculaceae is a medicinal plant that has been widely used for centuries throughout the world as a natural remedy. A wide range of chemical compounds found in N. sativa expresses its vast therapeutic effects. Thymoquinone (TQ is the main component (up to 50% in the essential oil of N. sativa. Also, pinene (up to 15%, p-cymene (40%, thymohydroquinone (THQ, thymol (THY, and dithymoquinone (DTQ are other pharmacologically active compounds of its oil. Other terpenoid compounds, such as carvacrol, carvone, 4-terpineol, limonenes, and citronellol, are also found in small quantities in its oil. The main pharmacological characteristics of this plant are immune system stimulatory, anti- inflammatory, hypotensive, hepatoprotective, antioxidant, anti-cancer, hypoglycemic, anti- tussive, milk production, uricosuric, choleretic, anti-fertility, and spasmolytic properties. In this regard, we have searched the scientific databases PubMed, Web of Science, and Google Scholar with keywords of N. sativa, anti-cancer, apoptotic effect, antitumor, antioxidant, and malignancy over the period from 2000 to 2017. The effectiveness of N. sativa against cancer in the blood system, kidneys, lungs, prostate, liver, and breast and on many malignant cell lines has been shown in many studies, but the molecular mechanisms behind that anti-cancer role are still not clearly understood. From among the many effects of N. sativa, including its anti-proliferative effect, cell cycle arrest, apoptosis induction, ROS generation, anti-metastasis/anti-angiogenesis effects, Akt pathway control, modulation of multiple molecular targets, including p53, p73, STAT-3, PTEN, and PPAR-γ, and activation of caspases, the main suggestive anti-cancer mechanisms of N. sativa are its free radical scavenger activity and the preservation of various anti-oxidant enzyme activities, such as glutathione peroxidase, catalase, and glutathione-S- transferase. In this review

  13. Involvement of postnatal apoptosis on sex difference in number of cells generated during late fetal period in the sexually dimorphic nucleus of the preoptic area in rats.

    Science.gov (United States)

    Kato, Yukinori; Nakashima, Shizuka; Maekawa, Fumihiko; Tsukahara, Shinji

    2012-05-16

    Postnatal apoptosis is involved in formation of the sex difference in neuron number of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in rats. In this study, we examined the origin of neurons that die with apoptosis on the postnatal period to exhibit the sex difference in neuron number of the SDN-POA. First, we measured the number of cells that were labeled with 5-bromo-2'-deoxyuridine (BrdU) on embryonic day (ED) 17, ED18, and ED19 in the SDN-POA of rats on postnatal day (PD) 4 and PD8. The SDN-POA had many more cells labeled with BrdU on ED17 and ED18 than those on ED19. Significantly fewer cells labeled with BrdU on ED18 in the female SDN-POA from PD4 to PD8 resulted in a significant sex difference in the number at PD8. Next, combination analyses of BrdU-labeling and immunohistochemistry for single-stranded DNA (ssDNA), an apoptotic marker, were succeeded to investigate whether SDN-POA neurons generated during ED17-18 were removed by apoptosis. Many more ssDNA-immunoreactive cells that had been labeled with BrdU during ED17-18 were found in the SDN-POA of PD8 females, but few in the SDN-POA of PD8 males and PD4 females and males. These results suggest that the sex difference in the number of SDN-POA neurons generated during the late fetal period was caused by postnatal apoptosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  14. Camalexin-induced apoptosis in prostate cancer cells involves alterations of expression and activity of lysosomal protease cathepsin D.

    Science.gov (United States)

    Smith, Basil; Randle, Diandra; Mezencev, Roman; Thomas, LeeShawn; Hinton, Cimona; Odero-Marah, Valerie

    2014-04-02

    Camalexin, the phytoalexin produced in the model plant Arabidopsis thaliana, possesses antiproliferative and cancer chemopreventive effects. We have demonstrated that the cytostatic/cytotoxic effects of camalexin on several prostate cancer (PCa) cells are due to oxidative stress. Lysosomes are vulnerable organelles to Reactive Oxygen Species (ROS)-induced injuries, with the potential to initiate and or facilitate apoptosis subsequent to release of proteases such as cathepsin D (CD) into the cytosol. We therefore hypothesized that camalexin reduces cell viability in PCa cells via alterations in expression and activity of CD. Cell viability was evaluated by MTS cell proliferation assay in LNCaP and ARCaP Epithelial (E) cells, and their respective aggressive sublines C4-2 and ARCaP Mesenchymal (M) cells, whereby the more aggressive PCa cells (C4-2 and ARCaPM) displayed greater sensitivity to camalexin treatments than the lesser aggressive cells (LNCaP and ARCaPE). Immunocytochemical analysis revealed CD relocalization from the lysosome to the cytosol subsequent to camalexin treatments, which was associated with increased protein expression of mature CD; p53, a transcriptional activator of CD; BAX, a downstream effector of CD, and cleaved PARP, a hallmark for apoptosis. Therefore, camalexin reduces cell viability via CD and may present as a novel therapeutic agent for treatment of metastatic prostate cancer cells.

  15. Camalexin-Induced Apoptosis in Prostate Cancer Cells Involves Alterations of Expression and Activity of Lysosomal Protease Cathepsin D

    Directory of Open Access Journals (Sweden)

    Basil Smith

    2014-04-01

    Full Text Available Camalexin, the phytoalexin produced in the model plant Arabidopsis thaliana, possesses antiproliferative and cancer chemopreventive effects. We have demonstrated that the cytostatic/cytotoxic effects of camalexin on several prostate cancer (PCa cells are due to oxidative stress. Lysosomes are vulnerable organelles to Reactive Oxygen Species (ROS-induced injuries, with the potential to initiate and or facilitate apoptosis subsequent to release of proteases such as cathepsin D (CD into the cytosol. We therefore hypothesized that camalexin reduces cell viability in PCa cells via alterations in expression and activity of CD. Cell viability was evaluated by MTS cell proliferation assay in LNCaP and ARCaP Epithelial (E cells, and their respective aggressive sublines C4-2 and ARCaP Mesenchymal (M cells, whereby the more aggressive PCa cells (C4-2 and ARCaPM displayed greater sensitivity to camalexin treatments than the lesser aggressive cells (LNCaP and ARCaPE. Immunocytochemical analysis revealed CD relocalization from the lysosome to the cytosol subsequent to camalexin treatments, which was associated with increased protein expression of mature CD; p53, a transcriptional activator of CD; BAX, a downstream effector of CD, and cleaved PARP, a hallmark for apoptosis. Therefore, camalexin reduces cell viability via CD and may present as a novel therapeutic agent for treatment of metastatic prostate cancer cells.

  16. The Growth Suppressing Effects of Girinimbine on Hepg2 Involve Induction of Apoptosis and Cell Cycle Arrest

    Directory of Open Access Journals (Sweden)

    Tang Sook Wah

    2011-08-01

    Full Text Available Murraya koenigii is an edible herb widely used in folk medicine. Here we report that girinimbine, a carbazole alkaloid isolated from this plant, inhibited the growth and induced apoptosis in human hepatocellular carcinoma, HepG2 cells. The MTT and LDH assay results showed that girinimbine decreased cell viability and increased cytotoxicity in a dose-and time-dependent manner selectively. Girinimbine-treated HepG2 cells showed typical morphological features of apoptosis, as observed from normal inverted microscopy and Hoechst 33342 assay. Furthermore, girinimbine treatment resulted in DNA fragmentation and elevated levels of caspase-3 in HepG2 cells. Girinimbine treatment also displayed a time-dependent accumulation of the Sub-G0/G1 peak (hypodiploid and caused G0/G1-phase arrest. Together, these results demonstrated for the first time that girinimbine could effectively induce programmed cell death in HepG2 cells and suggests the importance of conducting further investigations in preclinical human hepatocellular carcinoma models, especially on in vivo efficacy, to promote girinimbine for use as an anticancer agent against hepatocellular carcinoma.

  17. Mitochondrial and caspase pathways are involved in the induction of apoptosis by nardosinen in MCF-7 breast cancer cell line.

    Science.gov (United States)

    Shahali, Amirhosein; Ghanadian, Mustafa; Jafari, Seyyed Mehdi; Aghaei, Mahmoud

    2018-02-01

    Natural products isolated from plants provide a valuable source for expansion of new anticancer drugs. Nardosinen (4,9-dihydroxy-nardosin-6-en) is a natural sesquiterpene extracted from Juniperus foetidissima . Recently, we have reported the cytotoxic effects of nardosinen in various cancer cells. The aim of the current study was to investigate the anticancer features of nardosinen as well as its possible molecular mechanisms of the nardosinen cytotoxic effect on breast tumor cells. MTT assay showed that nardosinen notably inhibited cell proliferation in a dose-dependent manner in MCF-7 breast cancer cells. The growth inhibitory effect of nardosinen was associated with the induction of cell apoptosis, activation of caspase-6, increase of reactive oxygen species (ROS), and loss of mitochondrial membrane potentials (ΔΨm). Western blot assay following treatment with nardosinen showed that the expression levels of the Bax were significantly up-regulated and the expression levels of the Bcl-2 were significantly down-regulated. Our results finally exhibited that nardosinen induces apoptosis in breast cancer cells via the mitochondrial and caspase pathways.

  18. Early-life exposure to bisphenol a induces liver injury in rats involvement of mitochondria-mediated apoptosis.

    Directory of Open Access Journals (Sweden)

    Wei Xia

    Full Text Available Exposure to bisphenol A (BPA, a monomer widely used to manufacture polycarbonate plastics, has been reported to be associated with abnormalities of liver function and hepatic damage. However, the molecular mechanism under the pathogenesis of hepatic injury is unclear. In this study, the effect of perinatal exposure to BPA at the reference dose of 50 µg/kg/day on the apoptotic index in the liver of rat offspring was investigated. Increased levels of ALT and enhanced cell apoptosis were observed in the liver of rat offspring at 15 and 21 weeks, and significantly increased activity of caspase-3 and caspase-9 and elevated levels of cytochrome c were also confirmed. In addition, significant change in the expression levels of Bcl-2 and Bax were found in BPA-treated offspring at 21 weeks. For in vitro experiments, liver mitochondria were isolated from neonatal rats and were treated with BPA. BPA treatment led to a significant increase in mitochondrial permeability transition. Moreover, the supernatant from BPA-treated mitochondria significantly increased apoptotic changes in nuclei isolated from liver tissue. In conclusion, the study demonstrates that BPA induces mitochondria-mediated apoptosis in hepatic cells, which may contribute to long-term hepatotoxicity induced by early-life exposure to BPA.

  19. The Natural Stilbenoid Piceatannol Decreases Activity and Accelerates Apoptosis of Human Neutrophils: Involvement of Protein Kinase C

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    Viera Jancinova

    2013-01-01

    Full Text Available Neutrophils are able to release cytotoxic substances and inflammatory mediators, which, along with their delayed apoptosis, have a potential to maintain permanent inflammation. Therefore, treatment of diseases associated with chronic inflammation should be focused on neutrophils; formation of reactive oxygen species and apoptosis of these cells represent two promising targets for pharmacological intervention. Piceatannol, a naturally occurring stilbenoid, has the ability to reduce the toxic action of neutrophils. This substance decreased the amount of oxidants produced by neutrophils both extra- and intracellularly. Radicals formed within neutrophils (fulfilling a regulatory role were reduced to a lesser extent than extracellular oxidants, potentially dangerous for host tissues. Moreover, piceatannol did not affect the phosphorylation of p40phox—a component of NADPH oxidase, responsible for the assembly of functional oxidase in intracellular (granular membranes. The stilbenoid tested elevated the percentage of early apoptotic neutrophils, inhibited the activity of protein kinase C (PKC—the main regulatory enzyme in neutrophils, and reduced phosphorylation of PKC isoforms α, βII, and δ on their catalytic region. The results indicated that piceatannol may be useful as a complementary medicine in states associated with persisting neutrophil activation and with oxidative damage of tissues.

  20. Involvement of Bcl-xL degradation and mitochondrial-mediated apoptotic pathway in pyrrolizidine alkaloids-induced apoptosis in hepatocytes

    International Nuclear Information System (INIS)

    Ji Lili; Chen Ying; Liu Tianyu; Wang Zhengtao

    2008-01-01

    Pyrrolizidine alkaloids (PAs) are natural hepatotoxins with worldwide distribution in more than 6000 high plants including medicinal herbs or teas. The aim of this study is to investigate the signal pathway involved in PAs-induced hepatotoxicity. Our results showed that clivorine, isolated from Ligularia hodgsonii Hook, decreased cell viability and induced apoptosis in L-02 cells and mouse hepatocytes. Western-blot results showed that clivorine induced caspase-3/-9 activation, mitochondrial release of cytochrome c and decreased anti-apoptotic Bcl-xL in a time (8-48 h)- and concentration (1-100 μM)-dependent manner. Furthermore, inhibitors of pan-caspase, caspase-3 and caspase-9 significantly inhibited clivorine-induced apoptosis and rescued clivorine-decreased cell viability. Polyubiquitination of Bcl-xL was detected after incubation with 100 μM clivorine for 40 h in the presence of proteasome specific inhibitor MG132, indicating possible degradation of Bcl-xL protein. Furthermore, pretreatment with MG132 or calpain inhibitor I for 2 h significantly enhanced clivorine-decreased Bcl-xL level and cell viability. All the other tested PAs such as senecionine, isoline and monocrotaline decreased mouse hepatocytes viability in a concentration-dependent manner. Clivorine (10 μM) induced caspase-3 activation and decreased Bcl-xL was also confirmed in mouse hepatocytes. Meanwhile, another PA senecionine isolated from Senecio vulgaris L also induced apoptosis, caspase-3 activation and decreased Bcl-xL in mouse hepatocytes. In conclusion, our results suggest that PAs may share the same hepatotoxic signal pathway, which involves degradation of Bcl-xL protein and thus leading to the activation of mitochondrial-mediated apoptotic pathway

  1. N-Myc Downstream-Regulated Gene 2 (Ndrg2) Is Involved in Ischemia-Hypoxia-Induced Astrocyte Apoptosis: a Novel Target for Stroke Therapy.

    Science.gov (United States)

    Ma, Yu-Long; Zhang, Li-Xia; Liu, Guang-Lin; Fan, Yanhong; Peng, Ye; Hou, Wu-Gang

    2017-07-01

    Nearly all clinical trials that have attempted to develop effective strategies against ischemic stroke have failed, excluding those for thrombolysis, and most of these trials focused only on preventing neuronal loss. However, astrocytes have gradually become a target for neuroprotection in stroke. In previous studies, we showed that the newly identified molecular N-myc downstream-regulated gene 2 (Ndrg2) is specifically expressed in astrocytes in the brain and involved in some neurodegenerative diseases. However, the role of NDRG2 in ischemic stroke remained unclear. In this study, we investigated the role of NDRG2 in middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia and in oxygen-glucose deprivation (OGD)-induced cellular apoptosis in the M1800 astrocyte cell line. NDRG2 mRNA and protein expression began to increase at 6 and 2 h after reperfusion and peaked at 24 h in the ischemic penumbra and in M1800 cells, as detected by RT-PCR and Western blotting. Double immunofluorescence staining showed that the number of apoptotic cells increased as the NDRG2-positive signal increased and that the NDRG2 signal was sometimes co-localized with TUNEL-positive cells and translocated from the cytoplasm to the nucleus in both the ischemic penumbra and the M1800 cells. Using a lentivirus, we successfully constructed two stable astrocytic cell lines in which NDRG2 expression was significantly up- or down-regulated. NDRG2 silencing had a proliferative effect and reduced the percentage of apoptotic cells, reactive oxygen species (ROS) production, and cleaved Caspase-3 protein expression following OGD, whereas NDRG2 over-expression had the opposite effects. In conclusion, NDRG2 is involved in astrocyte apoptosis following ischemic-hypoxic injury, and inhibiting NDRG2 expression significantly reduces ROS production and astrocyte apoptosis. These findings provide insight into the role of NDRG2 in ischemic-hypoxic injury and provide potential targets for future

  2. Pyrogallol Structure in Polyphenols is Involved in Apoptosis-induction on HEK293T and K562 Cells

    Directory of Open Access Journals (Sweden)

    Akiko Saito

    2008-12-01

    Full Text Available As multiple mechanisms account for polyphenol-induced cytotoxicity, the development of structure-activity relationships (SARs may facilitate research on cancer therapy. We studied SARs of representatives of 10 polyphenol structural types: (+-catechin (1, (--epicatechin (2, (--epigallocatechin (3, (--epigallocatechin gallate (4, gallic acid (5, procyanidin B2 (6, procyanidin B3 (7, procyanidin B4 (8, procyanidin C1 (9, and procyanidin C2 (10. Amongst them, the polyphenols containing a pyrogallol moiety (3-5 showed the most potent cytotoxicic activity. These compounds evoked a typical DNA-laddering phenomenon in HEK293T, which indicated that the induction of apoptosis at least partly mediates their cytotoxic activity. Anti-oxidative capacity of compounds 3-5 were comparable to those of the trimers 9 and 10, which were not cytotoxic. Therefore, we suggest that pyrogallol moiety is important for fitting of polyphenols to their putative target molecule(s in non-oxidative mechanism.

  3. L-Xylulose reductase is involved in 9,10-phenanthrenequinone-induced apoptosis in human T lymphoma cells.

    Science.gov (United States)

    Matsunaga, Toshiyuki; Kamiya, Tetsuro; Sumi, Daigo; Kumagai, Yoshito; Kalyanaraman, B; Hara, Akira

    2008-03-15

    9,10-Phenanthrenequinone (9,10-PQ), a major component in diesel exhaust particles, is suggested to generate reactive oxygen species (ROS) through its redox cycling, leading to cell toxicity. l-Xylulose reductase (XR), a NADPH-dependent enzyme in the uronate pathway, strongly reduces alpha-dicarbonyl compounds and was thought to act as a detoxification enzyme against reactive carbonyl compounds. Here, we have investigated the role of intracellular ROS generation in apoptotic signaling in human acute T-lymphoblastic leukemia MOLT-4 cells treated with 9,10-PQ and the role of XR in the generation of ROS. Treatment with 9,10-PQ elicited not only apoptotic signaling, including mitochondrial membrane dysfunction and activation of caspases and poly(ADP-ribose) polymerase, but also intracellular ROS generation and consequent glutathione depletion. The apoptotic effects of 9,10-PQ were drastically mitigated by pretreatment with intracellular ROS scavengers, such as N-acetyl-l-cysteine, glutathione monoethyl ester, and polyethylene glycol-conjugated catalase, indicating that intracellular ROS generation is responsible for the 9,10-PQ-evoked apoptosis. Surprisingly, the ROS generation and cytotoxicity by 9,10-PQ were augmented in an XR-transformed cell line. XR indeed reduced 9,10-PQ and produced superoxide anion through redox cycling. In addition, the expression levels of XR and its mRNA in the T lymphoma cells were markedly enhanced after the exposure to 9,10-PQ, and the induction was completely abolished by the ROS scavengers. Moreover, the 9,10-PQ-induced apoptosis was partially inhibited by the pretreatment with XR-specific inhibitors. These results suggest that initially produced ROS induce XR, which accelerates the generation of ROS.

  4. Morphological adaptation of sheep's rumen epithelium to high-grain diet entails alteration in the expression of genes involved in cell cycle regulation, cell proliferation and apoptosis.

    Science.gov (United States)

    Xu, Lei; Wang, Yue; Liu, Junhua; Zhu, Weiyun; Mao, Shengyong

    2018-01-01

    The objectives of this study were to characterize changes in the relative mRNA expression of candidate genes and proteins involved in cell cycle regulation, cell proliferation and apoptosis in the ruminal epithelium (RE) of sheep during high-grain (HG) diet adaptation. Twenty sheep were assigned to four groups with five animals each. These animals were assigned to different periods of HG diet (containing 40% forage and 60% concentrate mix) feeding. The HG groups received an HG diet for 7 (G7, n  = 5), 14 (G14, n  = 5) and 28 d (G28, n  = 5), respectively. In contrast, the control group (CON, n  = 5) was fed the forage-based diet for 28 d. The results showed that HG feeding linearly decreased ( P  Bad mRNA expression tended to decrease (cubic, P  = 0.053) after HG feeding. These results demonstrated sequential changes in rumen papillae size, cell cycle regulation and the genes involved in proliferation and apoptosis as time elapsed in feeding a high-grain diet to sheep.

  5. Diallylsulfide attenuates excessive collagen production and apoptosis in a rat model of bleomycin induced pulmonary fibrosis through the involvement of protease activated receptor-2

    International Nuclear Information System (INIS)

    Kalayarasan, Srinivasan; Sriram, Narayanan; Soumyakrishnan, Syamala; Sudhandiran, Ganapasam

    2013-01-01

    Pulmonary fibrosis (PF) can be a devastating lung disease. It is primarily caused by inflammation leading to severe damage of the alveolar epithelial cells. The pathophysiology of PF is not yet been clearly defined, but studying lung parenchymal injury by involving reactive oxygen species (ROS) through the activation of protease activated receptor-2 (PAR-2) may provide promising results. PAR-2 is a G-protein coupled receptor is known to play an important role in the development of PF. In this study, we investigated the inhibitory role of diallylsulfide (DAS) against ROS mediated activation of PAR-2 and collagen production accompanied by epithelial cell apoptosis. Bleomycin induced ROS levels may prompt to induce the expression of PAR-2 as well as extracellular matrix proteins (ECM), such as MMP 2 and 9, collagen specific proteins HSP-47, α-SMA, and cytokines IL-6, and IL-8RA. Importantly DAS treatment effectively decreased the expression of all these proteins. The inhibitory effect of DAS on profibrotic molecules is mediated by blocking the ROS level. To identify apoptotic signaling as a mediator of PF induction, we performed apoptotic protein expression, DNA fragmentation analysis and ultrastructural details of the lung tissue were performed. DAS treatment restored all these changes to near normalcy. In conclusion, treatment of PF bearing rats with DAS results in amelioration of the ROS production, PAR-2 activation, ECM production, collagen synthesis and alveolar epithelial cell apoptosis during bleomycin induction. We attained the first evidence that treatment of DAS decreases the ROS levels and may provide a potential therapeutic effect attenuating bleomycin induced PF. - Highlights: • DAS inhibits PAR-2 activity; bleomycin stimulates PAR-2 activity. • Increase in PAR-2 activity is correlated with pulmonary fibrosis • DAS reduces pro-inflammatory activity linked to facilitating pulmonary fibrosis. • DAS inhibits apoptosis of alveolar epithelial cells

  6. Diallylsulfide attenuates excessive collagen production and apoptosis in a rat model of bleomycin induced pulmonary fibrosis through the involvement of protease activated receptor-2

    Energy Technology Data Exchange (ETDEWEB)

    Kalayarasan, Srinivasan, E-mail: kalaivasanbio@gmail.com; Sriram, Narayanan; Soumyakrishnan, Syamala; Sudhandiran, Ganapasam, E-mail: sudhandiran@yahoo.com

    2013-09-01

    Pulmonary fibrosis (PF) can be a devastating lung disease. It is primarily caused by inflammation leading to severe damage of the alveolar epithelial cells. The pathophysiology of PF is not yet been clearly defined, but studying lung parenchymal injury by involving reactive oxygen species (ROS) through the activation of protease activated receptor-2 (PAR-2) may provide promising results. PAR-2 is a G-protein coupled receptor is known to play an important role in the development of PF. In this study, we investigated the inhibitory role of diallylsulfide (DAS) against ROS mediated activation of PAR-2 and collagen production accompanied by epithelial cell apoptosis. Bleomycin induced ROS levels may prompt to induce the expression of PAR-2 as well as extracellular matrix proteins (ECM), such as MMP 2 and 9, collagen specific proteins HSP-47, α-SMA, and cytokines IL-6, and IL-8RA. Importantly DAS treatment effectively decreased the expression of all these proteins. The inhibitory effect of DAS on profibrotic molecules is mediated by blocking the ROS level. To identify apoptotic signaling as a mediator of PF induction, we performed apoptotic protein expression, DNA fragmentation analysis and ultrastructural details of the lung tissue were performed. DAS treatment restored all these changes to near normalcy. In conclusion, treatment of PF bearing rats with DAS results in amelioration of the ROS production, PAR-2 activation, ECM production, collagen synthesis and alveolar epithelial cell apoptosis during bleomycin induction. We attained the first evidence that treatment of DAS decreases the ROS levels and may provide a potential therapeutic effect attenuating bleomycin induced PF. - Highlights: • DAS inhibits PAR-2 activity; bleomycin stimulates PAR-2 activity. • Increase in PAR-2 activity is correlated with pulmonary fibrosis • DAS reduces pro-inflammatory activity linked to facilitating pulmonary fibrosis. • DAS inhibits apoptosis of alveolar epithelial cells.

  7. Ethanol extract of Prunus mume fruit attenuates hydrogen peroxide-induced oxidative stress and apoptosis involving Nrf2/HO-1 activation in C2C12 myoblasts

    Directory of Open Access Journals (Sweden)

    Ji Sook Kang

    Full Text Available ABSTRACT The fruit of the Prunus mume (Siebold Siebold & Zucc., Rosaceae (Korean name: Maesil has long been used as a health food or valuable medicinal material in traditional herb medicine in Southeast Asian countries. In this study, we determined the potential therapeutic efficacy of the ethanol extract of P. mume fruits (EEPM against H2O2-induced oxidative stress and apoptosis in the murine skeletal muscle myoblast cell line C2C12, and sought to understand the associated molecular mechanisms. The results indicated that exposure of C2C12 cells to H2O2 caused a reduction in cell viability by increasing the generation of intracellular reactive oxygen species and by disrupting mitochondrial membrane permeability, leading to DNA damage and apoptosis. However, pretreatment of the cells with EEPM before H2O2 exposure effectively attenuated these changes, suggesting that EEPM prevented H2O2-induced mitochondria-dependent apoptosis. Furthermore, the increased ex-pression and phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2 and up-regulation of heme oxygenase-1 (HO-1, a phase II antioxidant enzyme, were detected in EEPM-treated C2C12 cells. We also found that zinc protoporphyrin IX, an HO-1 inhibitor, attenuated the protective effects of EEPM against H2O2-induced reactive oxygen species accumulation and cytotoxicity. Therefore, these results indicate that the activation of the Nrf2/HO-1 pathway might be involved in the protection of EEPM against H2O2-induced cellular oxidative damage. In conclusion, these results show that EEPM contributes to the prevention of oxidative damage and could be used as a nutritional agent for oxidative stress-related diseases.

  8. Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways

    Science.gov (United States)

    Afsar, Tayyaba; Trembley, Janeen H.; Salomon, Christine E.; Razak, Suhail; Khan, Muhammad Rashid; Ahmed, Khalil

    2016-01-01

    Acacia hydaspica R. Parker is known for its medicinal uses in multiple ailments. In this study, we performed bioassay-guided fractionation of cytotoxic compounds from A. hydaspica and investigated their effects on growth and signaling activity in prostate and breast cancer cell lines. Four active polyphenolic compounds were identified as 7-O-galloyl catechin (GC), catechin (C), methyl gallate (MG), and catechin-3-O-gallate (CG). The four compounds inhibited prostate cancer PC-3 cell growth in a dose-dependent manner, whereas CG and MG inhibited breast cancer MDA-MB-231 cell growth. All tested compounds inhibited cell survival and colony growth in both cell lines, and there was evidence of chromatin condensation, cell shrinkage and apoptotic bodies. Further, acridine orange, ethidium bromide, propidium iodide and DAPI staining demonstrated that cell death occurred partly via apoptosis in both PC-3 and MDA-MB-231 cells. In PC-3 cells treatment repressed the expression of anti-apoptotic molecules Bcl-2, Bcl-xL and survivin, coupled with down-regulation of signaling pathways AKT, NFκB, ERK1/2 and JAK/STAT. In MDA-MB-231 cells, treatment induced reduction of CK2α, Bcl-xL, survivin and xIAP protein expression along with suppression of NFκB, JAK/STAT and PI3K pathways. Our findings suggest that certain polyphenolic compounds derived from A. hydaspica may be promising chemopreventive/therapeutic candidates against cancer. PMID:26975752

  9. Cloning and identification of two unique genes involved in UV induced apoptosis on human keratinocyte (HaCaT) cell line.

    Science.gov (United States)

    Gupta, Nishma; Raman, Govindarajan; Banerjee, Gautam

    2004-01-01

    Differential gene regulation during UVB induced apoptosis of human keratinocyte cell line (HaCaT) has been investigated. Rapid amplification of polymorphic DNA (RAPD)-PCR was done to identify novel/unique genes in the purified apoptotic and non-apoptotic populations. Two genes were identified and cloned in pGemT vector. One of these genes (apgene-1) was upregulated in UV induced apoptotic cells and in the non apoptotic cells exposed to UV. The other gene (apgene-2) was not detected in apoptotic cells but expressed in non-apoptotic/non necrotic cells that had been exposed to UV. The presence of apgene-1 mRNA was not detected in camptothecin induced apoptotic as well as non apoptotic cells. Apgene-2 was not detected in camptothecin induced apoptotic cells but expressed in non-apoptotic/non necrotic cells. This data indicates differential regulation of these two genes during UV and chemical induced apoptosis in human keratinocytes. Additionally, since apgene-2 was upregulated in the non necrotic/non apoptotic population could be involved in protection.

  10. Plumbagin elicits differential proteomic responses mainly involving cell cycle, apoptosis, autophagy, and epithelial-to-mesenchymal transition pathways in human prostate cancer PC-3 and DU145 cells

    Directory of Open Access Journals (Sweden)

    Qui JX

    2015-01-01

    Full Text Available Jia-Xuan Qiu,1,2 Zhi-Wei Zhou, 3,4 Zhi-Xu He,4 Ruan Jin Zhao,5 Xueji Zhang,6 Lun Yang,7 Shu-Feng Zhou,3,4 Zong-Fu Mao11School of Public Health, Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 3Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 4Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China; 5Center for Traditional Chinese Medicine, Sarasota, FL, USA; 6Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People’s Republic of China; 7Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education, Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaAbstract: Plumbagin (PLB has exhibited a potent anticancer effect in preclinical studies, but the molecular interactome remains elusive. This study aimed to compare the quantitative proteomic responses to PLB treatment in human prostate cancer PC-3 and DU145 cells using the approach of stable-isotope labeling by amino acids in cell culture (SILAC. The data were finally validated using Western blot assay. First, the bioinformatic analysis predicted that PLB could interact with 78 proteins that were involved in cell proliferation and apoptosis, immunity, and signal transduction. Our quantitative proteomic study using SILAC revealed that there were at least 1,225 and 267 proteins interacting with PLB and there were 341 and 107 signaling pathways and cellular functions potentially regulated by PLB in PC-3 and DU145 cells, respectively. These proteins and pathways played a

  11. Inhibition of human prostate cancer cells proliferation by a selective alpha1-adrenoceptor antagonist labedipinedilol-A involves cell cycle arrest and apoptosis

    International Nuclear Information System (INIS)

    Liou, S.-F.; Lin, H.-H.; Liang, J.-C.; Chen, I.-J.; Yeh, J.-L.

    2009-01-01

    In this research, we conducted an in vitro analysis to evaluate the prostate cancer cells response to labedipinedilol-A in order to determine the effect of this selective α 1 -adrenoceptor antagonist to suppress prostate cancer cell growth by affecting cell proliferation and apoptosis. Here, we report that treatment of androgen-sensitive (LNCaP) and androgen-insensitive (PC-3) prostate cancer cells with labedipinedilol-A inhibited cell proliferation in concentration-dependent and time-dependent manners. Moreover, norepinephrine-stimulated proliferation of both cell lines are markedly inhibited by labedipinedilol-A. The probable involvement of α 1 -adrenoceptors in this cellular response is suggested. Labedipinedilol-A-induced growth inhibition was associated with G 0 /G 1 arrest, and G 2 /M arrest depending upon concentrations. Cell cycle blockade was associated with reduced amounts of cyclin D1/2, cyclin E, Cdk2, Cdk4, and Cdk6 and increased levels of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27). In addition, labedipinedilol-A also induced apoptosis in PC-3 cells, as determined by using Hoechst 33342 staining, DNA fragmentation, and Annexin V staining assay. Furthermore, labedipinedilol-A triggered the mitochondrial apoptotic pathway, as indicated by increasing the expression of Bax, but decreasing the level of Bcl-2, resulting in mitochondrial membrane potential loss, cytochrome c release, and activation of caspase-9 and -3. We further investigated the role of MAPK cascades in the anti-proliferative and apoptosis effects of labedipinedilol-A, and confirmed that labedipinedilol-A could activate JNK1/2 but not p38 in both cell lines. Unlike JNK1/2, however, labedipinedilol-A treatment resulted in down-regulation of phospho-ERK1/2 expression. We concluded that labedipinedilol-A possessed the growth-suppressive and apoptotic effects on LNCaP and PC-3 cells by its α 1 -adrenoceptor blockade, and the apoptotic effects of labedipinedilol-A primarily through

  12. Penta-acetyl geniposide-induced apoptosis involving transcription of NGF/p75 via MAPK-mediated AP-1 activation in C6 glioma cells

    International Nuclear Information System (INIS)

    Peng, C.-H.; Huang, C.-N.; Hsu, S.-P.; Wang, C.-J.

    2007-01-01

    We have demonstrated the herbal derivative penta-acetyl geniposide ((Ac) 5 GP) induces C6 glioma cell apoptosis through the critical sphingomyelinase (SMase)/nerve growth factor (NGF)/p75 and its downstream signals. It has been reported mitogen-activated protein kinase (MAPK) mediates NGF synthesis induced by SMase activation. In this study, ERK, p38 and JNK are shown to mediate (Ac) 5 GP-induced glioma cell apoptosis and elevation of NGF and p75. Treatment of PD98059 (ERK-specific inhibitor), SB203580 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor) decreases the elevation of NGF and p75 mRNA induced by (Ac) 5 GP, indicating possible transcription regulation via MAPKs. The results of nuclear extract blotting and EMSA further confirm (Ac) 5 GP maximally increases AP-1 and NF-κB DNA binding at 6 h. Inhibition of ERK, p38 and JNK block the activation of AP-1 and NF-κB, suggesting these MAPKs are involved in (Ac) 5 GP-induced transcription regulation. We thereby used RT-PCR to analyze cells treated with (Ac) 5 GP, with or without AP-1 or NF-κB inhibitors. AP-1 inhibitor NDGA decreases NGF/p75 and expression of FasL and caspase 3 induced by (Ac) 5 GP, suggesting the importance of AP-1 in mediating NGF/p75 and their downstream apoptotic signals. However, FasL and caspase 3 do not change with the NF-κB inhibitor PDTC; NF-κB might be linked to other cellular events. Overall, we demonstrate that MAPK mediates (Ac) 5 GP-induced activation of AP-1, promoting the transcription of NGF/p75 and downstream apoptotic signals. These results further highlight the potential therapeutic effects of (Ac) 5 GP in chemoprevention or as an anti-tumor agent

  13. The adhesion G protein-coupled receptor G2 (ADGRG2/GPR64) constitutively activates SRE and NFκB and is involved in cell adhesion and migration

    DEFF Research Database (Denmark)

    Cornelia Peeters, Miriam; Fokkelman, Michiel; Boogaard, Bob

    2015-01-01

    Adhesion G protein-coupled receptors (ADGRs) are believed to be activated by auto-proteolytic cleavage of their very large extracellular N-terminal domains normally acting as a negative regulator of the intrinsically constitutively active seven transmembrane domain. ADGRG2 (or GPR64) which...... activity through the adhesion- and migration-related transcription factors serum response element (SRE) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) presumably via coupling to Gα12/13 and Gαq. However, activation of these two pathways appears to occur through distinct molecular...... intracellular signal transduction. Knockdown of ADGRG2 by siRNA in the highly motile breast cancer cell lines Hs578T and MDA-MB-231 resulted in a strong reduction in cell adhesion and subsequent cell migration which was associated with a selective reduction in RelB, an NFκB family member. It is concluded...

  14. PARM-1 is an endoplasmic reticulum molecule involved in endoplasmic reticulum stress-induced apoptosis in rat cardiac myocytes.

    Directory of Open Access Journals (Sweden)

    Koji Isodono

    Full Text Available To identify novel transmembrane and secretory molecules expressed in cardiac myocytes, signal sequence trap screening was performed in rat neonatal cardiac myocytes. One of the molecules identified was a transmembrane protein, prostatic androgen repressed message-1 (PARM-1. While PARM-1 has been identified as a gene induced in prostate in response to castration, its function is largely unknown. Our expression analysis revealed that PARM-1 was specifically expressed in hearts and skeletal muscles, and in the heart, cardiac myocytes, but not non-myocytes expressed PARM-1. Immunofluorescent staining showed that PARM-1 was predominantly localized in endoplasmic reticulum (ER. In Dahl salt-sensitive rats, high-salt diet resulted in hypertension, cardiac hypertrophy and subsequent heart failure, and significantly stimulated PARM-1 expression in the hearts, with a concomitant increase in ER stress markers such as GRP78 and CHOP. In cultured cardiac myocytes, PARM-1 expression was stimulated by proinflammatory cytokines, but not by hypertrophic stimuli. A marked increase in PARM-1 expression was observed in response to ER stress inducers such as thapsigargin and tunicamycin, which also induced apoptotic cell death. Silencing PARM-1 expression by siRNAs enhanced apoptotic response in cardiac myocytes to ER stresses. PARM-1 silencing also repressed expression of PERK and ATF6, and augmented expression of CHOP without affecting IRE-1 expression and JNK and Caspase-12 activation. Thus, PARM-1 expression is induced by ER stress, which plays a protective role in cardiac myocytes through regulating PERK, ATF6 and CHOP expression. These results suggested that PARM-1 is a novel ER transmembrane molecule involved in cardiac remodeling in hypertensive heart disease.

  15. ERK1/2/p53 and NF-κB dependent-PUMA activation involves in doxorubicin-induced cardiomyocyte apoptosis.

    Science.gov (United States)

    Zhang, D-X; Ma, D-Y; Yao, Z-Q; Fu, C-Y; Shi, Y-X; Wang, Q-L; Tang, Q-Q

    2016-06-01

    Numerous studies have demonstrated that Doxorubicin (DOX) induces cardiomyocyte apoptosis, which is associated with DOX-induced acute and chronic cardiotoxicity. DOX activated ERP1/2 and NF-KB signals has been linked to DOX-induced apoptosis and cardiotoxicity. However, the underlying mechanisms responsible for DOX-induced apoptosis have not been completely elucidated. In this study, we determine whether both ERK1/2/p53-dependent and NF-κB dependent-PUMA activation was related to DOX-induced apoptosis in H9c2 cells. H9c2 cells were treated with DOX (1 μM) for 2-48 hours. To explore the effect of ERK1/2, NF-KB, P53 and PUMA on DOX-induced apoptosis in H9c2 cells, H9c2 cells were transfected with PUMA siRNA or p65 siRNA, or treated with PFT-α (a chemical inhibitor of p53), or PD98059 (ERK inhibitor) before DOX treatment. MTT, Flow cytometry, TUNEL, Western blot and EMSA assay was used to detect cell survival, apoptosis, protein expression and NF-KB activity. DOX induced apoptosis and inhibited growth of H9c2 cells in a time-dependent manner. DOX activated ERK1/2, NF-KB, p53 and PUMA. Knockdown of PUMA completely blocked DOX-induced cell apoptosis and survival inhibition. Knockdown of NF-KB or ERK1/2 alone could partly block DOX-induced PUMA upregulation and cell apoptosis. However, knockdown of NF-KB and ERK1/2 together completely blocked DOX-induced cell apoptosis and PUMA upregulation. In addition, knockdown of ERK1/2 blocked p53-dependent PUMA upregulation. DOX induced apoptosis and inhibited growth of H9c2 cells by activation of ERK1/2/p53 and NF-κB dependent-PUMA signaling pathway.

  16. Apoptosis signaling and radiation protection

    International Nuclear Information System (INIS)

    Morita, Akinori; Suzuki, Norio; Hosoi, Yoshio

    2005-01-01

    Radiation protection by apoptosis control is the suppression of cell death in highly radiosensitive tissues. This paper describes the outline of radiation-induced apoptosis framework, apoptosis-concerned target molecules possibly related to apoptosis by radiation and their inhibitors. Although there are intrinsic (via mitochondria) and extrinsic (via death receptor) pathways in apoptosis, this review mainly mentions the former which is more important in radiation-induced apoptosis. Those molecules known at present in the apoptosis are caspase, Bcl-2 family and p53. Caspase, a group of cystein proteases, initiates apoptosis but its inhibition is known not always to result in apoptosis suppression, suggesting the existence of caspase-independent pathways. Bcl-2 family involves apoptosis-suppressing (possessing BH domains) and -promoting (lacking BH domains or possessing BH3 domain alone/BH3-only protein) groups. Two p53-transcription-dependent and one -independent pathways in p53-induced apoptosis are known and p53 can be a most possible target molecule since it positions at the start of apoptosis. Authors have found a vanadate inactivates p53. Inhibitors affecting upstream molecules of apoptosis will be the most useful candidate for apoptosis suppression/radiation protection. (S.I.) 106 refs

  17. Caspase-independent cell death mediated by apoptosis-inducing factor (AIF) nuclear translocation is involved in ionizing radiation induced HepG2 cell death

    International Nuclear Information System (INIS)

    Sun, Hengwen; Yang, Shana; Li, Jianhua; Zhang, Yajie; Gao, Dongsheng; Zhao, Shenting

    2016-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The aim of radiotherapy is to eradicate cancer cells with ionizing radiation. Except for the caspase-dependent mechanism, several lines of evidence demonstrated that caspase-independent mechanism is directly involved in the cell death responding to irradiation. For this reason, defining the contribution of caspase-independent molecular mechanisms represents the main goal in radiotherapy. In this study, we focused on the role of apoptosis-inducing factor (AIF), the caspase-independent molecular, in ionizing radiation induced hepatocellular carcinoma cell line (HepG2) cell death. We found that ionizing radiation has no function on AIF expression in HepG2 cells, but could induce AIF release from the mitochondria and translocate into nuclei. Inhibition of AIF could reduce ionizing radiation induced HepG2 cell death. These studies strongly support a direct relationship between AIF nuclear translocation and radiation induced cell death. What's more, AIF nuclear translocation is caspase-independent manner, but not caspase-dependent manner, in this process. These new findings add a further attractive point of investigation to better define the complex interplay between caspase-independent cell death and radiation therapy. - Highlights: • AIF nuclear translocation is involved in ionizing radiation induced hepatocellular carcinoma cell line HepG2 cell death. • AIF mediated cell death induced by ionizing radiation is caspase-independent. • Caspase-independent pathway is involved in ionzing radiation induced HepG2 cell death.

  18. Caspase-independent cell death mediated by apoptosis-inducing factor (AIF) nuclear translocation is involved in ionizing radiation induced HepG2 cell death

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Hengwen [Department of Radiation, Cancer Center of Guangdong General Hospital (Guangdong Academy of Medical Science), Guangzhou, 510080, Guangdong (China); Yang, Shana; Li, Jianhua [Department of Physiology, Guangzhou Medical University, Guangzhou, 510182, Guangdong (China); Zhang, Yajie [Department of Pathology, Guangzhou Medical University, Guangzhou, 510182, Guangdong (China); Gao, Dongsheng [Department of Oncology, Guangdong Medical College Affiliated Pengpai Memorial Hospital, Hai Feng, 516400, Gungdong (China); Zhao, Shenting, E-mail: zhaoshenting@126.com [Department of Physiology, Guangzhou Medical University, Guangzhou, 510182, Guangdong (China)

    2016-03-25

    Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The aim of radiotherapy is to eradicate cancer cells with ionizing radiation. Except for the caspase-dependent mechanism, several lines of evidence demonstrated that caspase-independent mechanism is directly involved in the cell death responding to irradiation. For this reason, defining the contribution of caspase-independent molecular mechanisms represents the main goal in radiotherapy. In this study, we focused on the role of apoptosis-inducing factor (AIF), the caspase-independent molecular, in ionizing radiation induced hepatocellular carcinoma cell line (HepG2) cell death. We found that ionizing radiation has no function on AIF expression in HepG2 cells, but could induce AIF release from the mitochondria and translocate into nuclei. Inhibition of AIF could reduce ionizing radiation induced HepG2 cell death. These studies strongly support a direct relationship between AIF nuclear translocation and radiation induced cell death. What's more, AIF nuclear translocation is caspase-independent manner, but not caspase-dependent manner, in this process. These new findings add a further attractive point of investigation to better define the complex interplay between caspase-independent cell death and radiation therapy. - Highlights: • AIF nuclear translocation is involved in ionizing radiation induced hepatocellular carcinoma cell line HepG2 cell death. • AIF mediated cell death induced by ionizing radiation is caspase-independent. • Caspase-independent pathway is involved in ionzing radiation induced HepG2 cell death.

  19. MiR-30b Is Involved in the Homocysteine-Induced Apoptosis in Human Coronary Artery Endothelial Cells by Regulating the Expression of Caspase 3

    Directory of Open Access Journals (Sweden)

    Feng Li

    2015-07-01

    Full Text Available Homocysteine (Hcy is an independent risk factor for a variety of cardiovascular diseases, such as coronary heart disease, hypertension, stroke, etc. There is a close relationship between the vascular endothelial cell apoptosis and these diseases. Recent studies have shown homocysteine can induce apoptosis in endothelial cells, which may be an important mechanism for the development of theses cardiovascular diseases. Although there are several reports about how the Hcy induces apoptosis in endothelial cells, the exact mechanism is not fully understood. MicroRNAs are small, non-coding RNA. Previous studies have shown that there is a close relationship between several microRNAs and cell apoptosis. However, there are no studies about the role of microRNAs in Hcy-induced apoptosis in endothelial cells so far. In this study, we constructed the model of homocysteine-induced apoptosis in human coronary artery endothelial cells (HCAECs and found miR-30b was significantly down-regulated by 1 mmol/L Hcy. In addition, overexpression of miR-30b can improve the Hcy-induced apoptosis in HCAECs by downregulating caspase-3 expression. Therefore, miR-30b may play an important role in Hcy-induced apoptosis in endothelial cells.

  20. The chemopreventive activity of the histone deacetylase inhibitor tributyrin in colon carcinogenesis involves the induction of apoptosis and reduction of DNA damage

    Energy Technology Data Exchange (ETDEWEB)

    Heidor, Renato [Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo (Brazil); Advanced Research Center in Food Science and Nutrition (NAPAN) and Food Research Center (FoRC), Faculty of Pharmaceutical Sciences, University of São Paulo (Brazil); Furtado, Kelly Silva; Ortega, Juliana Festa [Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo (Brazil); Oliveira, Tiago Franco de [Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo (Brazil); Tavares, Paulo Eduardo Latorre Martins; Vieira, Alessandra; Miranda, Mayara Lilian Paulino [Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo (Brazil); Purgatto, Eduardo [Laboratory of Food Chemistry and Biochemistry, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo (Brazil); Advanced Research Center in Food Science and Nutrition (NAPAN) and Food Research Center (FoRC), Faculty of Pharmaceutical Sciences, University of São Paulo (Brazil); Moreno, Fernando Salvador, E-mail: rmoreno@usp.br [Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo (Brazil); Advanced Research Center in Food Science and Nutrition (NAPAN) and Food Research Center (FoRC), Faculty of Pharmaceutical Sciences, University of São Paulo (Brazil)

    2014-04-15

    The chemopreventive activity of the histone deacetylase inhibitor (HDACi) tributyrin (TB), a prodrug of butyric acid (BA), was evaluated in a rat model of colon carcinogenesis. The animals were treated with TB (TB group: 200 mg/100 g of body weight, b.w.) or maltodextrin (MD isocaloric control group: 300 mg/100 g b.w.) daily for 9 consecutive weeks. In the 3rd and 4th weeks of treatment, the rats in the TB and MD groups were given DMH (40 mg/kg b.w.) twice a week. After 9 weeks, the animals were euthanized, and the distal colon was examined. Compared with the control group (MD group), TB treatment reduced the total number of aberrant crypt foci (ACF; p < 0.05) as well as the ACF with ≥ 4 crypts (p < 0.05), which are considered more aggressive, but not inhibited the formation of DMH-induced O6-methyldeoxyguanosine DNA adducts. The TB group also showed a higher apoptotic index (p < 0.05) and reduced DNA damage (p < 0.05) compared with MD group. TB acted as a HDACi, as rats treated with the prodrug of BA had higher levels of histone H3K9 acetylation compared with the MD group (p < 0.05). TB administration resulted in increased colonic tissue concentrations of BA (p < 0.05) compared with the control animals. These results suggest that TB can be considered a promising chemopreventive agent for colon carcinogenesis because it reduced the number of ACF, including those that were more aggressive. Induction of apoptosis and reduction of DNA damage are cellular mechanisms that appear to be involved in the chemopreventive activity of TB. - Highlights: • Tributyrin is a chemopreventive agent for rat colon aberrant crypt foci. • Tributyrin increased apoptosis in an experimental rat colon carcinogenesis model. • Tributyrin treatment in a rat colon carcinogenesis model decreased DNA damage. • Tributyrin treatment induced H3K9 acetylation in a rat colon carcinogenesis model.

  1. The chemopreventive activity of the histone deacetylase inhibitor tributyrin in colon carcinogenesis involves the induction of apoptosis and reduction of DNA damage

    International Nuclear Information System (INIS)

    Heidor, Renato; Furtado, Kelly Silva; Ortega, Juliana Festa; Oliveira, Tiago Franco de; Tavares, Paulo Eduardo Latorre Martins; Vieira, Alessandra; Miranda, Mayara Lilian Paulino; Purgatto, Eduardo; Moreno, Fernando Salvador

    2014-01-01

    The chemopreventive activity of the histone deacetylase inhibitor (HDACi) tributyrin (TB), a prodrug of butyric acid (BA), was evaluated in a rat model of colon carcinogenesis. The animals were treated with TB (TB group: 200 mg/100 g of body weight, b.w.) or maltodextrin (MD isocaloric control group: 300 mg/100 g b.w.) daily for 9 consecutive weeks. In the 3rd and 4th weeks of treatment, the rats in the TB and MD groups were given DMH (40 mg/kg b.w.) twice a week. After 9 weeks, the animals were euthanized, and the distal colon was examined. Compared with the control group (MD group), TB treatment reduced the total number of aberrant crypt foci (ACF; p < 0.05) as well as the ACF with ≥ 4 crypts (p < 0.05), which are considered more aggressive, but not inhibited the formation of DMH-induced O6-methyldeoxyguanosine DNA adducts. The TB group also showed a higher apoptotic index (p < 0.05) and reduced DNA damage (p < 0.05) compared with MD group. TB acted as a HDACi, as rats treated with the prodrug of BA had higher levels of histone H3K9 acetylation compared with the MD group (p < 0.05). TB administration resulted in increased colonic tissue concentrations of BA (p < 0.05) compared with the control animals. These results suggest that TB can be considered a promising chemopreventive agent for colon carcinogenesis because it reduced the number of ACF, including those that were more aggressive. Induction of apoptosis and reduction of DNA damage are cellular mechanisms that appear to be involved in the chemopreventive activity of TB. - Highlights: • Tributyrin is a chemopreventive agent for rat colon aberrant crypt foci. • Tributyrin increased apoptosis in an experimental rat colon carcinogenesis model. • Tributyrin treatment in a rat colon carcinogenesis model decreased DNA damage. • Tributyrin treatment induced H3K9 acetylation in a rat colon carcinogenesis model

  2. The Protective Role of Selenium on Scopolamine-Induced Memory Impairment, Oxidative Stress, and Apoptosis in Aged Rats: The Involvement of TRPM2 and TRPV1 Channels.

    Science.gov (United States)

    Balaban, Hasan; Nazıroğlu, Mustafa; Demirci, Kadir; Övey, İshak Suat

    2017-05-01

    Inhibition of Ca 2+ entry into the hippocampus and dorsal root ganglion (DRG) through inhibition of N-methyl-D-aspartate (NMDA) receptor antagonist drugs is the current standard of care in neuronal diseases such as Alzheimer's disease, dementia, and peripheral pain. Oxidative stress activates Ca 2+ -permeable TRPM2 and TRPV1, and recent studies indicate that selenium (Se) is a potent TRPM2 and TRPV1 channel antagonist in the hippocampus and DRG. In this study, we investigated the neuroprotective properties of Se in primary hippocampal and DRG neuron cultures of aged rats when given alone or in combination with scopolamine (SCOP). Thirty-two aged (18-24 months old) rats were divided into four groups. The first and second groups received a placebo and SCOP (1 mg/kg/day), respectively. The third and fourth groups received intraperitoneal Se (1.5 mg/kg/ over day) and SCOP + Se, respectively. The hippocampal and DRG neurons also were stimulated in vitro with a TRPV1 channel agonist (capsaicin) and a TRPM2 channel agonist (cumene hydroperoxide). We found that Se was fully effective in reversing SCOP-induced TRPM2 and TRPV1 current densities as well as errors in working memory and reference memory. In addition, Se completely reduced SCOP-induced oxidative toxicity by modulating lipid peroxidation, reducing glutathione and glutathione peroxidase. The Se and SCOP + Se treatments also decreased poly (ADP-ribose) polymerase activity, intracellular free Ca 2+ concentrations, apoptosis, and caspase 3, caspase 9, and mitochondrial membrane depolarization values in the hippocampus. In conclusion, the current study reports on the cellular level for SCOP and Se on the different endocytotoxic cascades for the first time. Notably, the research indicates that Se can result in remarkable neuroprotective and memory impairment effects in the hippocampal neurons of rats. Graphical abstract Possible molecular pathways of involvement of selenium (Se) in scopolamine (SCOP) induced

  3. ThDof1.4 and ThZFP1 constitute a transcriptional regulatory cascade involved in salt or osmotic stress in Tamarix hispida.

    Science.gov (United States)

    Zang, Dandan; Wang, Lina; Zhang, Yiming; Zhao, Huimin; Wang, Yucheng

    2017-07-01

    Identification of the upstream regulators of a gene is important to characterize the transcriptional pathway and the function of the gene. Previously, we found that a zinc finger protein (ThZFP1) is involved in abiotic stress tolerance of Tamarix hispida. In the present study, we further investigated the transcriptional pathway of ThZFP1. Dof motifs are abundant in the ThZFP1 promoter; therefore, we used them to screen for transcriptional regulators of ThZFP1. A Dof protein, ThDof1.4, binds to the Dof motif specifically, and was hypothesized as the upstream regulator of ThZFP1. Further study showed that overexpression of ThDof1.4 in T. hispida activated the expression of GUS controlled by the ThZFP1 promoter. In T. hispida, transient overexpression of ThDof1.4 increased the transcripts of ThZFP1; conversely, transient RNAi-silencing of ThDof1.4 reduced the expression of ThZFP1. Chromatin immunoprecipitation indicated that ThDof1.4 binds to the ThZFP1 promoter. Additionally, ThDof1.4 and ThZFP1 share similar expression patterns in response to salt or drought stress. Furthermore, like ThZFP1, ThDof1.4 could increase the proline level and enhance ROS scavenging capability to improve salt and osmotic stress tolerance. Together, these results suggested that ThDof1.4 and ThZFP1 form a transcriptional regulatory cascade involved in abiotic stress resistance in T. hispida.

  4. Identification and characterization of (E)-β-caryophyllene synthase and α/β-pinene synthase potentially involved in constitutive and herbivore-induced terpene formation in cotton.

    Science.gov (United States)

    Huang, Xinzheng; Xiao, Yutao; Köllner, Tobias G; Zhang, Wanna; Wu, Junxiang; Wu, Juan; Guo, Yuyuan; Zhang, Yongjun

    2013-12-01

    Cotton (Gossypium hirsutum L.) plants damaged by insects emit a blend of volatiles, including monoterpenes and sesquiterpenes, which can directly repel herbivores and/or indirectly protect the plant by attracting natural enemies of the herbivores. To understand the molecular basis of terpene biosynthesis and regulation in cotton, two terpene synthase genes, GhTPS1 and GhTPS2, were heterologously expressed and characterized. Recombinant GhTPS1 accepted farnesyl pyrophosphate as substrate and produced (E)-β-caryophyllene and α-humulene. GhTPS2 was characterized as a monoterpene synthase which formed α-pinene and β-pinene using geranyl pyrophosphate as substrate. Quantitative real-time PCR analysis revealed that GhTPS1 and GhTPS2 gene expression was elevated after methyl jasmonate (MeJA) treatment in cotton leaves. Moreover, feeding of the green plant bug Apolygus lucorum, a major cotton pest in northern China, resulted in increased GhTPS2 expression in young leaves, suggesting that GhTPS2 might be involved in plant defense in cotton. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  5. Induction of apoptosis in renal cell carcinoma by reactive oxygen species: involvement of extracellular signal-regulated kinase 1/2, p38delta/gamma, cyclooxygenase-2 down-regulation, and translocation of apoptosis-inducing factor.

    LENUS (Irish Health Repository)

    Ambrose, Monica

    2012-02-03

    Renal cell carcinoma (RCC) is the most common malignancy of the kidney. Unfortunately, RCCs are highly refractory to conventional chemotherapy, radiation therapy, and even immunotherapy. Thus, novel therapeutic targets need to be sought for the successful treatment of RCCs. We now report that 6-anilino-5,8-quinolinequinone (LY83583), an inhibitor of cyclic GMP production, induced growth arrest and apoptosis of the RCC cell line 786-0. It did not prove deleterious to normal renal epithelial cells, an important aspect of chemotherapy. To address the cellular mechanism(s), we used both genetic and pharmacological approaches. LY83583 induced a time- and dose-dependent increase in RCC apoptosis through dephosphorylation of mitogen-activated protein kinase kinase 1\\/2 and its downstream extracellular signal-regulated kinases (ERK) 1 and -2. In addition, we observed a decrease in Elk-1 phosphorylation and cyclooxygenase-2 (COX-2) down-regulation. We were surprised that we failed to observe an increase in either c-Jun NH(2)-terminal kinase or p38alpha and -beta mitogen-activated protein kinase activation. In contradiction, reintroduction of p38delta by stable transfection or overexpression of p38gamma dominant negative abrogated the apoptotic effect. Cell death was associated with a decrease and increase in Bcl-x(L) and Bax expression, respectively, as well as release of cytochrome c and translocation of apoptosis-inducing factor. These events were associated with an increase in reactive oxygen species formation. The antioxidant N-acetyl l-cysteine, however, opposed LY83583-mediated mitochondrial dysfunction, ERK1\\/2 inactivation, COX-2 down-regulation, and apoptosis. In conclusion, our results suggest that LY83583 may represent a novel therapeutic agent for the treatment of RCC, which remains highly refractory to antineoplastic agents. Our data provide a molecular basis for the anticancer activity of LY83583.

  6. The identification of a novel gene, MAPO2, that is involved in the induction of apoptosis triggered by O⁶-methylguanine.

    Directory of Open Access Journals (Sweden)

    Ryosuke Fujikane

    Full Text Available O⁶-Methylguanine, one of alkylated DNA bases, is especially mutagenic. Cells containing this lesion are eliminated by induction of apoptosis, associated with the function of mismatch repair (MMR proteins. A retrovirus-mediated gene-trap mutagenesis was used to isolate new genes related to the induction of apoptosis, triggered by the treatment with an alkylating agent, N-methyl-N-nitrosourea (MNU. This report describes the identification of a novel gene, MAPO2 (O⁶-methylguanine-induced apoptosis 2, which is originally annotated as C1orf201. The MAPO2 gene is conserved among a wide variety of multicellular organisms and encodes a protein containing characteristic PxPxxY repeats. To elucidate the function of the gene product in the apoptosis pathway, a human cell line derived from HeLa MR cells, in which the MAPO2 gene was stably knocked down by expressing specific miRNA, was constructed. The knockdown cells grew at the same rate as HeLa MR, thus indicating that MAPO2 played no role in the cellular growth. After exposure to MNU, HeLa MR cells and the knockdown cells underwent cell cycle arrest at G₂/M phase, however, the production of the sub-G₁ population in the knockdown cells was significantly suppressed in comparison to that in HeLa MR cells. Moreover, the activation of BAK and caspase-3, and depolarization of mitochondrial membrane, hallmarks for the induction of apoptosis, were also suppressed in the knockdown cells. These results suggest that the MAPO2 gene product might positively contribute to the induction of apoptosis triggered by O⁶-methylguanine.

  7. α-TEA-induced death receptor dependent apoptosis involves activation of acid sphingomyelinase and elevated ceramide-enriched cell surface membranes

    Directory of Open Access Journals (Sweden)

    Xiong Ailian

    2010-10-01

    Full Text Available Abstract Background Alpha-tocopherol ether-linked acetic acid (α-TEA, an analog of vitamin E (RRR-alpha-tocopherol, is a potent and selective apoptosis-inducing agent for human cancer cells in vivo and in vitro. α-TEA induces apoptosis via activation of extrinsic death receptors Fas (CD95 and DR5, JNK/p73/Noxa pathways, and suppression of anti-apoptotic mediators Akt, ERK, c-FLIP and survivin in breast, ovarian and prostate cancer cells. Results In this study, we demonstrate that α-TEA induces the accumulation of cell surface membrane ceramide, leading to co-localization with Fas, DR5, and FADD, followed by activation of caspases-8 and -9 and apoptosis in human MDA-MB-231 breast cancer cells. α-TEA treatment leads to increased acid sphingomyelinase (ASMase activity by 30 min, peaking at 4 hrs, which is correlated with ASMase translocation from cytosol to the cell surface membrane. Functional knockdown of ASMase with either the chemical inhibitor, desipramine, or siRNA markedly reduces α-TEA-induced cell surface membrane accumulation of ceramide and its co-localization with Fas, DR5, and FADD, cleavage of caspases-8 and -9 and apoptosis, suggesting an early and critical role for ASMase in α-TEA-induced apoptosis. Consistent with cell culture data, immunohistochemical analyses of tumor tissues taken from α-TEA treated nude mice bearing MDA-MB-231 xenografts show increased levels of cell surface membrane ceramide in comparison to tumor tissues from control animals. Conclusion Taken together, these studies demonstrate that ASMase activation and membrane ceramide accumulation are early events contributing to α-TEA-induced apoptosis in vitro and perhaps in vivo.

  8. Constitutional changes and the dilemmas of constitutionalism

    OpenAIRE

    Bačić, Arsen

    2009-01-01

    The need to develop constitutional mechanisms whose aim is to resolve fundamental relations in society demands the widest possible inclusion of all of society’s active participants in the discussion on the need to adopt or revise the Constitution. The opening of every new round of constitutional changes is of great importance because it always unlocks certain new and important questions. The answers to those questions should be offered by state authority (policy) and civil society including s...

  9. Hypoxia-inducible transcription factor-1α promotes hypoxia-induced A549 apoptosis via a mechanism that involves the glycolysis pathway

    International Nuclear Information System (INIS)

    Luo, FengMing; Liu, XiaoJing; Yan, NaiHong; Li, ShuangQing; Cao, GuiQun; Cheng, QingYing; Xia, QingJie; Wang, HongJing

    2006-01-01

    Hypoxia-inducible transcription factor-1α (HIF-1α), which plays an important role in controlling the hypoxia-induced glycolysis pathway, is a 'master' gene in the tissue hypoxia response during tumor development. However, its role in the apoptosis of non-small cell lung cancer remains unknown. Here, we have studied the effects of HIF-1α on apoptosis by modulating HIF-1α gene expression in A549 cells through both siRNA knock-down and over-expression. A549 cells were transfected with a HIF-1α siRNA plasmid or a HIF-1α expression vector. Transfected cells were exposed to a normoxic or hypoxic environment in the presence or absence of 25 mM HEPES and 2-deoxyglucose (2-DG) (5 mM). The expression of three key genes of the glycolysis pathway, glucose transporter type 1(GLUT1), phosphoglycerate kinase 1(PGK1), and hexokinase 1(HK1), were measured using real-time RT-PCR. Glycolysis was monitored by measuring changes of pH and lactate concentration in the culture medium. Apoptosis was detected by TUNEL assay and flow cytometry. Knocking down expression of HIF-1α inhibited the glycolysis pathway, increased the pH of the culture medium, and protected the cells from hypoxia-induced apoptosis. In contrast, over-expression of HIF-1α accelerated glycolysis in A549 cells, decreased the pH of the culture medium, and enhanced hypoxia-induced apoptosis. These effects of HIF-1α on glycolysis, pH of the medium, and apoptosis were reversed by treatment with the glycolytic inhibitor, 2-DG. Apoptosis induced by HIF-1α over-expression was partially inhibited by increasing the buffering capacity of the culture medium by adding HEPES. During hypoxia in A549 cells, HIF-1α promotes activity of the glycolysis pathway and decreases the pH of the culture medium, resulting in increased cellular apoptosis

  10. Hydra constitutively expresses transcripts involved in vertebrate ...

    Indian Academy of Sciences (India)

    Unknown

    participate in axis and head formation in Hydra too. In the present study we have employed cross-hybridization to detect noggin-like transcripts in Pelmatohydra oligactis. Noggin is crucial for nervous system development in. Xenopus (Smith and Harland 1992), chick (Connolly et al. 1997) and mammals (Bachiller et al 2000) ...

  11. Hydra constitutively expresses transcripts involved in vertebrate ...

    Indian Academy of Sciences (India)

    Unknown

    pus goosecoid clones and Dr Vidya Patwardhan for discus- sions. References. Bachiller D, Klingensmith J, Kemp C, Belo J A, Anderson,. R M, May S R, McMohan J A, McMohan A P, Harland R M,. Rossant J and De Robertis E M 2000 The organizer factors chordin and noggin are required for mouse forebrain deve-.

  12. Annona muricata leaves induced apoptosis in A549 cells through mitochondrial-mediated pathway and involvement of NF-κB.

    Science.gov (United States)

    Moghadamtousi, Soheil Zorofchian; Kadir, Habsah Abdul; Paydar, Mohammadjavad; Rouhollahi, Elham; Karimian, Hamed

    2014-08-15

    Annona muricata leaves have been reported to have antiproliferative effects against various cancer cell lines. However, the detailed mechanism has yet to be defined. The current study was designed to evaluate the molecular mechanisms of A. muricata leaves ethyl acetate extract (AMEAE) against lung cancer A549 cells. The effect of AMEAE on cell proliferation of different cell lines was analyzed by MTT assay. High content screening (HCS) was applied to investigate the suppression of NF-κB translocation, cell membrane permeability, mitochondrial membrane potential (MMP) and cytochrome c translocation from mitochondria to cytosol. Reactive oxygen species (ROS) formation, lactate dehydrogenase (LDH) release and activation of caspase-3/7, -8 and -9 were measured while treatment. The western blot analysis also carried out to determine the protein expression of cleaved caspase-3 and -9. Flow cytometry analysis was used to determine the cell cycle distribution and phosphatidylserine externalization. Quantitative PCR analysis was performed to measure the gene expression of Bax and Bcl-2 proteins. Cell viability analysis revealed the selective cytotoxic effect of AMEAE towards lung cancer cells, A549, with an IC50 value of 5.09 ± 0.41 μg/mL after 72 h of treatment. Significant LDH leakage and phosphatidylserine externalization were observed in AMEAE treated cells by fluorescence analysis. Treatment of A549 cells with AMEAE significantly elevated ROS formation, followed by attenuation of MMP via upregulation of Bax and downregulation of Bcl-2, accompanied by cytochrome c release to the cytosol. The incubation of A549 cells with superoxide dismutase and catalase significantly attenuated the cytotoxicity caused by AMEAE, indicating that intracellular ROS plays a pivotal role in cell death. The released cytochrome c triggered the activation of caspase-9 followed by caspase-3. In addition, AMEAE-induced apoptosis was accompanied by cell cycle arrest at G0/G1 phase. Moreover

  13. BcR-induced apoptosis involves differential regulation of C-16 and C-24-ceramide formation and sphingolipid-dependent activation of the proteasome

    NARCIS (Netherlands)

    Kroesen, BJ; Jacobs, Susan; Pettus, BJ; Sietsma, H; Kok, JW; Hannun, YA; de Leij, LFMH

    2003-01-01

    In this study, we describe an ordered formation of long- and very long-chain ceramide species in relation to the progression of B-cell receptor (BcR) triggering induced apoptosis. An early and caspase-independent increase in long-chain ceramide species, in which C-24-ceramide predominated, was

  14. Fluorochloridone induces primary cultured Sertoli cells apoptosis: Involvement of ROS and intracellular calcium ions-mediated ERK1/2 activation.

    Science.gov (United States)

    Liu, Luqing; Chang, Xiuli; Zhang, Yubin; Wu, Chunhua; Li, Rui; Tang, Liming; Zhou, Zhijun

    2018-03-01

    Fluorochloridone (FLC) is a widely used pyrrolidone selective herbicide and reported to induce testis injuries in male rats, but the underlying mechanism is largely unknown. In the present study, primary-cultured Sertoli cells were exposed to FLC at the concentration of 0-10.00μM to study the mechanism of FLC-induced apoptosis. The roles of ROS, intracellular calcium, endoplasmic reticulum (ER), and ERK1/2 were looked at with ROS scavenger N-acetyl-cysteine (NAC), intracellular calcium chelator BAPTA-AM, ER calcium depleting agent thapsigargin (TG), and ERK1/2 inhibitor U0126, respectively. FLC induced dose-dependent apoptosis increase as well as the elevation in levels of ROS, intracellular calcium, and ERK1/2 activation. FLC treatment led to constantly increasing apoptotic rates and ERK1/2 activation over time, while inversed-V shaped change tendencies of ROS and intracellular calcium levels were observed. FLC-induced ROS generation disrupted the intracellular calcium homeostasis by attacking the ER, and the elevated intracellular calcium levels resulted in ERK1/2 over-phosphorylation and consequently promoted Sertoli cell apoptosis. Taken together, ROS and intracellular calcium-mediated ERK1/2 activation led to FLC-induced Sertoli cell apoptosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Apoptosis induced by lipid-associated membrane proteins from Mycoplasma hyopneumoniae in a porcine lung epithelial cell line with the involvement of caspase 3 and the MAPK pathway.

    Science.gov (United States)

    Ni, B; Bai, F F; Wei, Y; Liu, M J; Feng, Z X; Xiong, Q Y; Hua, L Z; Shao, G Q

    2015-09-25

    Lipid-associated membrane proteins (LAMPs) are important in the pathogenicity of the Mycoplasma genus of bacteria. We investigated whether Mycoplasma hyopneumoniae LAMPs have pathogenic potential by inducing apoptosis in a St. Jude porcine lung epithelial cell line (SJPL). LAMPs from a pathogenic strain of M. hyopneumoniae (strain 232) were used in the research. Our investigation made use of diamidino-phenylindole (DAPI) and acridine orange/ethidium bromide (AO/EB) staining, terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) analysis, and Annexin-V-propidium iodide staining. After LAMP treatment for 24 h, typical changes were induced, chromosomes were concentrated, apoptotic bodies were observed, the 3'-OH groups of cleaved genomes were exposed, and the percentage of apoptotic cells reached 36.5 ± 11.66%. Caspase 3 and caspase 8 were activated and cytochrome c (cyt c) was released from the mitochondria into the cytoplasm; poly ADP ribose polymerase (PARP) was digested into two fragments; p38 mitogen-activated protein kinase (MAPK) was phosphorylated; and the expression of pro-apoptosis protein Bax increased while the anti-apoptosis protein Bcl-2 decreased. LAMPs also stimulated SJPL cells to produce nitric oxide (NO) and superoxide. This study demonstrated that LAMPs from M. hyopneumoniae can induce apoptosis in SJPL cells through the activation of caspase 3, caspase 8, cyt c, Bax, and p38 MAPK, thereby contributing to our understanding of the pathogenesis of M. hyopneumoniae, which should improve the treatment of M. hyopneumoniae infections.

  16. Identification of MicroRNAs Involved in Growth Arrest and Apoptosis in Hydrogen Peroxide-Treated Human Hepatocellular Carcinoma Cell Line HepG2

    Directory of Open Access Journals (Sweden)

    Yuan Luo

    2016-01-01

    Full Text Available Although both oxidative stress and microRNAs (miRNAs play vital roles in physiological and pathological processes, little is known about the interactions between them. In this study, we first described the regulation of H2O2 in cell viability, proliferation, cycle, and apoptosis of human hepatocellular carcinoma cell line HepG2. Then, miRNAs expression was profiled after H2O2 treatment. The results showed that high concentration of H2O2 (600 μM could decrease cell viability, inhibit cell proliferation, induce cell cycle arrest, and finally promote cell apoptosis. Conversely, no significant effects could be found under treatment with low concentration (30 μM. miRNAs array analysis identified 131 differentially expressed miRNAs (125 were upregulated and 6 were downregulated and predicted 13504 putative target genes of the deregulated miRNAs. Gene ontology (GO analysis revealed that the putative target genes were associated with H2O2-induced cell growth arrest and apoptosis. The subsequent bioinformatics analysis indicated that H2O2-response pathways, including MAPK signaling pathway, apoptosis, and pathways in cancer and cell cycle, were significantly affected. Overall, these results provided comprehensive information on the biological function of H2O2 treatment in HepG2 cells. The identification of miRNAs and their putative targets may offer new diagnostic and therapeutic strategies for liver cancer.

  17. utilizing constitutional values in constitutional comparison

    African Journals Online (AJOL)

    Administrator

    a distinct set of commonalities, principles, standards and values that have gained currency in constitutional dialogue all over the world. Perhaps the best proof of this ripeness of constitutionalism is to be found in the signs that new, postmodern thinking about the state, the law and the sustainability of the established tenets of.

  18. III-10, a newly synthesized flavonoid, induces cell apoptosis with the involvement of reactive oxygen species-mitochondria pathway in human hepatocellular carcinoma cells.

    Science.gov (United States)

    Dai, Qinsheng; Yin, Qian; Zhao, Yikai; Guo, Ruichen; Li, Zhiyu; Ma, Shiping; Lu, Na

    2015-10-05

    Study of the mechanisms of apoptosis in tumor cells is an important field of tumor therapy and cancer molecular biology. We recently established that III-10, a new flavonoid with a pyrrolidinyl and a benzyl group substitution, exerted its anti-tumor effect via inducing differentiation of human U937 leukemia cells. In this study, we demonstrated that III-10 induced cell apoptosis in human hepatocellular carcinoma cells. The activation of caspase-3, caspase-9, and the increased expression ratio of Bax/Bcl-2 were detected in III-10-induced apoptosis. Z-VAD-FMK, a pan-caspase inhibitor, partly attenuated the apoptotic induction of III-10 on both HepG2 and BEL-7402 cells. Furthermore, the increase of intracellular reactive oxygen species levels and the reduction of mitochondria ΔΨm were also observed in BEL-7402 and HepG2 cells after the treatment of III-10. Pretreatment with NAC, a reactive oxygen species production inhibitor, partly attenuated the apoptosis induced by III-10 via blocking the reactive oxygen species generation. Our data also showed that III-10 induced the release of cytochrome c and AIF to cytosol followed after the reactive oxygen species accumulation. Moreover, the GSH levels and ATP generation were both inhibited after III-10 treatment. Besides, the MAPK, the downstream effect of reactive oxygen species accumulation including JNK could be activated by III-10, as well as the inactivation of ERK. Collectively, the generation of reactive oxygen species might play an crucial role in III-10-induced mitochondrial apoptosis pathway, provided more stubborn evidence for III-10 as a potent anticancer therapeutic candidate. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. N-methyl-d-aspartate receptor-mediated calcium overload and endoplasmic reticulum stress are involved in interleukin-1beta-induced neuronal apoptosis in rat hippocampus.

    Science.gov (United States)

    Dong, Yilong; Kalueff, Allan V; Song, Cai

    2017-06-15

    Increased levels of interleukin (IL)-1β and its gene expression are implicated in the etiology of Alzheimer's disease (AD). IL-1β activates microglia and stimulates glutamatergic N-methyl-d-aspartate receptor NMDA receptor expression, thereby disturbing intracellular Ca 2+ homeostasis. Ca 2+ disequilibrium, in turn, may trigger endoplasmic reticulum (ER) stress, contributing to overall excitotoxicity and neuronal death that evoke AD. However, it is unclear whether IL-1β-induced neuronal apoptosis is mediated by the glutamatergic system, ER stress and/or Ca 2+ dysfunction. The present study investigated the role of NMDA receptor (NMDAR) in ER stress and IL-1β-evoked neuronal death by assessing NMDAR-induced Ca 2+ overload and NMDA-mediated ER stress. Male Long Evans rats were treated with IL-1β (with or without NMDAR antagonist MK801) injected intracerebroventricularly for 8days. Glutamate concentration was measured by HPLC, and mRNA and protein expression of microglial biomarkers and NMDAR, as well as markers of Ca 2+ overload (caplain2) and ER stress (glucose-regulated protein 78, GRP78, and C/EBP homologous protein-10, CHOP), were assessed by real-time PCR and western blot. Apoptosis was also evaluated in the hippocampal neurons using TUNEL. Overall, IL-1β induced robust neuronal apoptosis, accompanied by upregulated NMDAR, caplain2, GRP78 and CHOP. MK801 pretreatment significantly attenuated neuronal apoptosis and NMDA up-regulation, also reducing GRP78 and CHOP expression. In summary, these results suggest that IL-1β may disturb intracellular Ca 2+ homeostasis via NMDAR-mediated mechanism, thereby triggering neuronal apoptosis by enhancing ER stress. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: the involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway.

    Science.gov (United States)

    Jo, Guk Heui; Kim, Gi-Young; Kim, Wun-Jae; Park, Kun Young; Choi, Yung Hyun

    2014-10-01

    Sulforaphane, a naturally occurring isothiocyanate found in cruciferous vegetables, has received a great deal of attention because of its ability to inhibit cell proliferation and induce apoptosis in cancer cells. In this study, we investigated the anticancer activity of sulforaphane in the T24 human bladder cancer line, and explored its molecular mechanism of action. Our results showed that treatment with sulforaphane inhibited cell viability and induced apoptosis in T24 cells in a concentration-dependent manner. Sulforaphane-induced apoptosis was associated with mitochondria dysfunction, cytochrome c release and Bcl-2/Bax dysregulation. Furthermore, the increased activity of caspase-9 and -3, but not caspase-8, was accompanied by the cleavage of poly ADP-ribose polymerase, indicating the involvement of the mitochondria-mediated intrinsic apoptotic pathway. Concomitant with these changes, sulforaphane triggered reactive oxygen species (ROS) generation, which, along with the blockage of sulforaphane-induced loss of mitochondrial membrane potential and apoptosis, was strongly attenuated by the ROS scavenger N-acetyl-L-cysteine. Furthermore, sulforaphane was observed to activate endoplasmic reticulum (ER) stress and the nuclear factor-E2-related factor-2 (Nrf2) signaling pathway, as demonstrated by the upregulation of ER stress‑related proteins, including glucose-regulated protein 78 and C/EBP-homologous protein, and the accumulation of phosphorylated Nrf2 proteins in the nucleus and induction of heme oxygenase-1 expression, respectively. Taken together, these results demonstrate that sulforaphane has antitumor effects against bladder cancer cells through an ROS-mediated intrinsic apoptotic pathway, and suggest that ER stress and Nrf2 may represent strategic targets for sulforaphane-induced apoptosis.

  1. Cardiovascular molecular imaging of apoptosis

    International Nuclear Information System (INIS)

    Wolters, S.L.; Reutelingsperger, C.P.M.; Corsten, M.F.; Hofstra, L.; Narula, J.

    2007-01-01

    Molecular imaging strives to visualise processes at the molecular and cellular level in vivo. Understanding these processes supports diagnosis and evaluation of therapeutic efficacy on an individual basis and thereby makes personalised medicine possible. Apoptosis is a well-organised mode of cell suicide that plays a role in cardiovascular diseases (CVD). Apoptosis is associated with loss of cardiomyocytes following myocardial infarction, atherosclerotic plaque instability, congestive heart failure and allograft rejection of the transplanted heart. Thus, apoptosis constitutes an attractive target for molecular imaging of CVD. Our current knowledge about the molecular players and mechanisms underlying apoptosis offers a rich palette of potential molecular targets for molecular imaging. However, only a few have been successfully developed so far. This review highlights aspects of the molecular machinery and biochemistry of apoptosis relevant to the development of molecular imaging probes. It surveys the role of apoptosis in four major areas of CVD and portrays the importance and future perspectives of apoptosis imaging. The annexin A5 imaging protocol is emphasised since it is the most advanced protocol to measure apoptosis in both preclinical and clinical studies. (orig.)

  2. Cardiovascular molecular imaging of apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Wolters, S.L.; Reutelingsperger, C.P.M. [Maastricht University, Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht (Netherlands); Corsten, M.F.; Hofstra, L. [Maastricht University, Department of Cardiology, Cardiovascular Research Institute Maastricht, P.O. Box 616, Maastricht (Netherlands); Narula, J. [University of California Irvine, Department of Cardiology, Irvine (United States)

    2007-06-15

    Molecular imaging strives to visualise processes at the molecular and cellular level in vivo. Understanding these processes supports diagnosis and evaluation of therapeutic efficacy on an individual basis and thereby makes personalised medicine possible. Apoptosis is a well-organised mode of cell suicide that plays a role in cardiovascular diseases (CVD). Apoptosis is associated with loss of cardiomyocytes following myocardial infarction, atherosclerotic plaque instability, congestive heart failure and allograft rejection of the transplanted heart. Thus, apoptosis constitutes an attractive target for molecular imaging of CVD. Our current knowledge about the molecular players and mechanisms underlying apoptosis offers a rich palette of potential molecular targets for molecular imaging. However, only a few have been successfully developed so far. This review highlights aspects of the molecular machinery and biochemistry of apoptosis relevant to the development of molecular imaging probes. It surveys the role of apoptosis in four major areas of CVD and portrays the importance and future perspectives of apoptosis imaging. The annexin A5 imaging protocol is emphasised since it is the most advanced protocol to measure apoptosis in both preclinical and clinical studies. (orig.)

  3. Physician Education: Apoptosis.

    Science.gov (United States)

    Kataoka; Tsuruo

    1996-01-01

    We have come to understand apoptosis as not merely a single form of cell death, but as a fundamental theme in cell biology that has far-reaching implications in the fields of physiology and pathology. At the present time, however, the mechanism of apoptosis is not clearly understood, as research into apoptosis is still at the initial stages. Nevertheless, the links between apoptosis and a variety of pathological conditions are gradually becoming clearer. In this article, we will provide a simple explanation of apoptosis and its mechanism as a novel concept of cell death and discuss the way in which apoptosis has been linked to a variety of pathological conditions. WHAT IS APOPTOSIS?: In normal tissue, cells that are no longer needed are rapidly eliminated without affecting the overall function of the tissue. In this process cells undergo an active and spontaneous suicide called programmed cell death. In fact, the majority of physiological cell deaths take the form of apoptosis. The word apoptosis is used, in contrast to necrosis, to describe the situation in which a cell actively pursues a course toward death upon receiving certain stimuli [1]. The morphological changes of apoptosis found in most cell types first involve contraction in cell volume and condensation of the nucleus. When this happens the intracellular organelles such as the mitochondria retain their normal morphology. As apoptosis proceeds, blebbing of the plasma membrane occurs, and the nucleus becomes fragmented. Finally, the cell itself fragments to form apoptotic bodies that are engulfed by nearby phagocytes. With respect to biochemical changes, it is known that the chromosomes become fragmented into nucleosome units, and DNA forms characteristic ladder patterns when subjected to agarose gel electrophoresis. MECHANISM OF APOPTOSIS: It has been reported that apoptosis is induced in various cells by many kinds of irritations, but the precise mechanism is still unclear. Cell injuries that induce

  4. PRR7 Is a transmembrane adaptor protein expressed in activated T cells involved in regulation of T cell receptor signaling and apoptosis

    Czech Academy of Sciences Publication Activity Database

    Hrdinka, Matouš; Dráber, Peter; Štěpánek, Ondřej; Ormsby, Tereza; Otáhal, Pavel; Angelisová, Pavla; Brdička, Tomáš; Pačes, Jan; Hořejší, Václav; Drbal, Karel

    2011-01-01

    Roč. 286, č. 22 (2011), s. 19617-19629 ISSN 0021-9258 R&D Projects: GA MŠk 1M0506 Grant - others:GAČR(CZ) MEM/09/E011 Institutional research plan: CEZ:AV0Z50520514 Keywords : PRR7 * transmembrane adaptor protein * apoptosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.773, year: 2011

  5. Estrogen receptor-α36 is involved in pterostilbene-induced apoptosis and anti-proliferation in in vitro and in vivo breast cancer.

    Directory of Open Access Journals (Sweden)

    Chi Pan

    Full Text Available Pterostilbene (trans-3,5-dimethoxy-4'-hudroxystilbene is an antioxidant primarily found in blueberries. It also inhibits breast cancer regardless of conventional estrogen receptor (ER-α66 status by inducing both caspase-dependent and caspase-independent apoptosis. However, the pterostilbene-induced apoptosis rate in ER-α66-negative breast cancer cells is much higher than that in ER-α66-positive breast cancer cells. ER-α36, a variant of ER-α66, is widely expressed in ER-α66-negative breast cancer, and its high expression mediates the resistance of ER-α66-positive breast cancer patients to tamoxifen therapy. The aim of the present study is to determine the relationship between the antiproliferation activity of pterostilbene and ER-α36 expression in breast cancer cells. Methyl-thiazolyl-tetrazolium (MTT assay, apoptosis analysis, and an orthotropic xenograft mouse model were used to examine the effects of pterostilbene on breast cancer cells. The expressions of ER-α36 and caspase 3, the activation of ERK and Akt were also studied through RT-PCR, western blot analysis, and immunohistochemical (IHC staining. ER-α36 knockdown was found to desensitize ER-α66-negative breast cancer cells to pterostilbene treatment both in vitro and in vivo, and high ER-α36 expression promotes pterostilbene-induced apoptosis in breast cancer cells. Western blot analysis data indicate that MAPK/ERK and PI3K/Akt signaling in breast cancer cells with high ER-α36 expression are mediated by ER-α36, and are inhibited by pterostilbene. These results suggest that ER-α36 is a therapeutic target in ER-α36-positive breast cancer, and pterostilbene is an inhibitor that targets ER-α36 in the personalized therapy against ER-α36-positive breast cancer.

  6. Involvement of GDH3-encoded NADP+-dependent glutamate dehydrogenase in yeast cell resistance to stress-induced apoptosis in stationary phase cells.

    Science.gov (United States)

    Lee, Yong Joo; Kim, Kyung Jin; Kang, Hong Yong; Kim, Hye-Rim; Maeng, Pil Jae

    2012-12-28

    Glutamate metabolism is linked to a number of fundamental metabolic pathways such as amino acid metabolism, the TCA cycle, and glutathione (GSH) synthesis. In the yeast Saccharomyces cerevisiae, glutamate is synthesized from α-ketoglutarate by two NADP(+)-dependent glutamate dehydrogenases (NADP-GDH) encoded by GDH1 and GDH3. Here, we report the relationship between the function of the NADP-GDH and stress-induced apoptosis. Gdh3-null cells showed accelerated chronological aging and hypersusceptibility to thermal and oxidative stress during stationary phase. Upon exposure to oxidative stress, Gdh3-null strains displayed a rapid loss in viability associated with typical apoptotic hallmarks, i.e. reactive oxygen species accumulation, nuclear fragmentation, DNA breakage, and phosphatidylserine translocation. In addition, Gdh3-null cells, but not Gdh1-null cells, had a higher tendency toward GSH depletion and subsequent reactive oxygen species accumulation than did WT cells. GSH depletion was rescued by exogenous GSH or glutamate. The hypersusceptibility of stationary phase Gdh3-null cells to stress-induced apoptosis was suppressed by deletion of GDH2. Promoter swapping and site-directed mutagenesis of GDH1 and GDH3 indicated that the necessity of GDH3 for the resistance to stress-induced apoptosis and chronological aging is due to the stationary phase-specific expression of GDH3 and concurrent degradation of Gdh1 in which the Lys-426 residue plays an essential role.

  7. Oridonin effectively reverses the drug resistance of cisplatin involving induction of cell apoptosis and inhibition of MMP expression in human acute myeloid leukemia cells

    Directory of Open Access Journals (Sweden)

    Yuan Zhang

    2017-03-01

    Full Text Available Cisplatin is the first generation platinum-based chemotherapy agent. However, the extensive application of cisplatin inevitably causes drug resistance, which is a major obstacle to cancer chemotherapy. Oridonin is a diterpenoid isolated from Rabdosia rubescens with potent anticancer activity. The aim of our study is to investigate the role of oridonin to reverse the cisplatin-resistance in human acute myeloid leukemia (AML cells. The effect of oridonin on human AML cell proliferation was evaluated by MTT assay, cell migration and invasion were evaluated by transwell migration and invasion assays in cisplatin-resistant human AML cells. Furthermore, cell apoptosis was examined by flow cytometry. The inhibitive effect of oridonin in vivo was determined using xenografted nude mice. In addition, the expressions of MMP2 and MMP9 were detected by Western blot. There was a synergistic antitumor effect between cisplatin and oridonin on cisplatin-resistant human AML cells in vitro and in vivo. In addition, the combination of cisplatin and oridonin synergistically induced cell apoptosis. Furthermore, the combination treatment not only inhibited AML cell migration and invasion, but more significantly, decreased the expressions of MMP2 and MMP9 proteins. Our results suggest that the synergistic effect between both agents is likely to be driven by the inhibition of MMP expression and the resulting increased apoptosis.

  8. Changes of caspase activities involved in apoptosis of a macrophage-like cell line J774.1/JA-4 treated with lipopolysaccharide (LPS) and cycloheximide.

    Science.gov (United States)

    Karahashi, H; Amano, F

    2000-02-01

    The addition of lipopolysaccharide (LPS) together with cycloheximide (CHX) induced apoptosis in a subline of a J774.1 macrophage-like cell line, JA-4, as judged by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL)-staining and poly(adenosine 5'-diphosphate (ADP)-ribose) polymerase (PARP)-cleavage. Caspase activities were examined in these macrophages in vitro using fluorogenic substrates such as acetyl-DEVD-aminomethyl coumarine (Ac-DEVD-AMC, caspase-3-like), acetyl-YVAD-aminomethyl coumarine (Ac-YVAD-AMC, caspase-1-like), acetyl-VEID-aminomethyl coumarine (Ac-VEID-AMC, caspase-6-like), and carbobenzoxy-IETD-aminofluoro coumarine (Z-IETD-AFC; caspase-8-like). Kinetic studies revealed these caspase activities with different Km and Vmax values in extracts of apoptotic macrophages. In the course of apoptosis, caspase-3-like activity increased first at 75 min, simultaneously with the appearance of TUNEL staining and prior to PARP cleavage, and then caspase-6 and 8-like activities increased at 90 and 105 min, respectively. However, caspase-1-like activity did not change throughout the experiment. Furthermore, removal of LPS and CHX by extensive washing of the cells for 60 min completely abolished the apoptosis and the subsequent release of lactate dehydrogenase (LDH) during additional incubation until 4 h after LPS addition. However, washing of the cells after 75 min or later resulted in the progress of apoptosis and LDH release, which was coordinated with the elevation of caspase-3-like activity at 60 min and that of caspase-6 or 8-like activity at 90 min, but not with that of caspase-1-like activity. These results suggest that caspase-3-like activity represents the most apical caspase among these caspases in terms of the intiation of apoptosis in macrophages treated with LPS and CHX. In the present study, we also provide evidence on the relatively low specificities of a series of caspase inhibitors other

  9. Indomethacin-Induced Apoptosis in Esophageal Adenocarcinoma Cells Involves Upregulation of Bax and Translocation of Mitochondrial Cytochrome C Independent of COX-2 Expression

    Directory of Open Access Journals (Sweden)

    Sanjeev Aggarwal

    2000-07-01

    Full Text Available The prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs has been shown to exert a chemopreventive effect in esophageal and other gastrointestinal tumors. The precise mechanism by which this occurs, however, is unknown. While the inhibition of COX-2 as a potential explanation for this chemopreventive effect has gained a great deal of support, there also exists evidence supporting the presence of cyclooxygenase-independent pathways through which NSAIDs may exert their effects. In this study, immunohistochemical analysis of 29 Barrett's epithelial samples and 60 esophageal adenocarcinomas demonstrated abundant expression of the COX-2 protein in Barrett's epithelium, but marked heterogeneity of expression in esophageal adenocarcinomas. The three esophageal adenocarcinoma cell lines, Flo-1, Bic-1, Seg-1, also demonstrated varying expression patterns for COX-1 and COX-2. Indomethacin induced apoptosis in all three cell lines, however, in both a time- and dose-dependent manner. In Flo-1 cells, which expressed almost undetectable levels of COX-1 and COX-2, in Seg-1, which expressed significant levels of COX-1 and COX-2, indomethacin caused upregulation of the pro-apoptosic protein Bax. The upregulation of Bax was accompanied by the translocation of mitochondrial cytochrome c to the cytoplasm, activation of caspase 9. Pre-treatment of both cell lines with the specific caspase 9 inhibitor, z-LEHD-FMK, as well as the broad-spectrum caspase inhibitor, z-VAD-FMK, blocked the effect of indomethacin-induced apoptosis. These data demonstrate that induction of apoptosis by indomethacin in esophageal adenocarcinoma cells is associated with the upregulation of Bax expression and mitochondrial cytochrome c translocation, does not correlate with the expression of COX-2. This may have important implications for identifying new therapeutic targets in this deadly disease.

  10. Hexavalent chromium-induced apoptosis of granulosa cells involves selective sub-cellular translocation of Bcl-2 members, ERK1/2 and p53

    International Nuclear Information System (INIS)

    Banu, Sakhila K.; Stanley, Jone A.; Lee, JeHoon; Stephen, Sam D.; Arosh, Joe A.; Hoyer, Patricia B.; Burghardt, Robert C.

    2011-01-01

    Hexavalent chromium (CrVI) has been widely used in industries throughout the world. Increased usage of CrVI and atmospheric emission of CrVI from catalytic converters of automobiles, and its improper disposal causes various health hazards including female infertility. Recently we have reported that lactational exposure to CrVI induced a delay/arrest in follicular development at the secondary follicular stage. In order to investigate the underlying mechanism, primary cultures of rat granulosa cells were treated with 10 μM potassium dichromate (CrVI) for 12 and 24 h, with or without vitamin C pre-treatment for 24 h. The effects of CrVI on intrinsic apoptotic pathway(s) were investigated. Our data indicated that CrVI: (i) induced DNA fragmentation and increased apoptosis, (ii) increased cytochrome c release from the mitochondria to cytosol, (iii) downregulated anti-apoptotic Bcl-2, Bcl-XL, HSP70 and HSP90; upregulated pro-apoptotic BAX and BAD, (iv) altered translocation of Bcl-2, Bcl-XL, BAX, BAD, HSP70 and HSP90 to the mitochondria, (v) upregulated p-ERK and p-JNK, and selectively translocated p-ERK to the mitochondria and nucleus, (vi) activated caspase-3 and PARP, and (vii) increased phosphorylation of p53 at ser-6, ser-9, ser-15, ser-20, ser-37, ser-46 and ser-392, increased p53 transcriptional activation, and downregulated MDM-2. Vitamin C pre-treatment mitigated CrVI effects on apoptosis and related pathways. Our study, for the first time provides a clear insight into the effect of CrVI on multiple pathways that lead to apoptosis of granulosa cells which could be mitigated by vitamin C.

  11. Involvement of NF-κB and HSP70 signaling pathways in the apoptosis of MDA-MB-231 cells induced by a prenylated xanthone compound, α-mangostin, from Cratoxylum arborescens [Corrigendum] [Retraction

    Directory of Open Access Journals (Sweden)

    Ibrahim MY

    2018-03-01

    Full Text Available Ibrahim MY, Hashim NM, Mohan S, et al. Involvement of NF-κB and HSP70 signaling pathways in the apoptosis of MDA-MB-231 cells induced by a prenylated xanthone compound, α-mangostin, from Cratoxylum arborescens [Corrigendum]. Drug Des Devel Ther. 2015;9:3001–3002 was published subsequent to Ibrahim MY, Hashim NM, Mohan S, et al, Involvement of NF-ΚB and HSP70 signaling pathways in the apoptosis of MDA-MB-231 cells induced by a prenylated xanthone compound, α-mangostin, from Cratoxylum arborescens. Drug Des Devel Ther. 2014;8:2193–2211, and Ibrahim MY, Hashim NM, Mohan S, et al, α-Mangostin from Cratoxylum arborescens demonstrates apoptogenesis in MCF-7 with regulation of NF-κB and Hsp70 protein modulation in vitro, and tumor reduction in vivo. Drug Des Devel Ther. 2014;8:1629–1647.When comparing the papers it becomes apparent that they have an unacceptably high degree of similarity and re-use. Further, there is no clear scientific distinction between the cell lines and the results in both. Accordingly, the Editor-in-Chief and Publisher issued a Notice of Retraction for Ibrahim MY, Hashim NM, Mohan S, et al, Involvement of NF-ΚB and HSP70 signaling pathways in the apoptosis of MDA-MB-231 cells induced by a prenylated xanthone compound, α-mangostin, from Cratoxylum arborescens. Drug Des Devel Ther. 2014;8:2193–2211 and the subsequent Corrigendum. This retraction relates to this Corrigendum 

  12. Involvement of NF-?B and HSP70 signaling pathways in the apoptosis of MDA-MB-231 cells induced by a prenylated xanthone compound, ?-mangostin, from Cratoxylum arborescens [Retraction

    OpenAIRE

    2017-01-01

    Ibrahim MY, Hashim NM, Mohan S, et al. Involvement of NF-κB and HSP70 signaling pathways in the apoptosis of MDA-MB-231 cells induced by a prenylated xanthone compound, α-mangostin, from Cratoxylum arborescens. Drug Design, Development and Therapy. 2014;8:2193–2211 was published subsequent to Ibrahim MY, Hashim NM, Mohan S, et al. α-Mangostin from Cratoxylum arborescens demonstrates apoptogenesis in MCF-7 with regulation of NF-κB and Hsp70 pro...

  13. UNDERSTANDING INFORMAL CONSTITUTIONAL CHANGE

    Directory of Open Access Journals (Sweden)

    Stephen M. Griffin

    2016-01-01

    Full Text Available Amid much recent American work on the problem of informal constitutional change, this article stakes out a distinctive position. I argue that theories of constitutional change in the US must address the question of the relationship between the “small c” and “big C” Constitution and treat seriously the possibility of conflict between them. I stress the unavoidable role the text of the Constitution and structural doctrines of federalism and separation of powers play in this relationship and thus in constitutional change, both formal and informal. I therefore counsel against theories that rely solely on a practice-based approach or analogies between “small c” constitutional developments and British or Commonwealth traditions of the “unwritten” constitution and constitutional “conventions.” The alternative I advocate is to approach constitutional change from a historicist perspective that focuses attention on state building and the creation of new institutional capacities. This approach will allow us to make progress by highlighting that there can be multiple constitutional orders in a given historical era, thus accounting for the conflictual nature of contemporary constitutional development in the US.

  14. Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Xue [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001 (China); Li, Ling [Department of Brain Cognition Computing Lab, University of Kent, Kent CT2 7NZ (United Kingdom); Jiang, Hong; Jiang, Keping; Jin, Ye [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001 (China); Zheng, Jianhua, E-mail: zhengjianhua1115@126.com [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001 (China)

    2014-02-14

    Highlights: • Phosphorylation of mTOR is abnormal activation in SKOV3/DDP ovarian cancer cells. • Downregulation of mTOR by DHA helps to sensitize the SKOV3/DDP cells to chemotherapy. • DHA has the potential of induce autophagy in cancer cells. - Abstract: Dihydroartemisinin (DHA) exhibits anticancer activity in tumor cells but its mechanism of action is unclear. Cisplatin (DDP) is currently the best known chemotherapeutic available for ovarian cancer. However, tumors return de novo with acquired resistance over time. Mammalian target of rapamycin (mTOR) is an important kinase that regulates cell apoptosis and autophagy, and its dysregulation has been observed in chemoresistant human cancers. Here, we show that compared with control ovarian cancer cells (SKOV3), mTOR phosphorylation was abnormally activated in cisplatin-resistant ovarian cancer cells (SKOV3/DDP) following cisplatin monotherapy. Treatment with cisplatin combined with DHA could enhance cisplatin-induced proliferation inhibition in SKOV3/DDP cells. This mechanism is at least partially due to DHA deactivation of mTOR kinase and promotion of apoptosis. Although autophagy was also induced by DHA, the reduced cell death was not found by suppressing autophagic flux by Bafilomycin A1 (BAF). Taken together, we conclude that inhibition of cisplatin-induced mTOR activation is one of the main mechanisms by which DHA dramatically promotes its anticancer effect in cisplatin-resistant ovarian cancer cells.

  15. Cytotoxicity and expression of genes involved in the cellular stress response and apoptosis in mammalian fibroblast exposed to cotton cellulose nanofibers

    Science.gov (United States)

    Pereira, M. M.; Raposo, N. R. B.; Brayner, R.; Teixeira, E. M.; Oliveira, V.; Quintão, C. C. R.; Camargo, L. S. A.; Mattoso, L. H. C.; Brandão, H. M.

    2013-02-01

    Cellulose nanofibers (CNF) have mechanical properties that make them very attractive for applications in the construction of polymeric matrices, drug delivery and tissue engineering. However, little is known about their impact on mammalian cells. The objective of this study was to evaluate the cytotoxicity of CNF and their effect on gene expression of fibroblasts cultured in vitro. The morphology of CNF was analyzed by transmission electron microscopy and the surface charge by Zeta potential. Cell viability was analyzed by flow cytometry assay and gene expression of biomarkers focused on cell stress response such as Heat shock protein 70.1 (HSP70.1) and Peroxiredoxin 1 (PRDX1) and apoptosis as B-cell leukemia (BCL-2) and BCL-2 associated X protein (BAX) by RT-PCR assay. Low concentrations of CNF (0.02-100 μg ml-1) did not cause cell death; however, at concentrations above 200 μg ml-1, the nanofibers significantly decreased cell viability (86.41 ± 5.37%). The exposure to high concentrations of CNF (2000 and 5000 μg ml-1) resulted in increased HSP70.1, PRDX1 and BAX gene expression. The current study concludes that, under the conditions tested, high concentrations (2000 and 5000 μg ml-1) of CNF cause decreased cell viability and affect the expression of stress- and apoptosis-associated molecular markers.

  16. Hepatoprotective effect of grape seed proanthocyanidins on Cadmium-induced hepatic injury in rats: Possible involvement of mitochondrial dysfunction, inflammation and apoptosis

    Directory of Open Access Journals (Sweden)

    Selvaraj Miltonprabu

    Full Text Available The present study was undertaken to evaluate the possible ameliorative role of grape seed proanthocyanidins (GSP against Cadmium (Cd induced hepatic inflammation, apoptosis and hepatic mitochondrial toxicity in rats. Male Wistar rats were distributed in four experimental groups: control, GSP, Cd and Cd + GSP. Exposure to a hepatotoxic dose of Cd (5 mg/kg BW caused liver damage, coupled with enhanced reactive oxygen species (ROS generation, increased inflammation and apoptosis in liver with increased DNA damage in hepatocytes of rats. Mitochondria were isolated from the hepatic tissues of rats from each group. Our results showed significant decrease in the tri-carboxylic acid cycle enzymes, increased mitochondrial swelling, inhibition of cytochrome c oxidase activity and complex I–III, II–III and IV mediated electron transfer, decreased mitochondrial ATPases, a reduction in calcium content and mitochondrial oxygen consumption in Cd treated rats. All these molecular changes caused by Cd were alleviated by the pre-supplementation with GSP (100 mg/kg BW. The ultra structural changes in the liver also support our findings. From our results, it is clearly indicated that the free radical scavenging, metal chelating and antioxidant potentials of GSP might be the possible reason, responsible for the rescue action against Cd induced mitochondrial damage in the liver of rats. Keywords: Cd, GSP, Mitochondria, Oxidative stress, Liver, Rats

  17. Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy

    International Nuclear Information System (INIS)

    Feng, Xue; Li, Ling; Jiang, Hong; Jiang, Keping; Jin, Ye; Zheng, Jianhua

    2014-01-01

    Highlights: • Phosphorylation of mTOR is abnormal activation in SKOV3/DDP ovarian cancer cells. • Downregulation of mTOR by DHA helps to sensitize the SKOV3/DDP cells to chemotherapy. • DHA has the potential of induce autophagy in cancer cells. - Abstract: Dihydroartemisinin (DHA) exhibits anticancer activity in tumor cells but its mechanism of action is unclear. Cisplatin (DDP) is currently the best known chemotherapeutic available for ovarian cancer. However, tumors return de novo with acquired resistance over time. Mammalian target of rapamycin (mTOR) is an important kinase that regulates cell apoptosis and autophagy, and its dysregulation has been observed in chemoresistant human cancers. Here, we show that compared with control ovarian cancer cells (SKOV3), mTOR phosphorylation was abnormally activated in cisplatin-resistant ovarian cancer cells (SKOV3/DDP) following cisplatin monotherapy. Treatment with cisplatin combined with DHA could enhance cisplatin-induced proliferation inhibition in SKOV3/DDP cells. This mechanism is at least partially due to DHA deactivation of mTOR kinase and promotion of apoptosis. Although autophagy was also induced by DHA, the reduced cell death was not found by suppressing autophagic flux by Bafilomycin A1 (BAF). Taken together, we conclude that inhibition of cisplatin-induced mTOR activation is one of the main mechanisms by which DHA dramatically promotes its anticancer effect in cisplatin-resistant ovarian cancer cells

  18. Utilizing constitutional values in constitutional comparison

    Directory of Open Access Journals (Sweden)

    F Venter

    2001-12-01

    Full Text Available We are living in an era in which constitutional law has become a comparative science. A cogent, generally accepted methodology for constitutional comparison, however does not exist. There can, it is therefore submitted, be no such thing as a universal, monolithic science or discipline of comparative law, be it in the field of private or of public law. On the other hand, juridical comparison done unscientifically will not yield the fruits of useful knowledge.The law in general is replete with unspecific notions such as justice, reasonableness, public interest, boni mores, and many others. It should therefore not be disturbing to find that values are often foundational to the operation and application of constitutional law. The values underpinning different constitutional systems may be useful as a tertium comparationis in a comparative exercise. This however requires a penetrating consideration of the foundations of the systems being compared.In this contribution "a small comparative exercise" is undertaken by way of demonstration of the method. The South African constitutional provisions relating to equality and affirmative action are set against the background of the relevant norms and practices in the United States of America and Canada. This produces some useful insights:• in the USA equality increasingly underpins a strict proscription of discrimination, thus shrinking the scope for justifiable affirmative action programmes;• the South African law relating to discrimination and upliftment of the disadvantaged was clearly influenced by, and is therefore better understood against the background of, the equivalent arrangements in Canada, which was in its turn possibly conceived against the backdrop of early developments in this regard in the USA;• the Canadian doctrine and law of the constitution deals with affirmative action as an exception to the prohibition of discrimination and does not favour private affirmative action programmes

  19. Ferulago angulata activates intrinsic pathway of apoptosis in MCF-7 cells associated with G1 cell cycle arrest via involvement of p21/p27

    Directory of Open Access Journals (Sweden)

    Karimian H

    2014-09-01

    Full Text Available Hamed Karimian,1 Soheil Zorofchian Moghadamtousi,2 Mehran Fadaeinasab,3 Shahram Golbabapour,2 Mahboubeh Razavi,1 Maryam Hajrezaie,2 Aditya Arya,1 Mahmood Ameen Abdulla,4 Syam Mohan,5 Hapipah Mohd Ali,2 Mohamad Ibrahim Noordin1 1Department of Pharmacy, Faculty of Medicine, 2Institute of Biological Sciences, Faculty of Science, 3Department of Chemistry, 4Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia, 5Medical Research Centre, Jazan University, Jazan, Saudi Arabia Abstract: Ferulago angulata is a medicinal plant that is traditionally known for its ­anti-inflammatory and antiulcer properties. The present study was aimed to evaluate its anticancer activity and the possible mechanism of action using MCF-7 as an in vitro model. F. angulata leaf extracts were prepared using solvents in the order of increasing polarity. As determined by MTT assay, F. angulata leaves hexane extract (FALHE revealed the strongest cytotoxicity against MCF-7 cells with the half maximal inhibitory concentration (IC50 value of 5.3±0.82 µg/mL. The acute toxicity study of FALHE provided evidence of the safety of the plant extract. Microscopic and flow cytometric analysis using annexin-V probe showed an induction of apoptosis in MCF-7 by FALHE. Treatment of MCF-7 cells with FALHE encouraged the intrinsic pathway of apoptosis, with cell death transducing signals that reduced the mitochondrial membrane potential with cytochrome c release from mitochondria to cytosol. The released cytochrome c triggered the activation of caspase-9. Meanwhile, the overexpression of caspase-8 suggested the involvement of an extrinsic pathway in the induced apoptosis at the late stage of treatment. Moreover, flow cytometric analysis showed that FALHE treatment significantly arrested MCF-7 cells in the G1 phase, which was associated with upregulation of p21 and p27 assessed by quantitative polymerase chain reaction. Immunofluorescence

  20. Activation of Stat-3 is involved in the induction of apoptosis after ligation of major histocompatibility complex class I molecules on human Jurkat T cells

    DEFF Research Database (Denmark)

    Skov, S; Nielsen, M; Bregenholt, S

    1998-01-01

    Activation of Janus tyrosine kinases (Jak) and Signal transducers and activators of transcription (Stat) after ligation of major histocompatibility complex class I (MHC-I) was explored in Jurkat T cells. Cross-linking of MHC-I mediated tyrosine phosphorylation of Tyk2, but not Jak1, Jak2, and Jak3......-probe derived from the interferon-gamma activated site (GAS) in the c-fos promoter, a common DNA sequence for Stat protein binding. An association between hSIE and Stat-3 after MHC-I ligation was directly demonstrated by precipitating Stat-3 from nuclear extracts with biotinylated hSIE probe and avidin......-coupled agarose. To investigate the function of the activated Stat-3, Jurkat T cells were transiently transfected with a Stat-3 isoform lacking the transactivating domain. This dominant-negative acting Stat-3 isoform significantly inhibited apoptosis induced by ligation of MHC-I. In conclusion, our data suggest...

  1. Involvement of an aldo-keto reductase (AKR1C3) in redox cycling of 9,10-phenanthrenequinone leading to apoptosis in human endothelial cells.

    Science.gov (United States)

    Matsunaga, Toshiyuki; Arakaki, Marina; Kamiya, Tetsuro; Endo, Satoshi; El-Kabbani, Ossama; Hara, Akira

    2009-09-14

    9,10-Phenanthrenequinone (9,10-PQ), a major quinone found in diesel exhaust particles, is considered to generate reactive oxygen species (ROS) through its redox cycling. Here, we show that 9,10-PQ evokes apoptosis in human aortic endothelial cells (HAECs) and its apoptotic signaling includes ROS generation and caspase activation. The 9,10-PQ-induced cytotoxicity was inhibited by ROS scavengers, indicating that intracellular ROS generation is responsible for the 9,10-PQ-induced apoptosis. Comparison of mRNA expression levels and kinetic constants in the 9,10-PQ reduction among 10 human reductases suggests that aldo-keto reductase 1C3 (AKR1C3) is a 9,10-PQ reductase in HAECs. In in vitro 9,10-PQ reduction by AKR1C3, the reduced product 9,10-dihydroxyphenanthrene and superoxide anions were formed, suggesting the enzymatic two-electron reduction of 9,10-PQ that thereby causes oxidative stress through its redox cycling. In addition, the participation of AKR1C3 in 9,10-PQ-redox cycling was confirmed by the data that AKR1C3 overexpression in endothelial cells augmented the ROS generation and cytotoxicity by 9,10-PQ, and the ROS scavengers inhibited the toxic effects. Pretreatment of the overexpressing cells with AKR1C3 inhibitors, flufenamic acid and indomethacin, suppressed the 9,10-PQ-induced GSH depletion. These results suggest that AKR1C3 is a key enzyme in the initial step of 9,10-PQ-induced cytotoxicity in HAECs.

  2. Mycophenolic acid potentiates HER2-overexpressing SKBR3 breast cancer cell line to induce apoptosis: involvement of AKT/FOXO1 and JAK2/STAT3 pathways.

    Science.gov (United States)

    Aghazadeh, Safiyeh; Yazdanparast, Razieh

    2016-11-01

    Trastuzumab has been successfully used as a first-line therapy specific for HER2-overexressing breast cancer patients. However, despite the effectiveness of trastuzumab, the occurrence of inherent and acquired resistance remains as the main challenge of the therapy. Thus, this has motivated efforts toward finding new therapeutic strategies including combining trastuzumab with other drugs to enhance its therapeutic efficacy. In that line, we investigated the capability of mycophenolic acid (MPA), an inhibitor of de novo guanine nucleotide synthesis with potential anti-cancer activity, on improving the response to trastuzumab among SKBR3 cells as well as trastuzumab resistant SKBR3-TR cells. Our data indicated that irrespective to trastuzumab sensitivity of cells, MPA effectively inhibited cell growth through inducing adipocyte-like cell differentiation as well as blocking cell cycle progression at G 1 phase along with augmentation of p27 kip expression level. Furthermore, combined treatment with trastuzumab and MPA was more potent in cell growth inhibition, cell cycle arrest and apoptosis induction, as evident by flow cytometric analyses and caspase-3 production, in both trastuzumab sensitive and resistant SKBR3 cells. Besides, western blot analysis showed that elevated apoptosis induction in both cell groups was associated with attenuation in phosphorylation of some key elements of HER2 signaling pathway including AKT, ERK, STAT3 and consequently augmentation in FOXO1 expression level in response to combination of trastuzumab and MPA. These data suggest that manipulation of intracellular GTP level by MPA and consequent molecular perturbation in some of the cell survival and pro-apoptotic relevant signaling pathways might provide an alternative clinical strategy for chemosensitization of resistant breast cancer cells to anti- HER2 therapy.

  3. Attenuation of TNFSF10/TRAIL-induced apoptosis by an autophagic survival pathway involving TRAF2- and RIPK1/RIP1-mediated MAPK8/JNK activation

    Science.gov (United States)

    He, Weiyang; Wang, Qiong; Xu, Jennings; Xu, Xiuling; Padilla, Mabel T.; Ren, Guosheng; Gou, Xin; Lin, Yong

    2012-01-01

    Although it is known that tumor necrosis factor-related apoptosis-inducing ligand (TNFSF10/TRAIL) induces autophagy, the mechanism by which autophagy is activated by TNFSF10 is still elusive. In this report, we show evidence that TRAF2- and RIPK1-mediated MAPK8/JNK activation is required for TNFSF10-induced cytoprotective autophagy. TNFSF10 activated autophagy rapidly in cancer cell lines derived from lung, bladder and prostate tumors. Blocking autophagy with either pharmacological inhibitors or siRNAs targeting the key autophagy factors BECN1/Beclin 1 or ATG7 effectively increased TNFSF10-induced apoptotic cytotoxicity, substantiating a cytoprotective role for TNFSF10-induced autophagy. Blocking MAPK8 but not NFκB effectively blocked autophagy, suggesting that MAPK8 is the main pathway for TNFSF10-induced autophagy. In addition, blocking MAPK8 effectively inhibited degradation of BCL2L1/Bcl-xL and reduction of the autophagy-suppressing BCL2L1–BECN1complex. Knockdown of TRAF2 or RIPK1 effectively suppressed TNFSF10-induced MAPK8 activation and autophagy. Furthermore, suppressing autophagy inhibited expression of antiapoptosis factors BIRC2/cIAP1, BIRC3/cIAP2, XIAP and CFLAR/c-FLIP and increased the formation of TNFSF10-induced death-inducing signaling complex (DISC). These results reveal a critical role for the MAPK8 activation pathway through TRAF2 and RIPK1 for TNFSF10-induced autophagy that blunts apoptosis in cancer cells. Thus, suppression of MAPK8-mediated autophagy could be utilized for sensitizing cancer cells to therapy with TNFSF10. PMID:23051914

  4. Inhibition of CUG-binding protein 1 and activation of caspases are critically involved in piperazine derivative BK10007S induced apoptosis in hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Ju-Ha Kim

    Full Text Available Though piperazine derivative BK10007S was known to induce apoptosis in pancreatic cancer xenograft model as a T-type CaV3.1 a1G isoform calcium channel blocker, its underlying antitumor mechanism still remains unclear so far. Thus, in the present study, the antitumor mechanism of BK10007S was elucidated in hepatocellular carcinoma cells (HCCs. Herein, BK10007S showed significant cytotoxicity by 3-[4,5-2-yl]-2,5-diphenyltetra-zolium bromide (MTT assay and anti-proliferative effects by colony formation assay in HepG2 and SK-Hep1 cells. Also, apoptotic bodies and terminal deoxynucleotidyl transferase (TdT dUTP Nick End Labeling (TUNEL positive cells were observed in BK10007S treated HepG2 and SK-Hep1 cells by 4',6-diamidino-2-phenylinodole (DAPI staining and TUNEL assay, respectively. Consistently, BK10007S increased sub G1 population in HepG2 and SK-Hep1 cells by cell cycle analysis. Furthermore, Western blotting revealed that BK10007S activated the caspase cascades (caspase 8, 9 and 3, cleaved poly (ADP-ribose polymerase (PARP, and downregulated the expression of cyclin D1, survivin and for CUG-binding protein 1 (CUGBP1 or CELF1 in HepG2 and SK-Hep1 cells. Conversely, overexpression of CUGBP1 reduced cleavages of PARP and caspase 3, cytotoxicity and subG1 population in BK10007S treated HepG2 cells. Overall, these findings provide scientific evidences that BK10007S induces apoptosis via inhibition of CUGBP1 and activation of caspases in hepatocellular carcinomas as a potent anticancer candidate.

  5. Selected aspects of apoptosis in psoriasis

    Directory of Open Access Journals (Sweden)

    Hanna Myśliwiec

    2017-03-01

    Full Text Available Apoptosis is a physiological mechanism of programmed cell death, in contrast to necrosis, without eliciting an inflammatory response. It plays the key role in the functioning of different tissues and organs. The balance between proliferation and apoptosis of keratinocytes is important for epidermal maintenance of homeostasis. Dysfunctional apoptosis plays an important role in the development of several skin disorders. Diseases with an increase of apoptosis are usually acute, while those with inhibited apoptosis tend to be chronic. Psoriasis is an immune-mediated chronic inflammatory skin disease. It is characterized by keratinocyte hyperproliferation and abnormal differentiation. Psoriatic keratinocytes are resistant to apoptosis and this phenomenon can be the key event in psoriatic hyperplasia. Apoptosis disturbances can also affect immune cells involved in the pathogenesis of psoriasis. In this review, we describe the basic concept of apoptosis and its relevance in psoriatic pathogenesis.

  6. Interpreting the Constitution.

    Science.gov (United States)

    Brennan, William J., Jr.

    1987-01-01

    Discusses constitutional interpretations relating to capital punishment and protection of human dignity. Points out the document's effectiveness in creating a new society by adapting its principles to current problems and needs. Considers two views of the Constitution that lead to controversy over the legitimacy of judicial decisions. (PS)

  7. The Constitution by Cell

    Science.gov (United States)

    Greenhut, Stephanie; Jones, Megan

    2010-01-01

    On their visit to the National Archives Experience in Washington, D.C., students in Jenni Ashley and Gay Brock's U.S. history classes at the Potomac School in McLean, Virginia, participated in a pilot program called "The Constitution by Cell." Armed with their cell phones, a basic understanding of the Constitution, and a willingness to…

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

    Science.gov (United States)

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

    2010-01-01

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

  9. Involvement of Transient Receptor Potential Melastatin 7 Channels in Sophorae Radix-induced Apoptosis in Cancer Cells - Sophorae Radix and TRPM7 -

    Directory of Open Access Journals (Sweden)

    Kim Byung Joo

    2012-09-01

    Full Text Available Objective:Sophorae Radix (SR plays a role in a number of physiologic and pharmacologic functions in many organs. Methods:The aim of this study was to clarify the potential role for transient receptor potential melastatin 7 (TRPM7 channels in SR-inhibited growth and survival of AGS and MCF-7 cells, the most common human gastric and breast adenocarcinoma cell lines. Results:The AGS and the MCF-7 cells were treated with varying concentrations of SR. Analyses of the caspase-3 and - 9 activity, the mitochondrial depolarization and the poly (ADPribose polymerase (PARP cleavage were conducted to determine if AGS and MCF-7 cell death occured by apoptosis. TRPM7 channel blockers (Gd3+ or 2-APB and small interfering RNA (siRNA were used in this study to confirm the role of TRPM7 channels. Furthermore, TRPM7 channels were overexpressed in human embryonic kidney (HEK 293 cells to identify the role of TRPM7 channels in AGS and MCF-7 cell growth and survival. Conclusions:The addition of SR to a culture medium inhibited AGS and MCF-7 cell growth and survival. Experimental results showed that the caspase-3 and -9 activity, the mitochondrial depolarization, and the degree of PARP cleavage was increased. TRPM7 channel blockade, either by Gd3+ or 2-APB or by suppressing TRPM7 expression with small interfering RNA, blocked the SR-induced inhibition of cell growth and survival. Furthermore, TRPM7 channel overexpression in HEK 293 cells exacerbated SR-induced cell death. These findings indicate that SR inhibits the growth and survival of gastric and breast cancer cells due to a blockade of the TRPM7 channel activity. Therefore, TRPM7 channels may play an important role in the survival of patients with gastric and breast cancer.

  10. Dwindling of cardio damaging effect of isoproterenol by Punica granatum L. peel extract involve activation of nitric oxide-mediated Nrf2/ARE signaling pathway and apoptosis inhibition.

    Science.gov (United States)

    Gupta, Mahesh; Sharma, Pallavi; Mazumder, Arindam Ghosh; Patial, Vikram; Singh, Damanpreet

    2015-09-09

    Punica granatum L. (Punicaceae) peel is often considered as a food waste in-spite of its high bioactive metabolite composition. Primarily it is rich in therapeutically active phenolics that act on multiple cellular sites, through diverse mechanisms. Hence, the present study was envisaged to investigate the effect of standardised peel extract of P. granatum against isoproterenol (ISO)-induced myocardial infarction (MI). ISO administration at a dose of 150 mg/kg; s.c., twice at 24 h interval resulted in electrocardiographic abnormalities with increased heart weight and myocardial tissue damage signifying MI. Pretreatment with the extract at 50, 100 and 200 mg/kg; p.o., for 21 days prior to ISO intoxication (30 min prior to intoxication on day 22 and 23) attenuated the observed changes, along with increased myocardial tissue superoxide dismutase activity, reduced glutathione and nitrite levels, and decreased lipid peroxidation. The extract treated groups also showed reduced serum marker enzymes of MI, showing maximum effect at highest tested dose. Immunohistochemical studies revealed increased myocardial expression of nuclear factor erythroid 2-related factor 2 (Nrf2), endothelial nitric oxide synthase (eNOS) and Bcl-2 proteins in the extract treated groups with decreased Bax expression. From the results it can be concluded that the extract pretreatment prevents ISO-induced MI through increased myocardial expression of eNOS, leading to nitric oxide-mediated Nrf2 activation, thus upregulating antioxidant mechanisms, along with inhibition of apoptosis. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Global environmental constitutionalism

    OpenAIRE

    Bosselmann, Klaus

    2015-01-01

    This article supports the perspective that environmental constitutionalism is a global and foundational subject. Considering the novelty and thin base of this only emerging field of inquiry, it aims for making some suggestions for formulating the purpose and scope of environmental constitutionalism in a global range. Moreover, considering that the very nature of environmental rights is more fundamental than classic human rights, the mindset and methodology applied to the studies of constituti...

  12. Involvement of NF-ΚB and HSP70 signaling pathways in the apoptosis of MDA-MB-231 cells induced by a prenylated xanthone compound, α-mangostin, from Cratoxylum arborescens

    Directory of Open Access Journals (Sweden)

    Ibrahim MY

    2014-11-01

    the role of the central apoptosis-related proteins, a protein array followed by immunoblot analysis was conducted. Moreover, the involvement of nuclear factor-kappa B (NF-ΚB was also analyzed. Results: Apoptosis was confirmed by the apoptotic cells stained with annexin V and increase in chromatin condensation in nucleus. Treatment of cells with AM promoted cell death-transducing signals that reduced MMP by downregulation of Bcl-2 and upregulation of Bax, triggering cytochrome c release from the mitochondria to the cytosol. The released cytochrome c triggered the activation of caspase-9 followed by the executioner caspase-3/7 and then cleaved the PARP protein. Increase of caspase-8 showed the involvement of extrinsic pathway. AM treatment significantly arrested the cells at the S phase (P<0.05 concomitant with an increase in reactive oxygen species. The protein array and Western blotting demonstrated the expression of HSP70. Moreover, AM significantly blocked the induced translocation of NF-ΚB from cytoplasm to nucleus. Conclusion: Together, the results demonstrate that the AM isolated from C. arborescens inhibited the proliferation of MDA-MB-231 cells, leading to cell cycle arrest and programmed cell death, which was suggested to occur through both the extrinsic and intrinsic apoptosis pathways with involvement of the NF-ΚB and HSP70 signaling pathways. Keywords: mitochondria, protein array, caspase-3/7

  13. CONSTITUTIONAL FOUNDATIONS OF JURISDICTION

    Directory of Open Access Journals (Sweden)

    Alexandre Jamal Batista

    2016-06-01

    Full Text Available At the current stage of our State of Law there is no way to separate the study of the civil procedural law from the Federal Constitution, especially the jurisdiction, because it is in the Constitution that there are the legitimizing foundations of the jurisdiction institute. In this article, we carry on about the constitutional foundations of jurisdiction, such as: the principle of natural justice, principle of access to justice, principle of impartiality, principle of publicity, principle of motivation and principle of submission to res judicata. The conclusion is, after all, that jurisdiction, as one of the bulwarks of the citizen, finds in the “Citizen Constitution” of 1988 its foundations and decisive bases.

  14. The Constitution of Partnering

    DEFF Research Database (Denmark)

    Gottlieb, Stefan Christoffer

    The constitution of partnering. Afhandlingen behandler konstitueringen af ledelseskonceptet partnering og dets anvendelse i dansk byggeri. Partnering er et udbredt koncept i byggeriet som betoner samarbejde, tillid og gensidighed mellem de deltagende parter, og konceptet har de senere år har været...

  15. Communicative Constitution of Organizations

    DEFF Research Database (Denmark)

    Schoeneborn, Dennis; Vasquez, Consuelo

    2017-01-01

    The notion of the communicative constitution of organizations (CCO) is at the center of a growing theoretical development within organizational communication studies. CCO scholarship is based on the idea that organization emerges in and is sustained and transformed by communication. This entry...

  16. Sexuality and the Constitution.

    Science.gov (United States)

    Copelon, Rhonda

    1987-01-01

    Argues for abortion rights and protection of intimate decisions and relationships. Describes the role and position of women in eighteenth century American society as a means of exposing the fallacy of the anti-abortion movement's insistence on adherence to constitutional text. Discusses the recent attempts to overturn the Roe v. Wade ruling. (PS)

  17. Constitutional Law--State Action--A Lesser Standard of State Action Is to Be Employed for Claims Involving Sex Discrimination. Weise v. Syracuse University (2d Cir. 1975)

    Science.gov (United States)

    Ronan, James Michael

    1976-01-01

    The impact of Weise v. Syracuse University, involving alleged sex discrimination in university hiring practices, is unclear but the appeals court held that a less stringent state action standard should be employed in claims involving sex discrimination. (LBH)

  18. Requirement for non-regulated, constitutive calcium influx in macrophage survival signaling

    Energy Technology Data Exchange (ETDEWEB)

    Tano, Jean-Yves [Department of Physiology and Pharmacology, University of Toledo College of Medicine, Health Science Campus, 3000 Arlington Av., Toledo, OH 43614 (United States); Vazquez, Guillermo, E-mail: Guillermo.Vazquez@utoledo.edu [Department of Physiology and Pharmacology, University of Toledo College of Medicine, Health Science Campus, 3000 Arlington Av., Toledo, OH 43614 (United States)

    2011-04-08

    Highlights: {yields} We examine the role of constitutive Ca{sup 2+} influx in macrophage survival. {yields} Survival signaling exhibits a mandatory requirement for constitutive Ca{sup 2+} influx. {yields} CAM/CAMKII couples constitutive Ca{sup 2+} influx to survival signaling. -- Abstract: The phosphatidylinositol-3-kinase (PI3K)/AKT axis and the Nuclear Factor kappa B (NF{kappa}B) pathway play critical roles in macrophage survival. In cells other than macrophages proper operation of those two pathways requires Ca{sup 2+} influx into the cell, but if that is the case in macrophages remains unexplored. In the present work we used THP-1-derived macrophages and a pharmacological approach to examine for the first time the role of constitutive, non-regulated Ca{sup 2+} influx in PI3K/AKT and NF{kappa}B signaling. Blocking constitutive function of Ca{sup 2+}-permeable channels with the organic channel blocker SKF96365 completely prevented phosphorylation of I{kappa}B{alpha}, AKT and its downstream target BAD in TNF{alpha}-treated macrophages. A similar effect was observed upon treating macrophages with the calmodulin (CAM) inhibitor W-7 or the calmodulin-dependent kinase II (CAMKII) inhibitor KN-62. In addition, pre-treating macrophages with SKF96365 significantly enhanced TNF{alpha}-induced apoptosis. Our findings suggest that in THP-1-derived macrophages survival signaling depends, to a significant extent, on constitutive Ca{sup 2+} influx presumably through a mechanism that involves the CAM/CAMKII axis as a coupling component between constitutive Ca{sup 2+} influx and activation of survival signaling.

  19. What constitutes information integrity?

    Directory of Open Access Journals (Sweden)

    S. Flowerday

    2007-12-01

    Full Text Available This research focused on what constitutes information integrity as this is a problem facing companies today. Moreover, information integrity is a pillar of information security and is required in order to have a sound security management programme. However, it is acknowledged that 100% information integrity is not currently achievable due to various limitations and therefore the auditing concept of reasonable assurance is adopted. This is in line with the concept that 100% information security is not achievable and the notion that adequate security is the goal, using appropriate countermeasures. The main contribution of this article is to illustrate the importance of and provide a macro view of what constitutes information integrity. The findings are in harmony with Samuel Johnson's words (1751: 'Integrity without knowledge is weak and useless, and knowledge without integrity is dangerous and dreadful.'

  20. What constitutes information integrity?

    Directory of Open Access Journals (Sweden)

    S. Flowerday

    2008-01-01

    Full Text Available This research focused on what constitutes information integrity as this is a problem facing companies today. Moreover, information integrity is a pillar of information security and is required in order to have a sound security management programme. However, it is acknowledged that 100% information integrity is not currently achievable due to various limitations and therefore the auditing concept of reasonable assurance is adopted. This is in line with the concept that 100% information security is not achievable and the notion that adequate security is the goal, using appropriate countermeasures. The main contribution of this article is to illustrate the importance of and provide a macro view of what constitutes information integrity. The findings are in harmony with Samuel Johnson's words (1751: 'Integrity without knowledge is weak and useless, and knowledge without integrity is dangerous and dreadful.'

  1. The constitutional view

    Directory of Open Access Journals (Sweden)

    Roberto Horácio Sá Pereira

    2016-05-01

    Full Text Available http://dx.doi.org/10.5007/1808-1711.2016v20n2p165   This brief paper is devoted to criticizing the widespread reading of Kant’s first Critique, according to which reference to subject-independent objects is “constituted” by higherorder cognitive abilities (concepts. Let us call this the “constitutional view”. In this paper, I argue that the constitutional reading confuses the un-Kantian problem of how we come to represent objects (which I call the intentionality thesis, with the quite different problem of how we cognize (erkennen (which I call the “cognition thesis” that we do represent objects, that is, things that exist independently of the subject.

  2. The Bicentennial and State Constitutions.

    Science.gov (United States)

    Clay, Henry

    1988-01-01

    Illustrates how the Bicentennial of the U.S. Constitution provides an opportunity to teach about the broader concept of constitutionalism through study of the state constitutions. Presents an argument for teaching about state constitutions, their role in the federal system, and the values they convey. (LS)

  3. The constitutive sofa cushion

    DEFF Research Database (Denmark)

    Hanghøj, Sara

    2009-01-01

    body, space and artefact, thereby revealing the materialization process. Based on results of the analysis, ANT (Actor-Network- Theory) is used in order to discuss how The Danish Folk High School's conception of simplicity as an aesthetic and gendered ideal in the formal education of female handcraft...... personal values materialize through a hand-made everyday artefact, and how can the artefact constitute action and self-perception? The empirical research and analysis concerns how a former textile crafts teacher's subjective values and professional identity materialize through a hand-woven sofa cushion...

  4. Involvement of NF-κB and HSP70 signaling pathways in the apoptosis of MDA-MB-231 cells induced by a prenylated xanthone compound, α-mangostin, from Cratoxylum arborescens [Retraction

    Directory of Open Access Journals (Sweden)

    Ibrahim MY

    2017-05-01

    Full Text Available Ibrahim MY, Hashim NM, Mohan S, et al. Involvement of NF-κB and HSP70 signaling pathways in the apoptosis of MDA-MB-231 cells induced by a prenylated xanthone compound, α-mangostin, from Cratoxylum arborescens. Drug Design, Development and Therapy. 2014;8:2193–2211 was published subsequent to Ibrahim MY, Hashim NM, Mohan S, et al. α-Mangostin from Cratoxylum arborescens demonstrates apoptogenesis in MCF-7 with regulation of NF-κB and Hsp70 protein modulation in vitro, and tumor reduction in vivo. Drug Design, Development and Therapy. 2014;8:1629–1647.When comparing the papers it becomes apparent that they have an unacceptably high degree of similarity and re-use. Further, there is no clear scientific distinction between the cell lines and the results in both. Accordingly, the Editor-in-Chief and Publisher have issued this Notice of Retraction.This retraction relates to this paperThis retraction relates to this Corrigendum

  5. Interdependence of Bad and Puma during ionizing-radiation-induced apoptosis.

    Directory of Open Access Journals (Sweden)

    Cristhian Toruno

    Full Text Available Ionizing radiation (IR-induced DNA double-strand breaks trigger an extensive cellular signaling response that involves the coordination of hundreds of proteins to regulate DNA repair, cell cycle arrest and apoptotic pathways. The cellular outcome often depends on the level of DNA damage as well as the particular cell type. Proliferating zebrafish embryonic neurons are highly sensitive to IR-induced apoptosis, and both p53 and its transcriptional target puma are essential mediators of the response. The BH3-only protein Puma has previously been reported to activate mitochondrial apoptosis through direct interaction with the pro-apoptotic Bcl-2 family proteins Bax and Bak, thus constituting the role of an "activator" BH3-only protein. This distinguishes it from BH3-only proteins like Bad that are thought to indirectly promote apoptosis through binding to anti-apoptotic Bcl-2 family members, thereby preventing the sequestration of activator BH3-only proteins and allowing them to directly interact with and activate Bax and Bak. We have shown previously that overexpression of the BH3-only protein Bad in zebrafish embryos supports normal embryonic development but greatly sensitizes developing neurons to IR-induced apoptosis. While Bad has previously been shown to play only a minor role in promoting IR-induced apoptosis of T cells in mice, we demonstrate that Bad is essential for robust IR-induced apoptosis in zebrafish embryonic neural tissue. Moreover, we found that both p53 and Puma are required for Bad-mediated radiosensitization in vivo. Our findings show the existence of a hierarchical interdependence between Bad and Puma whereby Bad functions as an essential sensitizer and Puma as an essential activator of IR-induced mitochondrial apoptosis specifically in embryonic neural tissue.

  6. Reflections on the Establishment of Constitutional Government in Eastern Europe.

    Science.gov (United States)

    Varat, Jonathan D.

    Establishing constitutional government involves not simply the creation of a written document that purports to create the political structure of a nation and guarantee rights to its people, but "constitutionalism" in the sense of meaningful and effective adherence to constitutional norms of democratic organization and the protection of…

  7. Constitution, 5 May 1989.

    Science.gov (United States)

    1989-01-01

    This document contains provisions of Cambodia's Constitution of May 5, 1989. Article 7 gives men and women equal rights in marriage and the family, calls for monogamous marriages, and affords social protection to mothers and children. Article 8 guides parent-child relationships. The 14th article defines state property, and the 15th gives citizens full rights to own, use, and inherit land. The use of agricultural and forested land can only be changed with permission. Article 22 assigns educational responsibilities to the state, including free elementary education and a gradual expansion of higher education. Adult literacy classes are also promoted. Article 26 guarantees free medical consultations, and article 27 gives women a 90-day paid maternity leave. Breast-feeding women are also given special privileges. Article 33 guarantees the right to pay equity and to social security benefits. Article 36 grants the freedom to travel, the inviolability of homes, and privacy in correspondence of all types.

  8. Apoptosis in cancer: from pathogenesis to treatment

    Directory of Open Access Journals (Sweden)

    Wong Rebecca SY

    2011-09-01

    Full Text Available Abstract Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. It is also one of the most studied topics among cell biologists. An understanding of the underlying mechanism of apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. In some, the problem is due to too much apoptosis, such as in the case of degenerative diseases while in others, too little apoptosis is the culprit. Cancer is one of the scenarios where too little apoptosis occurs, resulting in malignant cells that will not die. The mechanism of apoptosis is complex and involves many pathways. Defects can occur at any point along these pathways, leading to malignant transformation of the affected cells, tumour metastasis and resistance to anticancer drugs. Despite being the cause of problem, apoptosis plays an important role in the treatment of cancer as it is a popular target of many treatment strategies. The abundance of literature suggests that targeting apoptosis in cancer is feasible. However, many troubling questions arise with the use of new drugs or treatment strategies that are designed to enhance apoptosis and critical tests must be passed before they can be used safely in human subjects.

  9. Placental apoptosis in recurrent miscarriage

    Directory of Open Access Journals (Sweden)

    Tarek A. Atia

    2017-09-01

    Full Text Available Apoptosis is an interactive and dynamic biological process involved in all phases of embryogenesis. We aimed to study the effect of placental apoptosis on recurrent miscarriage (RM. Placental tissue samples were collected from 40 women with RM (study group and 30 women with sporadic spontaneous abortion (control group. Samples were prepared and stained immunohistochemically with markers for both the apoptotic protein (p53 and anti-apoptotic Bcl-2 antibodies. Our results showed that expression of the apoptotic (p53 protein was significantly increased in the placental tissues of the RM group (p = 0.003. By contrast, the expression of anti-apoptotic (Bcl-2 antibodies was significantly increased in the placental tissues of the control group (p = 0.025. We concluded that placental apoptosis plays a crucial role in pregnancy continuation. However, increased p53 expression in placental tissue in early pregnancy could negatively affect pregnancy continuation.

  10. Constitution, 5 October 1988.

    Science.gov (United States)

    1989-01-01

    This document contains major provisions of the constitution adopted by Brazil on 5 October 1988. This constitution seeks to promote the welfare of all citizens without discrimination. The equality of all citizens is guaranteed, and the equal rights of women are specifically mentioned. Property rights are also guaranteed and defined. Female inmates are granted the right to remain with their children while breast feeding. Workers are guaranteed a minimum wage, a family allowance for dependents, maternity/paternity leave, specific incentives to protect the labor market for women, retirement benefits, free day care for preschool-age children, pay equity, and equal rights between tenured and sporadically employed workers. Agrarian reform provisions are given, including the authority to expropriate land. Social and economic policies to promote health are called for, and public health services are to be decentralized, to be integrated, and to foster community participation. Pension plan and social assistance provisions are outlined as are duties of the state in regard to education. The amount of money to be dedicated to education is set out, and a national educational plan is called for to achieve such goals as the eradication of illiteracy, the universalization of school attendance, the improvement of instruction, and the provision of vocational training. Specific measures are set out to protect and preserve the environment. Family policy deals with issues of marriage, the definition of a family, divorce, the right to family planning services, and the deterrence of domestic violence. Social protection provisions cover mothers and children, handicapped persons, and protection of minors. Finally, the customs and rights of Indians are protected, with special provisions given to protect land tenure and to protect the rights of Indians in water resource development and prospecting and mining activities.

  11. Apoptosis in mammalian oocytes: a review.

    Science.gov (United States)

    Tiwari, Meenakshi; Prasad, Shilpa; Tripathi, Anima; Pandey, Ashutosh N; Ali, Irfan; Singh, Arvind K; Shrivastav, Tulsidas G; Chaube, Shail K

    2015-08-01

    Apoptosis causes elimination of more than 99% of germ cells from cohort of ovary through follicular atresia. Less than 1% of germ cells, which are culminated in oocytes further undergo apoptosis during last phases of oogenesis and depletes ovarian reserve in most of the mammalian species including human. There are several players that induce apoptosis directly or indirectly in oocytes at various stages of meiotic cell cycle. Premature removal of encircling granulosa cells from immature oocytes, reduced levels of adenosine 3',5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate, increased levels of calcium (Ca(2+)) and oxidants, sustained reduced level of maturation promoting factor, depletion of survival factors, nutrients and cell cycle proteins, reduced meiotic competency, increased levels of proapoptotic as well as apoptotic factors lead to oocyte apoptosis. The BH3-only proteins also act as key regulators of apoptosis in oocyte within the ovary. Both intrinsic (mitochondria-mediated) as well as extrinsic (cell surface death receptor-mediated) pathways are involved in oocyte apoptosis. BID, a BH3-only protein act as a bridge between both apoptotic pathways and its cleavage activates cell death machinery of both the pathways inside the follicular microenvironment. Oocyte apoptosis leads to the depletion of ovarian reserve that directly affects reproductive outcome of various mammals including human. In this review article, we highlight some of the important players and describe the pathways involved during oocyte apoptosis in mammals.

  12. FOXO3a (Forkhead Transcription Factor O Subfamily Member 3a) Links Vascular Smooth Muscle Cell Apoptosis, Matrix Breakdown, Atherosclerosis, and Vascular Remodeling Through a Novel Pathway Involving MMP13 (Matrix Metalloproteinase 13).

    Science.gov (United States)

    Yu, Haixiang; Fellows, Adam; Foote, Kirsty; Yang, Zhaoqing; Figg, Nichola; Littlewood, Trevor; Bennett, Martin

    2018-03-01

    Vascular smooth muscle cell (VSMC) apoptosis accelerates atherosclerosis and promotes breakdown of the extracellular matrix, but the mechanistic links between these 2 processes are unknown. The forkhead protein FOXO3a (forkhead transcription factor O subfamily member 3a) is activated in human atherosclerosis and induces a range of proapoptotic and other transcriptional targets. We, therefore, determined the mechanisms and consequences of FOXO3a activation in atherosclerosis and arterial remodeling after injury. Expression of a conditional FOXO3a allele (FOXO3aA3ER) potently induced VSMC apoptosis, expression and activation of MMP13 (matrix metalloproteinase 13), and downregulation of endogenous TIMPs (tissue inhibitors of MMPs). mmp13 and mmp2 were direct FOXO3a transcriptional targets in VSMCs. Activation of endogenous FOXO3a also induced MMP13, extracellular matrix degradation, and apoptosis, and MMP13-specific inhibitors and fibronectin reduced FOXO3a-mediated apoptosis. FOXO3a activation in mice with VSMC-restricted FOXO3aA3ER induced MMP13 expression and activity and medial VSMC apoptosis. FOXO3a activation in FOXO3aA3ER/ApoE -/- (apolipoprotein E deficient) mice increased atherosclerosis, increased necrotic core and reduced fibrous cap areas, and induced features of medial degeneration. After carotid artery ligation, FOXO3a activation increased VSMC apoptosis, VSMC proliferation, and neointima formation, all of which were reduced by MMP13 inhibition. FOXO3a activation induces VSMC apoptosis and extracellular matrix breakdown, in part, because of transcriptional activation of MMP13. FOXO3a activation promotes atherosclerosis and medial degeneration and increases neointima after injury that is partly dependent on MMP13. FOXO3a-induced MMP activation represents a direct mechanistic link between VSMC apoptosis and matrix breakdown in vascular disease. © 2018 The Authors.

  13. Constitutive models in LAME.

    Energy Technology Data Exchange (ETDEWEB)

    Hammerand, Daniel Carl; Scherzinger, William Mark

    2007-09-01

    The Library of Advanced Materials for Engineering (LAME) provides a common repository for constitutive models that can be used in computational solid mechanics codes. A number of models including both hypoelastic (rate) and hyperelastic (total strain) constitutive forms have been implemented in LAME. The structure and testing of LAME is described in Scherzinger and Hammerand ([3] and [4]). The purpose of the present report is to describe the material models which have already been implemented into LAME. The descriptions are designed to give useful information to both analysts and code developers. Thus far, 33 non-ITAR/non-CRADA protected material models have been incorporated. These include everything from the simple isotropic linear elastic models to a number of elastic-plastic models for metals to models for honeycomb, foams, potting epoxies and rubber. A complete description of each model is outside the scope of the current report. Rather, the aim here is to delineate the properties, state variables, functions, and methods for each model. However, a brief description of some of the constitutive details is provided for a number of the material models. Where appropriate, the SAND reports available for each model have been cited. Many models have state variable aliases for some or all of their state variables. These alias names can be used for outputting desired quantities. The state variable aliases available for results output have been listed in this report. However, not all models use these aliases. For those models, no state variable names are listed. Nevertheless, the number of state variables employed by each model is always given. Currently, there are four possible functions for a material model. This report lists which of these four methods are employed in each material model. As far as analysts are concerned, this information is included only for the awareness purposes. The analyst can take confidence in the fact that model has been properly implemented

  14. Extended constitutive laws for lamellar phases

    Directory of Open Access Journals (Sweden)

    Chi-Deuk Yoo

    2013-10-01

    Full Text Available Classically, stress and strain rate in linear viscoelastic materials are related by a constitutive relationship involving the viscoelastic modulus G(t. The same constitutive law, within Linear Response Theory, relates currents of conserved quantities and gradients of existing conjugate variables, and it involves the autocorrelation functions of the currents in equilibrium. We explore the consequences of the latter relationship in the case of a mesoscale model of a block copolymer, and derive the resulting relationship between viscous friction and order parameter diffusion that would result in a lamellar phase. We also explicitly consider in our derivation the fact that the dissipative part of the stress tensor must be consistent with the uniaxial symmetry of the phase. We then obtain a relationship between the stress and order parameter autocorrelation functions that can be interpreted as an extended constitutive law, one that offers a way to determine them from microscopic experiment or numerical simulation.

  15. VALUATION IN THE CONSTITUTIONAL ERA

    African Journals Online (AJOL)

    Brimer

    16 ..... stem from the pre-constitutional era, and the constitutional framework and its legitimate reform efforts. A decision on what is just ...... Carroll L Alice's Adventures in Wonderland (Digital Scanning Scituate MA. 2007). Dagan 1999 Va L Rev.

  16. State provision of constitutional goods

    OpenAIRE

    Espinosa , Romain

    2016-01-01

    International audience; This paper investigates the impact of constitutional rights on the level of public expenditure in a large sample of countries. To do so, we construct a panel of 73 countries from 1960 to 2011. We first investigate factors that drive constitutional changes regarding constitutional rights. To address potential endogeneity concerns in the choice of constitutional rules, we rely on an instrumental variable within estimation (country and time fixed effects) to estimate the ...

  17. Start Of The French Constitutionalism: Constitution Of 1791

    Directory of Open Access Journals (Sweden)

    Sergey V. Bochkarev

    2014-12-01

    Full Text Available In the present article author analyzes questions of French constitutionalism origin. Author notes that in France, over the past two centuries, a state of law, which is based on the principles of popular sovereignty has been formed; observance of human rights and freedoms by the state; parliamentary democracy; supremacy of constitution in relation to all other laws and regulations; separation of powers and institute of authorities responsibility as an organizational framework for the legal state; independence of the judiciary; compliance with commitments taken by the State during international relations. These principles were laid down in the constitutional history of the country. In the present article an attempt to explore the beginning of the French constitutionalism through the prism of the Constitution of 1791 was made. Author makes concludes that in the Constitution of 1791 the fundamental principles of constitutional law were laid, some of which are reflected in the Constitution of the Fifth Republic in France and continue to operate. Constitution of the Fifth Republic proclaimed commitment to "human rights and principles of national sovereignty as defined by the Declaration of 1789, confirmed and complemented by the Preamble to the Constitution of 1946, and despite many disputes, Constitutional Council reaffirmed inviolability of the equality before the law principle, which exists in the Declaration.

  18. Ontoteleological Constitution of Entrepreneurship

    Directory of Open Access Journals (Sweden)

    Diego Luiz Teixeira Boava

    2017-06-01

    Full Text Available Entrepreneurship is a pluri-disciplinary phenomenon, object of research in several areas of knowledge. However, studies on this theme present approaches that start to consider entrepreneurship as a field of private knowledge in the phase of epistemological construction. In this context, the aim of this investigation is to contribute to the discussions on the theme, through studies on the ontoteleological constitution of entrepreneurship, in propaedeutic character, deflagrating new approaches. Thus, there is a presentation concerning the study of entrepreneurship, which may emphasize its ontical and ontological aspects. In addition, the reason why it is complex to define entrepreneurship is investigated. Subjects regarding the philosophy of entrepreneurship are introduced, seeking to present the bases for an ontoteleological approach to the phenomenon. Such an approach assumes that the finality of the entrepreneurial act relates to the main principles and transformations required into the organization. Finally, it is concluded that man is an entrepreneurial being, the meta-entrepreneur, and his entrepreneurial actions are not determined by external factors, but rather by the condition of his potentiality.

  19. The diffusion of constitutional rights

    NARCIS (Netherlands)

    Goderis, B.V.G.; Versteeg, M.

    Constitutions are commonly regarded as uniquely national products, shaped by domestic ideals and politics. This paper develops and empirically investigates a novel hypothesis, which is that constitutions are also shaped by transnational influence, or “diffusion.” Constitutional rights can diffuse

  20. Constitution, 1989. [Selected provisions].

    Science.gov (United States)

    1989-01-01

    Chapter XII of the Hungarian Constitution, 1989, details the Fundamental Rights and Duties of Citizens. Everyone lawfully within the territory of Hungary has the right to liberty of movement and the freedom to choose his or her residence, except when restricted by law, including the right to leave his or her residence or county. The Republic of Hungary grants asylum to foreign citizens who were persecuted for racial, religious ethnic, linguistic, or political reasons. Men and women shall equally enjoy all civil, political, economic, social and political rights. Mothers are entitled to special care and protection before and after childbirth; women and juveniles are protected at work by special regulations. Every child has the right to special care an assistance from his or her family, the State, and society, for appropriate physical, spiritual, and moral development. Parents shall decide the kind of education their children receive. Hungary grants equal rights to all person within its territories, without regard to race, color, sex, language, religion, political, or other opinion, national, and social origin, property, birth and other status. Prejudicial discrimination shall be severely punished. Everyone has the right to work, to the free choice of employment and profession and to equal pay for equal work. Citizens have the right to social security, including social services necessary in old age, sickness, disability, widowhood, orphanhood an unemployment through no fault of their own. Hungary guarantees the right to culture for its citizens and realized this right by free and compulsory elementary education, by secondary and higher education which is accessible to all on the basis of capacity, and by the financial support of those receiving an education.

  1. Dilemmas on the European Constitution

    Directory of Open Access Journals (Sweden)

    Zvonko Posavec

    2005-01-01

    Full Text Available In this paper, the author discusses the dilemmas associated with the role of the European Constitution in the further development of the Union. Analysing the implications of the rejection of the European Constitution by the referenda in France and the Netherlands, the author sets forth arguments why such decisions should be neither overrated nor underrated. Aiming to broaden the basis for understanding the European constitutional crisis, the author further discusses the categories of state, constitution and nation. Scrutiny into these categories, he argues, is a crucial prerequisite for understanding the sources of dilemmas regarding the European Constitution and for further development of the EU political system

  2. Constitutional judges (guarantee of the Constitution and responsibility

    Directory of Open Access Journals (Sweden)

    Francisco Javier Ansuátegui Roig

    2012-06-01

    Full Text Available My aim in this paper is to propose a reflection on the position and the importance that the constitutional judge has in the legal systems of contemporary constitutionalism. The figure of the judge responsible of protecting the Constitution is a key institution, without which we cannot understand the laws of constitutional democracies, their current lines of development, and the guarantee of rights and freedoms that constitute the normative core of these systems. Moreover, the reflection on the exercise of the powers of the judge, its scope and its justification is an important part of contemporary legal discussion, still relevant, albeit not exclusively - in the field of legal philosophy. The object of attention of my reflection is the judge who has the power of judicial review, in a scheme of defense of the Constitution, regardless the specific ways of this defense.

  3. HSV and glycoprotein J inhibit caspase activation and apoptosis induced by granzyme B or Fas.

    Science.gov (United States)

    Jerome, K R; Chen, Z; Lang, R; Torres, M R; Hofmeister, J; Smith, S; Fox, R; Froelich, C J; Corey, L

    2001-10-01

    HSV-1 inhibits apoptosis of infected cells, presumably to ensure that the infected cell survives long enough to allow completion of viral replication. Because cytotoxic lymphocytes kill their targets via the induction of apoptosis, protection from apoptosis could constitute a mechanism of immune evasion for HSV. Several HSV genes are involved in the inhibition of apoptosis, including Us5, which encodes glycoprotein J (gJ). Viruses deleted for Us5 showed defects in inhibition of caspase activation after Fas ligation or UV irradiation. Transfected cells expressing the Us5 gene product gJ were protected from Fas- or UV-induced apoptosis, as measured by morphology, caspase activation, membrane permeability changes, or mitochondrial transmembrane potential. In contrast, caspase 3 activation in mitochondria-free cell lysates by granzyme (gr)B was inhibited equivalently by Us5 deletion and rescue viruses, suggesting that gJ is not required for HSV to inhibition this process. However, mitochondria-free lysates from transfected cells expressing Us5/gJ were protected from grB-induced caspase activation, suggesting that Us5/gJ is sufficient to inhibit this process. Transfected cells expressing Us5/gJ were also protected from death induced by incubation with purified grB and perforin. These findings suggest that HSV has a comprehensive set of immune evasion functions that antagonize both Fas ligand- and grB-mediated pathways of CTL-induced apoptosis. The understanding of HSV effects on killing by CTL effector mechanisms may shed light on the incomplete control of HSV infections by the immune system and may allow more rational approaches to the development of immune modulatory treatments for HSV infection.

  4. The Spanish Constitution, the Constitutional Court and the Catalan Referendum

    DEFF Research Database (Denmark)

    Abat Ninet, Antoni

    2015-01-01

    This chapter deals with a core topic in constitutional law, that of the conflict between constitutions and will of the demos. Aristotle in Book IV of the Politics had already anticipated the possible conflict between these two forms of Politeia (constitutions), when defining the types of democracy...... and politeia that Aristotle defined now clashes between two powerful symbolic and romantic phenomena. In the Spanish-Catalan binomial scenario, there are some elements that need to be analysed to obtain a complete picture of the constitutional possibilities to of accommodating a Catalan self...

  5. Bid truncation, Bid/Bax targeting to the mitochondria, and caspase activation associated with neutrophil apoptosis are inhibited by granulocyte colony-stimulating factor

    NARCIS (Netherlands)

    Maianski, Nikolai A.; Roos, Dirk; Kuijpers, Taco W.

    2004-01-01

    Neutrophil apoptosis constitutes a way of managing neutrophil-mediated reactions. It allows coping with infections, but avoiding overt bystander tissue damage. Using digitonin-based subcellular fractionation and Western blotting, we found that spontaneous apoptosis of human neutrophils (after

  6. Constitutively activated ERK sensitizes cancer cells to doxorubicin ...

    Indian Academy of Sciences (India)

    2017-02-03

    Feb 3, 2017 ... The tumour suppressor gene p53 is mutated in approximately 50% of the human cancers. p53 is involved in genotoxic stress-induced cellular responses. The role of EGFR and ERK in DNA-damage-induced apoptosis is well known. We investigated the involvement of activation of ERK signalling as a ...

  7. Constitutively activated ERK sensitizes cancer cells to doxorubicin ...

    Indian Academy of Sciences (India)

    The tumour suppressor gene p53 is mutated in approximately 50% of the human cancers. p53 is involved in genotoxicstress-induced cellular responses. The role of EGFR and ERK in DNA-damage-induced apoptosis is well known. Weinvestigated the involvement of activation of ERK signalling as a consequence of ...

  8. Essential Medicines in National Constitutions

    Science.gov (United States)

    Toebes, Brigit; Hogerzeil, Hans

    2016-01-01

    Abstract A constitutional guarantee of access to essential medicines has been identified as an important indicator of government commitment to the progressive realization of the right to the highest attainable standard of health. The objective of this study was to evaluate provisions on access to essential medicines in national constitutions, to identify comprehensive examples of constitutional text on medicines that can be used as a model for other countries, and to evaluate the evolution of constitutional medicines-related rights since 2008. Relevant articles were selected from an inventory of constitutional texts from WHO member states. References to states’ legal obligations under international human rights law were evaluated. Twenty-two constitutions worldwide now oblige governments to protect and/or to fulfill accessibility of, availability of, and/or quality of medicines. Since 2008, state responsibilities to fulfill access to essential medicines have expanded in five constitutions, been maintained in four constitutions, and have regressed in one constitution. Government commitments to essential medicines are an important foundation of health system equity and are included increasingly in state constitutions. PMID:27781006

  9. Civil and Constitutional Rights of Adjudicated Youth.

    Science.gov (United States)

    Landess, Jacqueline

    2016-01-01

    Mental health clinicians serving child and adolescent patients are frequently asked to evaluate youth who have been arrested for various offenses or who are otherwise involved with the juvenile justice system. To help orient clinicians and other stakeholders involved with such cases, this article describes the evolution of the juvenile justice system and summarizes the history and current status of the civil and constitutional rights of youth involved in the adjudicatory process. This article also points out key areas in which due process rights are still evolving, particularly in the case of status offenders. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Apoptosis in Drosophila: which role for mitochondria?

    Science.gov (United States)

    Clavier, Amandine; Rincheval-Arnold, Aurore; Colin, Jessie; Mignotte, Bernard; Guénal, Isabelle

    2016-03-01

    It is now well established that the mitochondrion is a central regulator of mammalian cell apoptosis. However, the importance of this organelle in non-mammalian apoptosis has long been regarded as minor, mainly because of the absence of a crucial role for cytochrome c in caspase activation. Recent results indicate that the control of caspase activation and cell death in Drosophila occurs at the mitochondrial level. Numerous proteins, including RHG proteins and proteins of the Bcl-2 family that are key regulators of Drosophila apoptosis, constitutively or transiently localize in mitochondria. These proteins participate in the cell death process at different levels such as degradation of Diap1, a Drosophila IAP, production of mitochondrial reactive oxygen species or stimulation of the mitochondrial fission machinery. Here, we review these mitochondrial events that might have their counterpart in human.

  11. Constitutional Issues--Watergate and the Constitution. Teaching with Documents.

    Science.gov (United States)

    National Archives and Records Administration, Washington, DC.

    When U.S. President Richard Nixon resigned in 1974 in the wake of the Watergate scandal, it was only the second time that impeachment of a president had been considered. Although the U.S. Constitution has provisions for a person removed from office to be indicted, there are no guidelines in the Constitution about a President who has resigned. The…

  12. Constitutions compared : An introduction to comparative constitutional law

    NARCIS (Netherlands)

    Heringa, Aalt Willem

    2016-01-01

    This book provides a user-friendly introduction to comparative constitutional law. For each area of constitutional law, a general introduction and a comparative overview is provided, which is then followed by more detailed country chapters on that specific area. The subjects covered are the origins

  13. La Constitution économique parmi les Constitutions européennes

    OpenAIRE

    Kaarlo Tuori

    2011-01-01

    In the European context, the place of the revolutionary notions of constitutive power, demos and constitutional moment is occupied by the evolutionary concept of constitutionalisation. Economic constitution is merely one aspect in multi-dimensional European constitution (alisation). My tentative proposal is to distinguish between the following dimensions of constitution : economic constitution ; juridical constitution ; political constitution ; social constitution ; and security constitution....

  14. National constitutional courts in the European Constitutional Democracy

    DEFF Research Database (Denmark)

    Komárek, Jan

    2014-01-01

    This article critically assesses the transformation of national constitutional courts’ place in the law and politics of the EU and its member states. This process eliminates the difference between constitutional and ordinary national courts, which is crucial for the institutional implementation...... the EU and its member states, understood together as the European Constitutional Democracy—the central notion developed in this article in order to support an argument that should speak to both EU lawyers and national constitutionalists....... of the discourse theory of law and democracy. It also disrupts the symbiotic relationship between national constitutional democracies established after World War II and European integration. The article argues that maintaining the special place of national constitutional courts is in the vital interest of both...

  15. Mouse Lung Fibroblast Resistance to Fas-Mediated Apoptosis Is Dependent on the Baculoviral Inhibitor of Apoptosis Protein 4 and the Cellular FLICE-Inhibitory Protein

    Science.gov (United States)

    Predescu, Sanda A.; Zhang, Jian; Bardita, Cristina; Patel, Monal; Godbole, Varun; Predescu, Dan N.

    2017-01-01

    A characteristic feature of idiopathic pulmonary fibrosis (IPF) is accumulation of apoptotic resistant fibroblasts/myofibroblasts in the fibroblastic foci. As caveolin (Cav)-null mice develop pulmonary fibrosis (PF), we hypothesized that the participating fibroblasts display an apoptosis-resistant phenotype. To test this hypothesis and identify the molecular mechanisms involved we isolated lung fibroblasts from Cav-null mice and examined the expression of several inhibitors of apoptosis (IAPs), of c-FLIP, of Bcl-2 proteins and of the death receptor CD95/Fas. We found significant increase in XIAP and c-FLIP constitutive protein expression with no alteration of Bcl-2 and lower levels of CD95/Fas. The isolated fibroblasts were then treated with the CD95/Fas ligand (FasL) to induce apoptosis. While the morphological and biochemical alterations induced by FasL were similar in wild-type (wt) and Cav-null mouse lung fibroblasts, the time course and the extent of the alterations were greater in the Cav-null fibroblasts. Several salient features of Cav-null fibroblasts response such as loss of membrane potential, fragmentation of the mitochondrial continuum concurrent with caspase-8 activation, and subsequent Bid cleavage, prior to caspase-3 activation were detected. Furthermore, M30 antigen formation, phosphatidylserine expression and DNA fragmentation were caspase-3 dependent. SiRNA-mediated silencing of XIAP and c-FLIP, individually or combined, enhanced the sensitivity of lung fibroblasts to FasL-induced apoptosis. Pharmacological inhibition of Bcl-2 had no effect. Together our findings support a mechanism in which CD95/Fas engagement activates caspase-8, inducing mitochondrial apoptosis through Bid cleavage. XIAP and c-FLIP fine tune this process in a cell-type specific manner. PMID:28352235

  16. The Constitution and American Radicalism.

    Science.gov (United States)

    Lobel, Jules

    1987-01-01

    Discusses the history of the following movements' attitudes towards the Constitution: (1) abolition; (2) feminism; (3) trade unions; (4) socialism and communism; and (5) civil rights and anti-war. Maintains that the tensions in these movements' towards the Constitution represent basic contradictions in the document itself. (PS)

  17. The Constitution and Its Critics

    Science.gov (United States)

    Main, Thomas J.

    2011-01-01

    In planning a freshman undergraduate curriculum with colleagues recently, the question arose as to what type of understanding educators wanted to impart to their students about the Constitution. The alleged defects of the Constitution that these books point to are wide-ranging and can be classified into various categories. Some problems--such as…

  18. Constitutive Effects of Performance Indicators

    DEFF Research Database (Denmark)

    Dahler-Larsen, Peter

    2014-01-01

    that are demonstrably problematic. Based on a distinction between trivial and advanced measure fixation, an argument is made for constitutive effects that are based on less problematic assumptions. Through this conceptual move, the political dimension of performance indicators is appreciated. The conceptual dimensions...... of constitutive effects are carved out, empirical illustrations of their applicability are offered and implications discussed....

  19. Constitutive rules, language, and ontology

    NARCIS (Netherlands)

    Hindriks, Frank

    It is a commonplace within philosophy that the ontology of institutions can be captured in terms of constitutive rules. What exactly such rules are, however, is not well understood. They are usually contrasted to regulative rules: constitutive rules (such as the rules of chess) make institutional

  20. Apoptosis in oral erythema multiforme.

    Science.gov (United States)

    Chrysomali, E; Lozada-Nur, F; Dekker, N P; Papanicolaou, S I; Regezi, J A

    1997-02-01

    Cell death was evaluated in oral erythema multiforme to test the hypothesis that apoptosis may be a mechanism by which keratinocytes die in this condition. Ten erythema multiforme and five control oral mucosa biopsy specimens were evaluated in immunohistochemically stained sections for apoptosis-regulating proteins Bcl-2, Bcl-x, Bax, p53, Fas, and Fas-ligand. Apoptotic keratinocytes, determined by a detection method for DNA fragmentation (TUNEL) and by conventional morphologic criteria were counted per high power field. Keratinocyte staining for Bcl-2 protein was comparable in erythema multiforme and controls. Bcl-x expression was reduced in five erythema multiforme cases. Staining for Bax protein differed in six erythema multiforme cases and showed variable intensity in layers under the parakeratin. Only slight differences in staining patterns of Fas and Fas-ligand proteins were noted between erythema multiforme and controls. The number of apoptotic keratinocytes evaluated by morphologic examination was significantly higher in erythema multiforme (mean per high power field, 0.90 +/- 0.2; controls, 0.06 +/- 0.04; p < 0.05, Mann-Whitney test) and was limited in significance by the TUNEL method (erythema multiforme, 0.43 +/- 0.1; controls, 0.02 +/- 0.02). Overexpression of p53 protein was seen in basal keratinocytes in five erythema multiforme specimens (mean, 17.5 +/- 4.03 per high power field; controls 1.2 +/- 0.3). There is evidence that cell death in erythema multiforme is at least in part due to apoptosis. The apoptotic mechanism may be related to an altered expression of apoptosis-regulating proteins. Although measurable alterations in the phenotypic expression of Fas and Fas-ligand proteins were not apparent, activation of Fas/Fas-ligand system could still be involved in the induction of apoptosis in erythema multiforme.

  1. Legal theology in imposed constitutionalism

    DEFF Research Database (Denmark)

    Abat Ninet, Antoni

    2018-01-01

    The focus of this paper is the question of legitimacy, and how can we consider legitimate an imposed constitution and the subsequent constitutional principles, practices and values that go hand-in-hand with the legal and political acculturation. Constitutional texts around the world are good...... examples of transposition and complicity of theological and juridical thoughts. For the purpose of this paper, imposed constitutions are political and legal norms of a state enacted and enforced without the free and full agreement of the Demos. Legal theology implies the application of religious phenomena......, theories and concepts to achieve undisputed legal legitimacy. Imposed constitutions as rules imposed for salvation for those “Platonic Philosophes” who have seen the “light”, that known the episteme are paramount examples of legal and political theology. The paper has two main sections. The first one...

  2. IRE1α-TRAF2-ASK1 pathway is involved in CSTMP-induced apoptosis and ER stress in human non-small cell lung cancer A549 cells.

    Science.gov (United States)

    Zhang, Jiexia; Liang, Ying; Lin, Yongbin; Liu, Yuanbin; YouYou; Yin, Weiqiang

    2016-08-01

    CSTMP, a Tetramethylpyrazine (TMP) analogue, is designed and synthesized based on the pharmacophores of TMP and resveratrol. Recent studies showed that CSTMP had strong protective effects in endothelial cells apoptosis by its anti-oxidant activity. However, the pharmacological function of CSTMP in cancer have not been elucidated to date. The objective of this study was to investigate the anti-cancer effect of CSTMP against human non-small cell lung cancer (NSCLC) A549 cells and the underlying mechanisms. The cell proliferation and apoptosis were detected by MTT assay and flow cytometry. Caspases activity was determined spectrophotometricaly at 405nm using a microtiter plate reader. Western blot and real-time PCR was used to assess the protein and mRNA expression. Immunoprecipitation was used to examine the protein-protein interactions. CSTMP inhibited the proliferation and induced cell cycle arrest and apoptosis of A549 cells. Caspase3, 8, 9 and PARP-1 activation, and Bax/Bcl-2 ratio analyses demonstrated that the anti-cancer effect of CSTMP in A549 cells was mediated by promoting caspase- and mitochondria-dependent apoptosis. Furthermore, CSTMP induced ER stress in A549 cells as evidenced by elevated levels of GRP78, GRP94, CHOP, IRE1α, TRAF2, p-ASK1 and p-JNK, activation of caspase12 and 4, and enhanced formation of an IRE1α-TRAF2-ASK1 complex. Knockdown of IRE1α by siRNA suppressed activation of IRE1α, TRAF2, p-ASK1 and p-JNK in CSTMP treated A549 cells. In addition, the effects of CSTMP on the formation of an IRE1α-TRAF2-ASK1 complex, caspase- and mitochondria-dependent apoptosis were also reversed by IRE1α siRNA in A549 cells. Collectively, we showed that CSTMP induced apoptosis of A549 cells were through IRE1α-TRAF2-ASK1 complex-mediated ER stress, JNK activation, and mitochondrial dysfunction. These insights on this novel compound CSTMP may provide a novel anti-cancer candidate for the treatment of NSCLC. Copyright © 2016 Elsevier Masson SAS. All

  3. Fluid shear stress suppresses TNF-α-induced apoptosis in MC3T3-E1 cells: Involvement of ERK5-AKT-FoxO3a-Bim/FasL signaling pathways

    International Nuclear Information System (INIS)

    Bin, Geng; Bo, Zhang; Jing, Wang; Jin, Jiang; Xiaoyi, Tan; Cong, Chen; Liping, An; Jinglin, Ma; Cuifang, Wang; Yonggang, Chen; Yayi, Xia

    2016-01-01

    TNF-α is known to induce osteoblasts apoptosis, whereas mechanical stimulation has been shown to enhance osteoblast survival. In the present study, we found that mechanical stimulation in the form of fluid shear stress (FSS) suppresses TNF-α induced apoptosis in MC3T3-E1 cells. Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family that has been implicated in cell survival. We also demonstrated that FSS imposed by flow chamber in vitro leads to a markedly activation of ERK5, which was shown to be protective against TNF-α-induced apoptosis, whereas the transfection of siRNA against ERK5 (ERK5-siRNA) reversed the FSS-medicated anti-apoptotic effects. An initial FSS-mediated activation of ERK5 that phosphorylates AKT to increase its activity, and a following forkhead box O 3a (FoxO3a) was phosphorylated by activated AKT. Phosphorylated FoxO3a is sequestered in the cytoplasm, and prevents it from translocating to nucleus where it can increase the expression of FasL and Bim. The inhibition of AKT-FoxO3a signalings by a PI3K (PI3-kinase)/AKT inhibitor (LY294002) or the transfection of ERK5-siRNA led to the nuclear translocation of non-phosphorylated FoxO3a, and increased the protein expression of FasL and Bim. In addition, the activation of caspase-3 by TNF-α was significantly inhibited by aforementioned FSS-medicated mechanisms. In brief, the activation of ERK5-AKT-FoxO3a signaling pathways by FSS resulted in a decreased expression of FasL and Bim and an inhibition of caspase-3 activation, which exerts a protective effect that prevents osteoblasts from apoptosis. - Highlights: • Fluid shear stress inhibits osteoblast apoptosis induced by TNF-α. • Inhibition of ERK5 activity by transfection of ERK5 siRNA blocks FSS-mediated anti-apoptotic effect in osteoblast. • Activated ERK5-AKT-FoxO3a-Bim/FasL signaling pathways by FSS is required to protect osteoblast from apoptosis.

  4. Fluid shear stress suppresses TNF-α-induced apoptosis in MC3T3-E1 cells: Involvement of ERK5-AKT-FoxO3a-Bim/FasL signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Bin, Geng; Bo, Zhang; Jing, Wang; Jin, Jiang; Xiaoyi, Tan; Cong, Chen; Liping, An; Jinglin, Ma; Cuifang, Wang; Yonggang, Chen [The Second Hospital of Lanzhou University, #82 Cuiyingmen, Lanzhou, 730000 Gansu (China); Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000 Gansu (China); Yayi, Xia, E-mail: xiayayildey@163.com [The Second Hospital of Lanzhou University, #82 Cuiyingmen, Lanzhou, 730000 Gansu (China); Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000 Gansu (China)

    2016-05-01

    TNF-α is known to induce osteoblasts apoptosis, whereas mechanical stimulation has been shown to enhance osteoblast survival. In the present study, we found that mechanical stimulation in the form of fluid shear stress (FSS) suppresses TNF-α induced apoptosis in MC3T3-E1 cells. Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family that has been implicated in cell survival. We also demonstrated that FSS imposed by flow chamber in vitro leads to a markedly activation of ERK5, which was shown to be protective against TNF-α-induced apoptosis, whereas the transfection of siRNA against ERK5 (ERK5-siRNA) reversed the FSS-medicated anti-apoptotic effects. An initial FSS-mediated activation of ERK5 that phosphorylates AKT to increase its activity, and a following forkhead box O 3a (FoxO3a) was phosphorylated by activated AKT. Phosphorylated FoxO3a is sequestered in the cytoplasm, and prevents it from translocating to nucleus where it can increase the expression of FasL and Bim. The inhibition of AKT-FoxO3a signalings by a PI3K (PI3-kinase)/AKT inhibitor (LY294002) or the transfection of ERK5-siRNA led to the nuclear translocation of non-phosphorylated FoxO3a, and increased the protein expression of FasL and Bim. In addition, the activation of caspase-3 by TNF-α was significantly inhibited by aforementioned FSS-medicated mechanisms. In brief, the activation of ERK5-AKT-FoxO3a signaling pathways by FSS resulted in a decreased expression of FasL and Bim and an inhibition of caspase-3 activation, which exerts a protective effect that prevents osteoblasts from apoptosis. - Highlights: • Fluid shear stress inhibits osteoblast apoptosis induced by TNF-α. • Inhibition of ERK5 activity by transfection of ERK5 siRNA blocks FSS-mediated anti-apoptotic effect in osteoblast. • Activated ERK5-AKT-FoxO3a-Bim/FasL signaling pathways by FSS is required to protect osteoblast from apoptosis.

  5. Mitochondrial disfunction and apoptosis in leukemia cells

    Directory of Open Access Journals (Sweden)

    Annamaria PALLAG

    2008-05-01

    Full Text Available Apoptosis or programmed cell death is a process which involves the intentional degradation of the cell from the inside, the participation of the mitochondria to propagate the apoptotic signal, the alteration of the phospholipid cell membrane composition, the perturbation and alteration of the cell metabolism.The antineoplastic drugs is inducing the apoptotic process in the sensitive cells.It have been studied acute lymphoblastic leukemia cells. Using Annexin V-PE Apoptosis Detection Kit and flow cytometer, the amount of cells undergoing apoptosis, in various stages of the antineoplasic treatment, was detected. At the same time, were monitored, the serum level of malondialdehyde. The results obtained confirm the alteration of the mitochondrial metabolism. We can observed the mitochondrial dysfunction role in cell apoptosis.

  6. Cellular response after irradiation: Cell cycle control and apoptosis

    International Nuclear Information System (INIS)

    Siles, E.; Valenzuela, M.T.; Nunez, M.I.; Guerrero, R.; Villalobos, M.; Ruiz de Almodovar, J.M.

    1997-01-01

    The importance of apoptotic death was assessed in a set of experiments, involving eight human tumour cell lines (breast cancer, bladder carcinoma, medulloblastoma). Various aspects of the quantitative study of apoptosis and methods based on the detection of DNA fragmentation (in situ tailing and comet assay) are described and discussed. Data obtained support the hypothesis that apoptosis is not crucial for cellular radiosensitivity and that the relationship between p53 functionality or clonogenic survival and apoptosis may bee cell type specific. (author)

  7. Apoptosis of neutrophils

    NARCIS (Netherlands)

    Maianski, N. A.; Maianski, A. N.; Kuijpers, T. W.; Roos, D.

    2004-01-01

    Regulation of the neutrophil life span by apoptosis provides a fine balance between their function as effector cells of host defense and a safe turnover of these potentially harmful cells. Alterations of neutrophil apoptosis are associated with a number of diseases. As do other cell types,

  8. Ubiquitination in apoptosis signaling

    NARCIS (Netherlands)

    van de Kooij, L.W.

    2014-01-01

    The work described in this thesis focuses on ubiquitination and protein degradation, with an emphasis on how these processes regulate apoptosis signaling. More specifically, our aims were: 1. To increase the understanding of ubiquitin-mediated regulation of apoptosis signaling. 2. To identify the E3

  9. Hyperthermia-induced apoptosis

    NARCIS (Netherlands)

    Nijhuis, E.H.A.

    2008-01-01

    This thesis describes a number of studies that investigated several aspects of heat-induced apoptosis in human lymphoid malignancies. Cells harbour both pro- and anti-apoptotic proteins and the balance between these proteins determines whether a cell is susceptible to undergo apoptosis. In this

  10. The Constitution's Prescription for Freedom.

    Science.gov (United States)

    Peach, Lucinda

    1986-01-01

    Examines how the framers of the Constitution came to choose our system of government, how that system was designed to function, and how the separation of powers has served to maintain our democracy despite attempts to violate it. (JDH)

  11. Constitutive Modelling in Geomechanics Introduction

    CERN Document Server

    Puzrin, Alexander M

    2012-01-01

    The purpose of this book is to bridge the gap between the traditional Geomechanics and Numerical Geotechnical Modelling with applications in science and practice. Geomechanics is rarely taught within the rigorous context of Continuum Mechanics and Thermodynamics, while when it comes to Numerical Modelling, commercially available finite elements or finite differences software utilize constitutive relationships within the rigorous framework. As a result, young scientists and engineers have to learn the challenging subject of constitutive modelling from a program manual and often end up with using unrealistic models which violate the Laws of Thermodynamics.  The book is introductory, by no means does it claim any completeness and state of the art in such a dynamically developing field as numerical and constitutive modelling of soils. The author gives basic understanding of conventional continuum mechanics approaches to constitutive modelling, which can serve as a foundation for exploring more advanced theories....

  12. The merits of global constitutionalism

    Directory of Open Access Journals (Sweden)

    Anne Peters

    2017-12-01

    Full Text Available Global constitutionalism is an agenda that identifies and advocates for the application of constitutionalist principles in the international legal sphere. Global constitutionalization is the gradual emergence of constitutionalist features in international law. Critics of global constitutionalism doubt the empirical reality of constitutionalization, call into question the analytic value of constitutionalism as an academic approach, and fear that the discourse is normatively dangerous because it is anti-pluralist, artificially creates a false legitimacy, and promises an unrealistic end of politics. This article addresses these objections. I argue that global constitutionalization is likely to compensate for globalization induced constitutionalist deficits on the national level, that a constitutionalist reading of international law can serve as a hermeneutic device, and that the constitutionalist vocabulary uncovers legitimacy deficits of international law and suggests remedies. Global constitutionalism, therefore, has a responsibilizing and much-needed critical potential.

  13. A survey on constitutional justice

    Directory of Open Access Journals (Sweden)

    Kheirollah Parvin

    2015-05-01

    Full Text Available The idea of supervising the conformity of statutory law with constitutional law, is due to necessities rooted in two essential principles: the supremacy of constitution and the hierarchy of the law. Constitution as the supreme law in the sense of status and legal value , is placed at the top of the legal pyramid of every political system and therefore requires a special organization and discipline that will act as the sanction of the principles and the main content incorporated in this legal instrument. this special organization and discipline known as Constitutional justice in legal Literature now and have studing in two main patterns. Firs pattern based on Supervision of courts on rules and other pattern is Apply by Emphasis on role of Political Institutions in Supervision on rules. This two patterns have common purpose but have different backgrounds and methods.

  14. Cleanup liability and the Constitution

    International Nuclear Information System (INIS)

    Friedland, D.M.; Hagen, P.E.

    1992-01-01

    It was observed in the July 1992 issue of this Journal that a plain reading of the Constitution's prohibition on open-quotes ex post factoclose quotes suggests that some environmental statutes such as the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund) and the Resource Conservation and Recovery Act of 1976 (RCRA) conflict with Constitutional principles. Like many Constitutional principles, however, the Supreme Court's interpretation of the Constitution's bar on ex post facto laws has a long history. The Court has consistently interpreted this clause as limited to criminal or penal statutes. This article discusses the history of the ex post facto clause, the retroactive application of CERCLA and RCRA, the decision that retroactive application of CERCLA and RCRA does not violate the ex post facto clause, and laws, regulations, and guidance. 27 refs

  15. CONSTITUTIONALISM

    African Journals Online (AJOL)

    eliasn

    Mao Zedong's statement seems to hold true in the contemporary world as well. In democratic countries, it is the democratically elected officials who are allowed to govern or control the military, although technical affairs are left to the military personnel. Instead, if full autonomy or sovereignty is granted to the military leaders,.

  16. Constitutional Verbosity and Social Trust

    DEFF Research Database (Denmark)

    Bjørnskov, Christian; Voigt, Stefan

    2014-01-01

    A common argument in the trust literature is that high-trust cultures allow efficient commercial contracts to be shorter, covering fewer contingencies. We take this idea to the topic of social contracts. Specifically, we ask whether social trust affects the length and detail of constitutions. Cross......-country estimates suggest that national trust levels are indeed robustly and negatively associated with the length of countries’ constitutions....

  17. Global Survey of National Constitutions

    Science.gov (United States)

    Perehudoff, Katrina

    2017-01-01

    Abstract General Comment No. 22, issued in 2016 by the Committee on Economic, Social and Cultural Rights (CESCR), clarifies states’ legal duties to respect, protect, and fulfill the right to sexual and reproductive health (SRH). Our study analyzes domestic constitutions around the world to investigate whether and to what extent the right to sexual and reproductive health is respected, protected, and fulfilled; to what extent these provisions are inclusive and non-discriminatory; and to what degree the interlinkages between this and other human rights are acknowledged. Of the 195 constitutions accessed, 27 enshrine sexual and/or reproductive health, and seven adopt restrictive approaches to this right. In the 27 constitutions, provisions most frequently enshrine respect of one’s sexual health and family planning decisions, the protection of sexual health, and the provision of reproductive health care and family planning services (fulfillment). Most of the 27 constitutions fail to adequately respect reproductive health rights; to protect reproductive health, family planning, and abortion services from third-party interference; and to fulfill all dimensions of sexual health and access to abortion. Three of the 27 constitutions enshrine a universal right to SRH, and additional constitutions protect specific vulnerable groups (such as women, children) and/or restrict the scope of rights holders to couples. Among the 27 constitutions, nine explicitly link the right to sexual and reproductive health to the rights to education, science, and/or to make autonomous decisions about sexuality and reproduction. Our results can serve as a baseline measure to track constitutional reforms in pursuit of the realization of sexual and reproductive health and rights, and as building blocks for future lawmakers committed to realizing these rights through domestic legal reform. PMID:29302182

  18. Right Product, Wrong Packaging: Not 'Constitution', but 'Constitutional Charter'

    Directory of Open Access Journals (Sweden)

    John Law

    2007-05-01

    Full Text Available The article seeks to locate the principal cause of Europe’s prevailing ratification crisis in the inappropriate title arrived at in the European Convention, Treaty Establishing a Constitution for Europe. This over-ambitious styling led the media to characterise the text as simply an ‘EU Constitution’. Yet, the text was not a Constitution as we traditionally understand the term, i.e. the founding document of a State: scholars are agreed that the EU is not, and will not become upon ratification, a State.In terms of substance, whilst the text certainly strengthened some emerging constitutional aspects, it was not a major departure from the status quo like the Single European Act and Treaty on European Union had been; and it remained technically a treaty like all its predecessors. Arguably, therefore, it did not require referenda to ratify. However, confusion over the scale and importance of what was proposed, stemming from ambiguity in the title, pushed politicians down this unfortunate path.The article identifies a high level of consensus among commentators as to the true nature of the text: most are happy designating it a treaty (noun with constitutional (adjective aspects. The early proposed title Constitutional Treaty for Europe was arguably, therefore, the correct one; but it is now too late to choose this option, as the terms Constitution and Constitutional Treaty have already been muddled in debate. A more distinctive change is required. One idea could be to follow the principle employed elsewhere in the text of codifying the generally accepted but presently unwritten legal concepts of the European Court of Justice, as was done for example for ‘primacy’ and ‘direct effect’. The Court has characterised the EU treaties as a ‘constitutional charter’ for over twenty years now, and on this basis a modified title could read Treaty Establishing a Constitutional Charter for Europe. Importantly, the term ‘charter’ is recognised

  19. Restoring Sensitivity to Apoptosis in Prostate Cancer Cells by Reconstitution of the Tumor Suppressor PTEN

    National Research Council Canada - National Science Library

    Whang, Young

    2003-01-01

    ... suppressor PTEN in regulating sensitivity to apoptosis in prostate cancer. We have previously shown that loss of HEN function leads to excessive antiapoptotic signaling through constitutive activation of the Akt protein kinase...

  20. Ambiguous involvement

    DEFF Research Database (Denmark)

    Dannesboe, Karen Ida

    2016-01-01

    This edited collection shows that good parenthood is neither fixed nor stable. The contributors show how parenthood is equally done by men, women and children, in and through practices involving different normative guidelines. The book explores how normative layers of parenthood are constituted...... by notions such as good childhood, family ideals, national public health and educational strategies. The authors illustrate how different versions of parenthood coexist and how complex sets of actions are demanded to fulfil today’s expectations of parenthood in Western societies. This interdisciplinary book...

  1. Identification of miR-508-3p and miR-509-3p that are associated with cell invasion and migration and involved in the apoptosis of renal cell carcinoma

    International Nuclear Information System (INIS)

    Zhai, Qingna; Zhou, Liang; Zhao, Chunjuan; Wan, Jun; Yu, Zhendong; Guo, Xin; Qin, Jie; Chen, Jing; Lu, Ruijing

    2012-01-01

    Highlights: ► Previous method was the second-generation sequencing technology. ► miR-508-3p and miR-509-3p were significantly down-regulated in RCC tissues. ► They can inhibit cell proliferation and migration and promote cell apoptosis. ► The expression of miR-508-3p was significantly decreased in RCC patients plasma. ► miR-508-3p may be a novel diagnostic marker of RCC. -- Abstract: MicroRNAs (miRNAs) have emerged as powerful regulators of multiple processes linked to human cancer, including cell apoptosis, proliferation and migration, suggesting that the regulation of miRNA function could play a critical role in cancer progression. Recent studies have found that human serum/plasma contains stably expressed miRNAs. If they prove indicative of disease states, miRNAs measured from peripheral blood samples may be a source for routine clinical detection of cancer. Our studies showed that both miR-508-3p and miR-509-3p were down-regulated in renal cancer tissues. The level of miR-508-3p but not miR-509-3p in renal cell carcinoma (RCC) patient plasma demonstrated significant differences from that in control plasma. In addition, the overexpression of miR-508-3p and miR-509-3p suppressed the proliferation of RCC cells (786-0), induced cell apoptosis and inhibited cell migration in vitro. Our data demonstrated that miR-508-3p and miR-509-3p played an important role as tumor suppressor genes during tumor formation and that they may serve as novel diagnostic markers for RCC.

  2. Kelussia odoratissima Mozaff. activates intrinsic pathway of apoptosis in breast cancer cells associated with S phase cell cycle arrest via involvement of p21/p27 in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Karimian H

    2017-02-01

    Full Text Available Hamed Karimian,1 Aditya Arya,2 Mehran Fadaeinasab,3 Mahboubeh Razavi,1 Maryam Hajrezaei,4 Ataul Karim Khan,1 Hapipah Mohd Ali,3 Mahmood Ameen Abdulla,4 Mohamad Ibrahim Noordin1,5 1Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, 2School of Medicine, Taylor’s University, Subang Jaya, 3Centre for Natural Products Research and Drug Discovery, 4Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, 5Malaysian Institute of Pharmaceuticals and Nutraceuticals (IPharm, Pulau Pinang, Malaysia Background: The aim of this study was to evaluate the anticancer potential of Kelussia odoratissima. Several in vitro and in vivo biological assays were applied to explore the direct effect of an extract and bioactive compound of this plant against breast cancer cells and its possible mechanism of action. Materials and methods: K. odoratissima methanol extract (KME was prepared, and MTT assay was used to evaluate the cytotoxicity. To identify the cytotoxic compound, a bioassay-guided investigation was performed on methanol extract. 8-Hydroxy-ar-turmerone was isolated as a bioactive compound. In vivo study was performed in the breast cancer rat model. LA7 cell line was used to induce the breast tumor. Histopathological and expression changes of PCNA, Bcl-2, Bax, p27 and p21 and caspase-3 were examined. The induction of apoptosis was tested using Annexin V-fluorescein isothiocyanate (FITC assay. To confirm the intrinsic pathway of apoptosis, caspase-7 and caspase-9 assays were utilized. In addition, cell cycle arrest was evaluated. Results: Our results demonstrated that K. odoratissima has an obvious effect on the arrest of proliferation of cancer cells. It induced apoptosis, transduced the cell death signals, decreased the threshold of mitochondrial membrane potential (MMP, upregulated Bax and downregulated Bcl-2. Conclusion: This study demonstrated that K. odoratissima exhibits antitumor activity

  3. Mechanism of constitution liquid film migration

    Energy Technology Data Exchange (ETDEWEB)

    Zuo, Hongjun [Univ. of Alabama, Birmingham, AL (United States)

    1999-06-01

    Liquid film migration (LFM) in liquid phase sintering classically involves a large metastable liquid volume adjacent to solid, and migration occurs at an isolated solid-liquid (S-L) interface. Constitutional liquid film migration (CLFM), discovered in alloy 718, has major characteristics similar to those of LFM, except that the metastable liquid is from the constitutional liquation of precipitates on the grain boundary. The similarity between LFM and CLFM has led to the theory that coherency lattice strain responsible for LFM is also responsible for CLFM. The coherency strain hypothesis was tested in this study by evaluating whether the Hillert model of LFM would also apply for CLFM. Experimental results of CLFM in alloy 718 showed that migration velocity followed the trend predicted by the Hillert model. This indicates that the coherency strain hypothesis of LFM also applies for CLFM and that the coherency lattice strain responsible for LFM is also the driving force for CLFM.

  4. Laboratory investigation of constitutive property scaling behavior

    International Nuclear Information System (INIS)

    Tidwell, V.C.

    1994-01-01

    Because many constitutive rock properties must be measured at one scale but applied at another, scaling behavior is an issue facing many applied disciplines, including the petroleum industry. A research program has been established to investigate and a quantify scaling behavior through systematic physical experimentation, with the aim of developing and testing models that describe scaling behavior in a quantitative manner. Scaling of constitutive rock properties is investigated through physical experimentation involving the collection of gas-permeability data measured over a range of discrete scales. The approach is to systematically isolate those factors that influence property scaling and investigate their relative contributions to overall scaling behavior. Two blocks of rock, each exhibiting differing heterogeneity structure. have recently been examined. The two samples were found to yield different scaling behavior, as exhibited by changes in the distribution functions and semi-variograms. Simple models have been fit to the measured scaling behavior that are of similar functional form but of different magnitude

  5. Constitutional problems in the handling of plutonium

    International Nuclear Information System (INIS)

    Witt, S. de.

    1989-01-01

    Reprocessing and final storage involve two different systems of nuclear energy utilization: with or without the use of plutonium. There is a choice available between these two systems. The paper discusss the constitutional implications of this choice. The permission of the use of plutonium as nuclear fuel by the Atomic Energy Law is irreconcilable with the Basic Law, i.e. the Constitution. If the corresponding provisions of the Atomic Energy Law are repealed, then only the plutonium-related branch will be revoked and not the legal permission of nuclear energy as a whole. The fact is not ignored that the Atomic Energy law does not permit the construction and operation of a plant or the handling of plutonium if this were to violate a basic right. However, the plutonium-related branch of nculear energy utilization inevitably results in such basic right violations; hence the Atomic Energy law is unconstitutional in this respect. (orig./HSCH) [de

  6. Caspases: An apoptosis mediator

    Directory of Open Access Journals (Sweden)

    Tapan Kumar Palai

    2015-03-01

    Full Text Available The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy - dependent biochemical mechanisms. Apoptosis is a widely conserved phenomenon helping many processes, including normal cell turnover, proper development and functioning of the immune system, hormone dependent atrophy etc. Inappropriate apoptosis (either low level or high level leads to many developmental abnormalities like, neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. To use cells for therapeutic purposes through generating cell lines, it is critical to study the cell cycle machinery and signalling pathways that controls cell death and apoptosis. Apoptotic pathways provide a fundamental protective mechanism that decreases cellular sensitivity to damaging events and allow proper developmental process in multi-cellular organisms. Major mediator of apoptosis is a family of proteins known as caspases. There are mainly fourteen types of caspases but out of them only ten caspasese have got essential role in controlling the process of apoptosis. These ten caspases have been categorized into either initiator caspases (caspase 2, 8, 9, 10 or executioner caspases (caspase 3, 6, 7. Although various types of caspases have been identified so far, the exact mechanisms of action of these groups of proteins is still to be fully understood. The aim of this review is to provide a detail overview of role of different caspases in regulating the process of apoptosis.

  7. Constitutional compatibility of energy systems

    International Nuclear Information System (INIS)

    Rossnagel, A.

    1983-01-01

    The paper starts from the results of the Enquiry Commission on 'Future Nuclear Energy Policy' of the 8th Federal German Parliament outlining technically feasible energy futures in four 'pathways'. For the purpose of the project, which was to establish the comparative advantages and disadvantages of different energy systems, these four scenarios were reduced to two alternatives: cases K (= nuclear energy) and S (= solar energy). The question to Ge put is: Which changes within our legal system will be ushered in by certain technological developments and how do these changes relate to the legal condition intended so far. Proceeding in this manner will not lead to the result of a nuclear energy system or a solar energy system being in conformity or in contradiction with the constitutional law, but will provide a catalogue of implications orientated to the aims of legal standards: a person deciding in favour of a nuclear energy system or a solar energy system supports this or that development of constitutional policy, and a person purishing this or that aim of legal policy should be consistent and decide in favour of this or that energy system. The investigation of constitutional compatibility leads to the question what effects different energy systems will have on the forms of political intercourse laid down in the constitutional law, which are orientated to models of a liberal constitutional tradition of citizens. (orig./HSCH) [de

  8. Environmental liability in constitutional law

    Directory of Open Access Journals (Sweden)

    Larissa Gabrielle Braga e Silva

    2016-04-01

    Full Text Available This article is scope to undertake a study of the Brazilian constitutional treatment given to environmental liability institute. This institute enters the constitutional law of special and unique way in the Constitution of the Federative Republic of Brazil in 1988, stamped on Article 225, third paragraph. The Federal Constitution gives broad protection to the environment and inserts it into the list of social rights and assigns it still status of fundamental right. With regard to environmental liability, the Constitution welcomes the normative content of Article 14, first paragraph, of the Act establishing the National Environmental Policy, Law 6.938 / 81, and includes the environmental objective accountability. The study called State Environmental Law is the new and necessary law paradigm that conjunctiva presents proposal of economic, social, cultural and environmental rights and advocates the idea of a broad existential minimum, not merely physical or biological. Finally, the liability was highlighted in its objective application in their individual and collective achievements. The literature review was the methodology used, whose deductive method to corroborate the findings made by this study. It is concluded that environmental liability is an institute that is associated with the consolidation of a Social and Environmental rule of law and that this is a challenge that everyone, without distinction, is presented.

  9. Shifting the balance of mitochondrial apoptosis: therapeutic perspectives

    International Nuclear Information System (INIS)

    Fulda, Simone

    2012-01-01

    Signaling via the intrinsic (mitochondrial) pathway of apoptosis represents one of the critical signal transduction cascades that control the regulation of cell death. This pathway is typically altered in human cancers, thereby providing a suitable target for therapeutic intervention. Members of the Bcl-2 family of proteins as well as cell survival signaling cascades such as the PI3K/Akt/mTOR pathway are involved in the regulation of mitochondria-mediated apoptosis. Therefore, further insights into the molecular mechanisms that form the basis for the control of mitochondria-mediated apoptosis will likely open new perspectives to bypass evasion of apoptosis and treatment resistance in human cancers.

  10. Shifting the balance of mitochondrial apoptosis: therapeutic perspectives

    Directory of Open Access Journals (Sweden)

    Simone eFulda

    2012-10-01

    Full Text Available Signaling via the intrinsic (mitochondrial pathway of apoptosis represents one of the critical signal transduction cascades that control the regulation of cell death. This pathway is typically altered in human cancers, thereby providing a suitable target for therapeutic intervention. Members of the Bcl-2 family of proteins as well as cell survival signaling cascades such as the PI3K/Akt/mTOR pathway are involved in the regulation of mitochondria-mediated apoptosis. Therefore, further insights into the molecular mechanisms that form the basis for the control of mitochondria-mediated apoptosis will likely open new perspectives to bypass evasion of apoptosis and treatment resistance in human cancers.

  11. Constitutionalism and Development in Nigeria: The 1999 Constitution

    African Journals Online (AJOL)

    Fr. Ikenga

    The Nigeria nation has experienced many Constitutional changes since Sir. Frederick Lugard in 1914 to the .... Exclusive for the Federal Government and Concurrent for both Federal and Regional. Residual matters were also left for .... Mechanism for stability in the polity and change of government e. Adoption to economic ...

  12. Time and constitution of sense

    Directory of Open Access Journals (Sweden)

    Pedro Gerardo Acosta

    2014-06-01

    Full Text Available This article proposes a reflection over our time-consciousness under the Phenomenology of Edmund Husserl. The idea is make a release the key role of the sense constitution like the fundament and development of the ongoing intentionality, a shape that make the possibility to catch sight of the sense of every life situation like conscience experience that displays itself over the time, and open the world of the Phenomenon World, constituted in the flux and flow of our live experience. The immanent time in which the things served in a lived-present inevitably displays to its own immediate-past of retentions, then of commemorations, constituting and enabling, not just the sense of ever present, but the sense of our own past like memory and our future like expectative. This reflection is based and supporter over the text “Phenomenology Lesson of the Internal Time-Consiusness” (Husserl, 2002.

  13. Immigration, naturalization and the Constitution.

    Science.gov (United States)

    Vecoli, R J

    1987-03-01

    This essay focuses upon major decisions made by the US government affecting aliens and the constitutional bases for them. These include: 1) the admission and exclusion of aliens, 2) the deportation of aliens, 3) the rights of aliens within the US, and 4) naturalization and denaturalization. The recourse to the extra-constitutional doctrine of sovereignty by the Supreme Court was the source of the plenary power of the Congress over immigration, thus denying the authority of the judiciary to extend the guarantees of due process of law and the equal protection of the law to aliens. The courts in the last 2 decades have assumed a more activist posture with respect to the rights of aliens, extending a greater degree of constitutional protection to the security of acquired citizenship and to the rights of due process and equal protection of foreigners, even to undocumented aliens.

  14. Constitutional Analysis of Intellectual Property

    Directory of Open Access Journals (Sweden)

    AJ van der Walt

    2014-04-01

    Full Text Available This article analyses the Constitutional Court’s treatment of property interests in the face of state regulation to gain an understanding of the type of state interference that is justifiable in terms of section 25(1 of the Bill of Rights. This is done by examining the Constitutional Court’s dicta relating to the meaning of deprivation and how these inform the meaning of property in the constitutional context. The methodology that the Constitutional Court has formulated to assess if state interference complies with the provisions of section 25 is explained to show the type of state regulation that has been found legitimate. We then consider how this understanding of constitutional property and the state’s legitimate exercise of its inherent police power interact in the setting of intellectual property by contrasting the various policy objectives underlying the different statutory regimes governing intellectual property. This theoretical analysis is then applied to two contemporary examples of feasible state interference with existing intellectual property interests, namely the proposed plain packaging measures which severely restrict the use of tobacco trade marks, and a fair dealing exception allowing the use of copyright works for the purpose of parody. These examples serve to illustrate the context and manner in which intellectual property interests may come before the Court and the necessary differentiation with which these interests should be treated. The appropriate judicial assessment of the true impact that state action could have on vested property interests is explained and contrasted with the balancing exercise that is employed at the earlier stage of policy making. This discussion is concluded by highlighting some of the interpretational issues that will arise and how some constitutional values could be curtailed in the absence of legislative intervention.

  15. 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.

  16. Aspartame-induced apoptosis in PC12 cells.

    Science.gov (United States)

    Horio, Yukari; Sun, Yongkun; Liu, Chuang; Saito, Takeshi; Kurasaki, Masaaki

    2014-01-01

    Aspartame is an artificial sweetner added to many low-calorie foods. The safety of aspartame remains controversial even though there are many studies on its risks. In this study, to understand the physiological effects of trace amounts of artificial sweetners on cells, the effects of aspartame on apoptosis were investigated using a PC12 cell system. In addition, the mechanism of apoptosis induced by aspartame in PC12 cells and effects on apoptotic factors such as cytochrome c, apoptosis-inducing factor, and caspase family proteins were studied by Western blotting and RT-PCR. Aspartame-induced apoptosis in PC12 cells in a dose-dependent manner. In addition, aspartame exposure increased the expressions of caspases 8 and 9, and cytochrome c. These results indicate that aspartame induces apoptosis mainly via mitochondrial pathway involved in apoptosis due to oxigen toxicity. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Apoptosis in Pneumovirus Infection

    Directory of Open Access Journals (Sweden)

    Reinout A. Bem

    2013-01-01

    Full Text Available Pneumovirus infections cause a wide spectrum of respiratory disease in humans and animals. The airway epithelium is the major site of pneumovirus replication. Apoptosis or regulated cell death, may contribute to the host anti-viral response by limiting viral replication. However, apoptosis of lung epithelial cells may also exacerbate lung injury, depending on the extent, the timing and specific location in the lungs. Differential apoptotic responses of epithelial cells versus innate immune cells (e.g., neutrophils, macrophages during pneumovirus infection can further contribute to the complex and delicate balance between host defense and disease pathogenesis. The purpose of this manuscript is to give an overview of the role of apoptosis in pneumovirus infection. We will examine clinical and experimental data concerning the various pro-apoptotic stimuli and the roles of apoptotic epithelial and innate immune cells during pneumovirus disease. Finally, we will discuss potential therapeutic interventions targeting apoptosis in the lungs.

  18. Reaper-Induced Apoptosis

    National Research Council Canada - National Science Library

    Perry, Jennifer

    2005-01-01

    Reaper is a central regulator of apoptosis in the fly, Drosophila melanogaster. At the start of this proposal our laboratory identified what was believed to be a pro-apoptotic human homolog of Reaper...

  19. Viruses and apoptosis.

    Science.gov (United States)

    Roulston, A; Marcellus, R C; Branton, P E

    1999-01-01

    Successful viral replication requires not only the efficient production and spread of progeny, but also evasion of host defense mechanisms that limit replication by killing infected cells. In addition to inducing immune and inflammatory responses, infection by most viruses triggers apoptosis or programmed cell death of the infected cell. This cell response often results as a compulsory or unavoidable by-product of the action of critical viral replicative functions. In addition, some viruses seem to use apoptosis as a mechanism of cell killing and virus spread. In both cases, successful replication relies on the ability of certain viral products to block or delay apoptosis until sufficient progeny have been produced. Such proteins target a variety of strategic points in the apoptotic pathway. In this review we summarize the great amount of recent information on viruses and apoptosis and offer insights into how this knowledge may be used for future research and novel therapies.

  20. Towards a global climate constitution

    NARCIS (Netherlands)

    Weikard, H.P.

    2011-01-01

    In this paper my concern is the study of the incentives of individual countries to sign an international climate agreement that sets the terms of a climate constitution, that is, it establishes emission rights and rules for trading these rights to combat the climate problem effectively and

  1. The Constitutive Power of Twitter

    DEFF Research Database (Denmark)

    Albu, Oana Brindusa; Etter, Michael Andreas

    organizations. The analysis illustrates how specific Twitter interactions, i.e., hashtags, become hypertexts—a type of authoritative texts—which simultaneously constitute an organizational actor or act as a pastiche of it. The study contributes to extant research by illustrating how hypertextuality...

  2. Unconstitutional constitutional amendments in Ethiopia: the practice ...

    African Journals Online (AJOL)

    Such constitutional provisions serve to confine the power to amend the constitution within the prescribed legal requirements as well as help to control arbitrary changes to the constitution, which consequently promotes constitutionalism within the country. The FDRE Constitution has been amended twice within these twenty ...

  3. Numerically abnormal chromosome constitutions in humans

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1993-12-31

    Chapter 24, discusses numerically abnormal chromosome constitutions in humans. This involves abnormalities of human chromosome number, including polyploidy (when the number of sets of chromosomes increases) and aneuploidy (when the number of individual normal chromosomes changes). Chapter sections discuss the following chromosomal abnormalities: human triploids, imprinting and uniparental disomy, human tetraploids, hydatidiform moles, anomalies caused by chromosomal imbalance, 13 trisomy (D{sub 1} trisomy, Patau syndrome), 21 trisomy (Down syndrome), 18 trisomy syndrome (Edwards syndrome), other autosomal aneuploidy syndromes, and spontaneous abortions. The chapter concludes with remarks on the nonrandom participation of chromosomes in trisomy. 69 refs., 3 figs., 4 tabs.

  4. PUMA mediates ER stress-induced apoptosis in portal hypertensive gastropathy

    OpenAIRE

    Tan, S; Wei, X; Song, M; Tao, J; Yang, Y; Khatoon, S; Liu, H; Jiang, J; Wu, B

    2014-01-01

    Mucosal apoptosis has been demonstrated to be an essential pathological feature in portal hypertensive gastropathy (PHG). p53-upregulated modulator of apoptosis (PUMA) was identified as a BH3-only Bcl-2 family protein that has an essential role in apoptosis induced by a variety of stimuli, including endoplasmic reticulum (ER) stress. However, whether PUMA is involved in mucosal apoptosis in PHG remains unclear, and whether PUMA induces PHG by mediating ER stress remains unknown. The aim of th...

  5. Valuation In The Constitutional Era

    Directory of Open Access Journals (Sweden)

    Elmien du Plessis

    2015-12-01

    Full Text Available The Constitution brought about a new compensation regime for expropriations. Compensation for expropriation must now be "just and equitable". Whereas before the Constitution came into force market value played a central role in compensation for expropriation, market value is now only one factor or aspect of compensation that the court needs to take into account. Yet we find that courts tend to focus on market value and to still employ the valuation methods used to calculate market value. This article argues that the methods used to calculate the market value, once thought to be objective, are not as objective as was believed. While it is impossible to give judges specific tools for the assessment of market value, this article provides guidelines on how the calculation of compensation should be approached.

  6. [Women, gender, and the Constitution].

    Science.gov (United States)

    1993-12-01

    Although all the constitutions of Latin America directly or indirectly acknowledge the juridical equality of the sexes, these patriarchal societies continue to maintain institutional power in male hands and to neutralize legal actions favoring women. International instruments such as the Convention on Elimination of All Forms of Discrimination Against Women, approved by the UN in 1979, have given a firmer basis to policies and actions to improve the status of women. Obstacles to full equality of Latin American women are rooted in economic and sociopolitical factors, but lack of true political will also plays a significant role. A number of new laws in the past several years as well as the new Constitution have improved the legal position of Colombian women. The new Constitution recognizes fundamental rights that may be claimed directly before a judge, and social, economic, and collective rights requiring legislative development. Article 43 of the new Constitution states that women will not be subjected to any form of discrimination. Another norm states that women will enjoy special assistance and protection before and after childbirth, in recognition of the social functions of maternity. Article 43 also states that women who are heads of households will receive special assistance, but the corresponding regulations have not yet been promulgated. The mechanism of tutelage has become an important recourse that has been used in several cases in which fundamental rights of women have been violated or threatened because of their sex. The order of tutelage has been used in cases of adolescents expelled from school for pregnancy and of abused wives, as well as to force recognition of the social and economic contributions of housework.

  7. miR-296-3p, miR-298-5p and their downstream networks are causally involved in the higher resistance of mammalian pancreatic α cells to cytokine-induced apoptosis as compared to β cells

    Directory of Open Access Journals (Sweden)

    Barbagallo Davide

    2013-01-01

    Full Text Available Abstract Background The molecular bases of mammalian pancreatic α cells higher resistance than β to proinflammatory cytokines are very poorly defined. MicroRNAs are master regulators of cell networks, but only scanty data are available on their transcriptome in these cells and its alterations in diabetes mellitus. Results Through high-throughput real-time PCR, we analyzed the steady state microRNA transcriptome of murine pancreatic α (αTC1-6 and β (βTC1 cells: their comparison demonstrated significant differences. We also characterized the alterations of αTC1-6 cells microRNA transcriptome after treatment with proinflammatory cytokines. We focused our study on two microRNAs, miR-296-3p and miR-298-5p, which were: (1 specifically expressed at steady state in αTC1-6, but not in βTC1 or INS-1 cells; (2 significantly downregulated in αTC1-6 cells after treatment with cytokines in comparison to untreated controls. These microRNAs share more targets than expected by chance and were co-expressed in αTC1-6 during a 6–48 h time course treatment with cytokines. The genes encoding them are physically clustered in the murine and human genome. By exploiting specific microRNA mimics, we demonstrated that experimental upregulation of miR-296-3p and miR-298-5p raised the propensity to apoptosis of transfected and cytokine-treated αTC1-6 cells with respect to αTC1-6 cells, treated with cytokines after transfection with scramble molecules. Both microRNAs control the expression of IGF1Rβ, its downstream targets phospho-IRS-1 and phospho-ERK, and TNFα. Our computational analysis suggests that MAFB (a transcription factor exclusively expressed in pancreatic α cells within adult rodent islets of Langerhans controls the expression of miR-296-3p and miR-298-5p. Conclusions Altogether, high-throughput microRNA profiling, functional analysis with synthetic mimics and molecular characterization of modulated pathways strongly suggest that specific

  8. Mathematical modeling and the two-phase constitutive equations

    International Nuclear Information System (INIS)

    Boure, J.A.

    1975-01-01

    The problems raised by the mathematical modeling of two-phase flows are summarized. The models include several kinds of equations, which cannot be discussed independently, such as the balance equations and the constitutive equations. A review of the various two-phase one-dimensional models proposed to date, and of the constitutive equations they imply, is made. These models are either mixture models or two-fluid models. Due to their potentialities, the two-fluid models are discussed in more detail. To avoid contradictions, the form of the constitutive equations involved in two-fluid models must be sufficiently general. A special form of the two-fluid models, which has particular advantages, is proposed. It involves three mixture balance equations, three balance equations for slip and thermal non-equilibriums, and the necessary constitutive equations [fr

  9. Constitutional collisions of criminal law

    Directory of Open Access Journals (Sweden)

    Sergey M. Inshakov

    2016-12-01

    Full Text Available Objective to identify and resolve conflicts between the norms of constitutional and criminal law which regulate the issue of legal liability of senior officials of the state. Methods formallogical systematic comparativelegal. Results the article analyzes the embodiment of the principle of citizensrsquo equality under the law regarding the criminal responsibility of the President of the Russian Federation as one of the segments of the elite right other criminal and legal conflicts are considered associated with the creation of conditions for derogation from the principle of equality. Basing on this analysis the means of overcoming collisions between the norms of constitutional and criminal law are formulated. Scientific novelty in the article for the first time it has been shown that in the Russian criminal law there are exceptions to the principle of citizensrsquo equality under the law relating to the President of the Russian Federation the conflicts are identified between the norms of constitutional and criminal law regulating the issue of legal liability of senior officials of the state ways of overcoming conflicts are suggested. Practical significance the main provisions and conclusions of the article can be used in research and teaching in the consideration of issues of senior state officialsrsquo criminal liability.

  10. Cyclin-dependent kinases regulate apoptosis of intestinal epithelial cells

    Science.gov (United States)

    Bhattacharya, Sujoy; Ray, Ramesh M.; Johnson, Leonard R.

    2014-01-01

    Homeostasis of the gastrointestinal epithelium is dependent upon a balance between cell proliferation and apoptosis. Cyclin-dependent kinases (Cdks) are well known for their role in cell proliferation. Previous studies from our group have shown that polyamine-depletion of intestinal epithelial cells (IEC-6) decreases cyclin-dependent kinase 2 (Cdk2) activity, increases p53 and p21Cip1 protein levels, induces G1 arrest, and protects cells from camptothecin (CPT)-induced apoptosis. Although emerging evidence suggests that members of the Cdk family are involved in the regulation of apoptosis, their roles directing apoptosis of IEC-6 cells are not known. In this study, we report that inhibition of Cdk1, 2, and 9 (with the broad range Cdk inhibitor, AZD5438) in proliferating IEC-6 cells triggered DNA damage, activated p53 signaling, inhibited proliferation, and induced apoptosis. By contrast, inhibition of Cdk2 (with NU6140) increased p53 protein and activity, inhibited proliferation, but had no effect on apoptosis. Notably, AZD5438 sensitized, whereas, NU6140 rescued proliferating IEC-6 cells from CPT-induced apoptosis. However, in colon carcinoma (Caco2) cells with mutant p53, treatment with either AZD5438 or NU6140 blocked proliferation, albeit more robustly with AZD5438. Both Cdk inhibitors induced apoptosis in Caco2 cells in a p53-independent manner. In serum starved quiescent IEC-6 cells, both AZD5438 and NU6140 decreased TNF- /CPT-induced activation of p53 and, consequently, rescued cells from apoptosis, indicating that sustained Cdk activity is required for apoptosis of quiescent cells. Furthermore, AZD5438 partially reversed the protective effect of polyamine depletion whereas NU6140 had no effect. Together, these results demonstrate that Cdks possess opposing roles in the control of apoptosis in quiescent and proliferating cells. In addition, Cdk inhibitors uncouple proliferation from apoptosis in a p53-dependent manner. PMID:24242917

  11. LEGAL SYSTEM IN BRAZILIAN CONSTITUTIONALISM: PERPLEXITIES REFERRING TO CIVIL LAW

    OpenAIRE

    Iribure Júnior, Hamilton da Cunha; Guimarães, Henrique Cassalho

    2017-01-01

    The contemporaneous constitutionalism outlines a new manner to conceive and interpret the legal system, considering the alignment of law with society and society with law in order to emancipate the individual in the factual level. This results in the repercussion of humanization purpose in the Constitution of Federative Republic of Brazil of 1988 in civil law, to the extent of approaching it under a new perspective. However, such relationship involves several aspects which cannot be neglected...

  12. Picornaviruses and Apoptosis: Subversion of Cell Death.

    Science.gov (United States)

    Croft, Sarah N; Walker, Erin J; Ghildyal, Reena

    2017-09-19

    Infected cells can undergo apoptosis as a protective response to viral infection, thereby limiting viral infection. As viruses require a viable cell for replication, the death of the cell limits cellular functions that are required for virus replication and propagation. Picornaviruses are single-stranded RNA viruses that modify the host cell apoptotic response, probably in order to promote viral replication, largely as a function of the viral proteases 2A, 3C, and 3CD. These proteases are essential for viral polyprotein processing and also cleave cellular proteins. Picornavirus proteases cleave proapoptotic adaptor proteins, resulting in downregulation of apoptosis. Picornavirus proteases also cleave nucleoporins, disrupting the orchestrated manner in which signaling pathways use active nucleocytoplasmic trafficking, including those involved in apoptosis. In addition to viral proteases, the transmembrane 2B protein alters intracellular ion signaling, which may also modulate apoptosis. Overall, picornaviruses, via the action of virally encoded proteins, exercise intricate control over and subvert cell death pathways, specifically apoptosis, thereby allowing viral replication to continue. Copyright © 2017 Croft et al.

  13. Autophagy and apoptosis in planarians.

    Science.gov (United States)

    González-Estévez, Cristina; Saló, Emili

    2010-03-01

    Adult planarians are capable of undergoing regeneration and body remodelling in order to adapt to physical damage or extreme environmental conditions. Moreover, most planarians can tolerate long periods of starvation and during this time, they shrink from an adult size to, and sometimes beyond, the initial size at hatching. Indeed, these properties have made them a classic model to study stem cells and regeneration. Under such stressful conditions, food reserves from the gastrodermis and parenchyma are first used up and later the testes, copulatory organs and ovaries are digested. More surprisingly, when food is again made available to shrunken individuals, they grow back to adult size and all their reproductive structures reappear. These cycles of growth and shrinkage may occur over long periods without any apparent impairment to the individual, or to its future maturation and breeding capacities. This plasticity resides in a mesoderm tissue known as the parenchyma, which is formed by several differentiated non-proliferating cell types and only one mitotically active cell type, the neoblasts, which represent approximately 20-30% of the cells in the parenchyma. Neoblasts are generally thought to be somatic stem-cells that participate in the normal continuous turnover of all cell types in planarians. Hence, planarians are organisms that continuously adapt their bodies (morphallaxis) to different environmental stresses (i.e.: injury or starvation). This adaptation involves a variety of processes including proliferation, differentiation, apoptosis and autophagy, all of which are perfectly orchestrated and tightly regulated to remodel or restore the body pattern. While neoblast biology and body re-patterning are currently the subject of intense research, apoptosis and autophagy remain much less studied. In this review we will summarize our current understanding and hypotheses regarding where and when apoptosis and autophagy occur and fulfil an essential role in

  14. Spaceflight Associated Apoptosis

    Science.gov (United States)

    Ichiki, Albert T.; Gibson, Linda A.; Allebban, Zuhair

    1996-01-01

    Lymphoid tissues have been shown to atrophy in rats flown on Russian spaceflights. Histological examination indicated evidence for cell degradation. Lymphoid tissues from rats flown on Spacelab Life Sciences-2 mission were analyzed for apoptosis by evidence of fragmented lymphocytes, which could be engulfed by macrophages, or DNA strand breaks using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. Apoptosis was not detected in the thymus and spleen collected inflight or from the synchronous ground rats but was detected in the thymus, spleen and inguinal lymph node of the flight animals on recovery. These results indicate that the apoptosis observed in the lymphatic tissues of the rats on recovery could have been induced by the gravitational stress of reentry, corroborating the findings from the early space-flight observations.

  15. Time-course of cadmium-induced acute hepatotoxicity in the rat liver: the role of apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Tzirogiannis, Konstantinos N.; Panoutsopoulos, Georgios I.; Hereti, Rosa I.; Alexandropoulou, Katerina N.; Basayannis, Aristidis C.; Mykoniatis, Michael G. [Department of Experimental Pharmacology, Medical School, Athens University, 75 Mikras Asias St., 115 27, Athens (Greece); Demonakou, Maria D. [Histopathology Laboratory, Sismanoglion G.D. Hospital, Sismanogliou 1, Marousi, Attiki 151 27 (Greece)

    2003-12-01

    Exposure to toxic metals and pollutants is a major environmental problem. Cadmium is a metal causing acute hepatic injury but the mechanism of this phenomenon is poorly understood. In the present study, we investigated the mechanism and time-course of cadmium-induced liver injury in rats, with emphasis being placed on apoptosis in parenchymal and nonparenchymal liver cells. Cadmium (3.5 mg/kg body weight) was injected intraperitoneally and the rats were killed 0, 9, 12, 16, 24, 48 and 60 h later. The extent of liver injury was evaluated for necrosis, apoptosis, peliosis, mitoses and inflammatory infiltration in hematoxylin-eosin-stained liver sections, and by assaying serum enzyme activities. The number of cells that died via apoptosis was quantified by TUNEL assay. The identification of nonparenchymal liver cells and activated Kupffer cells was performed histochemically. Liver regeneration was evaluated by assaying the activity of liver thymidine kinase and by the rate of {sup 3}H-thymidine incorporation into DNA. Both cadmium-induced necrotic cell death and parenchymal cell apoptosis showed a biphasic elevation at 12 and 48 h and peaked at 48 and 12 h, respectively. Nonparenchymal cell apoptosis peaked at 48 h. Peliosis hepatis, another characteristic form of liver injury, was first observed at 16 h and, at all time points, closely correlated with the apoptotic index of nonparenchymal liver cells, where the lesion was also maximial at 48 h. Kupffer cell activation and neutrophil infiltration were minimal for all time points examined. Based on thymidine kinase activity, liver regeneration was found to discern a classic biphasic peak pattern at 12 and 48 h. It was very interesting to observe that cadmium-induced liver injury did not involve inflammation at any time point. Apoptosis seems to be a major mechanism for the removal of damaged cells, and constitutes the major type of cell death in nonparenchymal liver cells. Apoptosis of nonparenchymal cells is the basis

  16. 75 FR 57835 - Constitution Day and Citizenship Day, Constitution Week, 2010

    Science.gov (United States)

    2010-09-22

    ... Part II The President Proclamation 8562--Constitution Day and Citizenship Day, Constitution Week... Constitution Day and Citizenship Day, Constitution Week, 2010 By the President of the United States of America... journey. On Constitution Day and Citizenship Day, and during Constitution Week, we commemorate the legacy...

  17. Cl- channels in apoptosis

    DEFF Research Database (Denmark)

    Wanitchakool, Podchanart; Ousingsawat, Jiraporn; Sirianant, Lalida

    2016-01-01

    A remarkable feature of apoptosis is the initial massive cell shrinkage, which requires opening of ion channels to allow release of K(+), Cl(-), and organic osmolytes to drive osmotic water movement and cell shrinkage. This article focuses on the role of the Cl(-) channels LRRC8, TMEM16/anoctamin......, and cystic fibrosis transmembrane conductance regulator (CFTR) in cellular apoptosis. LRRC8A-E has been identified as a volume-regulated anion channel expressed in many cell types. It was shown to be required for regulatory and apoptotic volume decrease (RVD, AVD) in cultured cell lines. Its presence also...

  18. 32 CFR 536.42 - Constitutional torts.

    Science.gov (United States)

    2010-07-01

    ... AGAINST THE UNITED STATES Investigation and Processing of Claims § 536.42 Constitutional torts. A claim for violation of the U.S. Constitution does not constitute a state tort and is not cognizable under... 32 National Defense 3 2010-07-01 2010-07-01 true Constitutional torts. 536.42 Section 536.42...

  19. A Communicatively Constituted Online Crisis

    DEFF Research Database (Denmark)

    Valentini, Chiara; Romenti, Stefania; Kruckeberg, Dean

    2017-01-01

    into specific public crisis perceptions. Drawing from a communicative constitution perspective, the authors argue that if crises are perceptions or experiences of difficult situations that exceed a person’s current resources and coping mechanisms, and if perceptions and experiences in social media are typically......This chapter presents a theoretical proposition that could serve as foundation to explain how people become aware, develop an understanding, and create meanings about specific critical situations through social media conversations and how, eventually, these transform critical situations...... in social media....

  20. Dysregulated apoptosis and NFκB expression in COPD subjects

    Directory of Open Access Journals (Sweden)

    Ennis Madeleine

    2009-03-01

    Full Text Available Abstract Background The abnormal regulation of neutrophil apoptosis may contribute to the ineffective resolution of inflammation in chronic lung diseases. Multiple signalling pathways are implicated in regulating granulocyte apoptosis, in particular, NFκB (nuclear factor-kappa B signalling which delays constitutive neutrophil apoptosis. Although some studies have suggested a dysregulation in the apoptosis of airway cells in chronic obstructive pulmonary disease (COPD, no studies to date have directly investigated if NFκB is associated with apoptosis of airway neutrophils from COPD patients. The objectives of this study were to examine spontaneous neutrophil apoptosis in stable COPD subjects (n = 13, healthy smoking controls (n = 9 and non-smoking controls (n = 9 and to investigate whether the neutrophil apoptotic process in inflammatory conditions is associated with NFκB activation. Methods Analysis of apoptosis in induced sputum was carried out by 3 methods; light microscopy, Annexin V/Propidium iodide and the terminal transferase-mediated dUTP nick end-labeling (TUNEL method. Activation of NFκB was assessed using a flow cytometric method and the phosphorylation state of IκBα was carried out using the Bio-Rad Bio-Plex phosphoprotein IκBα assay. Results Flow cytometric analysis showed a significant reduction in the percentage of sputum neutrophils undergoing spontaneous apoptosis in healthy smokers and subjects with COPD compared to non-smokers (p Conclusion These results demonstrate that apoptosis is reduced in the sputum of COPD subjects and in healthy control smokers and may be regulated by an associated activation of NFκB.

  1. Involvement of NF-κB and HSP70 signaling pathways in the apoptosis of MDA-MB-231 cells induced by a prenylated xanthone compound, α-mangostin, from Cratoxylum arborescens [Corrigendum

    Directory of Open Access Journals (Sweden)

    Ibrahim MY

    2015-06-01

    Full Text Available Ibrahim MY, Hashim NM, Mohan S, et al. Drug Des Devel Ther. 2014;8:2193–2211. On page 2193, author affiliations, “Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia” should be “Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia”. Introduction, first paragraph, the text should read: “Breast cancer has become a major cause of morbidity and mortality in women globally. The American Cancer Society (ACS reported that breast cancer incidence has an estimation of 26% of all new cancer cases, which is the highest in ratio among all the cancers in American women.1 The National Cancer Registry (NCR in Malaysia has reported that one in twenty Malaysian women are at a risk of acquiring breast in their lifetime.2 The incidence rate in Malaysia is still considered low if compared to Europe and United States.3 Up to 70% of breast cancer development causes occur in women is reported to be of environmental factors and lifestyle.4,5”  Introduction, second paragraph, first sentence, the text should read: “Radiation therapy has become a valuable tool among cancer treatment strategies for the control of local and regional diseases after 1960 with the invention of the linear accelerator, but, like surgery, radiation therapy alone cannot enucleate metastatic cancer.”  Discussion, first paragraph, first sentence, the text should read: “Apoptosis has a vital role in many functions, ranging from fetal development to adult tissue homeostasis.32”   Read the original article

  2. Metal-Matrix Composites and Porous Materials: Constitute Models, Microstructure Evolution and Applications

    National Research Council Canada - National Science Library

    Castafieda, P

    2000-01-01

    Constitutive models were developed and implemented numerically to account for the evolution of microstructure and anisotropy in finite-deformation processes involving porous and composite materials...

  3. Essence and constitution in Zubiri

    Directory of Open Access Journals (Sweden)

    Alfonso Gómez Fernández

    2015-03-01

    Full Text Available The aim of this article is to expound Zubiri’s concept of essence and to begin a critical discussion and evaluation of his proposal. Before explaining what essence is, it is necessary to observe that, for our author, not all things have an essence: only «reality-things» but not «meaning-things» form part of the «essentiable domain». This distinction between «reality-things» and «meaning-things» supposes a new conception of nature. (Nature is not the opposite of the artificial, as the Greek term physis is.«Reality-things» form a constitutional and «closed» system of non-causal and non-«external» characteristics or traits. These «foundational characteristics» of constitution, then, are precisely the essence. The article discusses critically the assumptions of this doctrine (reality, ontological pluralism, foundation and its possible limits in the light of contemporary science. It can be a useful theory for the philosophy of language.

  4. Mitochondria in neutrophil apoptosis

    NARCIS (Netherlands)

    van Raam, B. J.; Verhoeven, A. J.; Kuijpers, T. W.

    2006-01-01

    Central in the regulation of the short life span of neutrophils are their mitochondria. These organelles hardly contribute to the energy status of neutrophils but play a vital role in the apoptotic process. Not only do the mitochondria contain cytotoxic proteins that are released during apoptosis

  5. Apoptosis-inducing factor (Aif1) mediates anacardic acid-induced apoptosis in Saccharomyces cerevisiae.

    Science.gov (United States)

    Muzaffar, Suhail; Chattoo, Bharat B

    2017-03-01

    Anacardic acid is a medicinal phytochemical that inhibits proliferation of fungal as well as several types of cancer cells. It induces apoptotic cell death in various cell types, but very little is known about the mechanism involved in the process. Here, we used budding yeast Saccharomyces cerevisiae as a model to study the involvement of some key elements of apoptosis in the anacardic acid-induced cell death. Plasma membrane constriction, chromatin condensation, DNA degradation, and externalization of phosphatidylserine (PS) indicated that anacardic acid induces apoptotic cell death in S. cerevisiae. However, the exogenous addition of broad-spectrum caspase inhibitor Z-VAD-FMK or deletion of the yeast caspase Yca1 showed that the anacardic acid-induced cell death is caspase independent. Apoptosis-inducing factor (AIF1) deletion mutant was resistant to the anacardic acid-induced cell death, suggesting a key role of Aif1. Overexpression of Aif1 made cells highly susceptible to anacardic acid, further confirming that Aif1 mediates anacardic acid-induced apoptosis. Interestingly, instead of the increase in the intracellular reactive oxygen species (ROS) normally observed during apoptosis, anacardic acid caused a decrease in the intracellular ROS levels. Quantitative real-time PCR analysis showed downregulation of the BIR1 survivin mRNA expression during the anacardic acid-induced apoptosis.

  6. Beryllium-stimulated apoptosis in macrophage cell lines.

    Science.gov (United States)

    Sawyer, R T; Fadok, V A; Kittle, L A; Maier, L A; Newman, L S

    2000-08-21

    In vitro stimulation of bronchoalveolar lavage cells from patients with chronic beryllium disease (CBD) induces the production of TNF-alpha. We tested the hypothesis that beryllium (Be)-stimulated TNF-alpha might induce apoptosis in mouse and human macrophage cell lines. These cell lines were selected because they produce a range of Be-stimulated TNF-alpha. The mouse macrophage cell line H36.12j produces high levels of Be-stimulated TNF-alpha. The mouse macrophage cell line P388D.1 produces low, constitutive, levels of TNF-alpha and does not up-regulate Be-stimulated TNF-alpha production. The DEOHS-1 human CBD macrophage cell line does not produce constitutive or Be-stimulated TNF-alpha. Apoptosis was determined by microscopic observation of propidium iodide stained fragmented nuclei in unstimulated and BeSO(4)-stimulated macrophage cell lines. BeSO(4) induced apoptosis in all macrophage cell lines tested. Beryllium-stimulated apoptosis was dose-responsive and maximal after 24 h of exposure to 100 microM BeSO(4). In contrast, unstimulated and Al(2)(SO(4))(3)-stimulated macrophage cell lines did not undergo apoptosis. The general caspase inhibitor BD-fmk inhibited Be-stimulated macrophage cell line apoptosis at concentrations above 50 microM. Our data show that Be-stimulated macrophage cell line apoptosis was caspase-dependent and not solely dependent on Be-stimulated TNF-alpha levels. We speculate that the release of Be-antigen from apoptotic macrophages may serve to re-introduce Be material back into the lung microenvironment, make it available for uptake by new macrophages, and thereby amplify Be-stimulated cytokine production, promoting ongoing inflammation and granuloma maintenance in CBD.

  7. Apoptosis and inflammation

    Directory of Open Access Journals (Sweden)

    C. Haanen

    1995-01-01

    Full Text Available During the last few decades it has been recognized that cell death is not the consequence of accidental injury, but is the expression of a cell suicide programme. Kerr et al. (1972 introduced the term apoptosis. This form of cell death is under the influence of hormones, growth factors and cytokines, which depending upon the receptors present on the target cells, may activate a genetically controlled cell elimination process. During apoptosis the cell membrane remains intact and the cell breaks into apoptotic bodies, which are phagocytosed. Apoptosis, in contrast to necrosis, is not harmful to the host and does not induce any inflammatory reaction. The principal event that leads to inflammatory disease is cell damage, induced by chemical/physical injury, anoxia or starvation. Cell damage means leakage of cell contents into the adjacent tissues, resulting in the capillary transmigration of granulocytes to the injured tissue. The accumulation of neutrophils and release of enzymes and oxygen radicals enhances the inflammatory reaction. Until now there has been little research into the factors controlling the accumulation and the tissue load of granulocytes and their histotoxic products in inflammatory processes. Neutrophil apoptosis may represent an important event in the control of intlamtnation. It has been assumed that granulocytes disintegrate to apoptotic bodies before their fragments are removed by local macrophages. Removal of neutrophils from the inflammatory site without release of granule contents is of paramount importance for cessation of inflammation. In conclusion, apoptotic cell death plays an important role in inflammatory processes and in the resolution of inflammatory reactions. The facts known at present should stimulate further research into the role of neutrophil, eosinophil and macrophage apoptosis in inflammatory diseases.

  8. Nuclear energy as reflected in Constitutional Law

    International Nuclear Information System (INIS)

    Ossenbuehl, F.

    1981-01-01

    The author analyses the Federal Constitutional Court's decision on the Kalkar and Muehlheim-Kaerlich reactors with regard to its content relating to the Atomic Energy Law. He examines the Atomic Energy Law within the system in which power is shared: The legal provisio of the Atomic Energy Law, the application of undetermined legal terms, the involvement of extra-legislative bodies, the statements made on residual risks. He discusses the statutory obligation of the legislator to protect, and the protection of basic rights by means of participation in procedures, the effecting of basic rights protection by means of participation in procedures, the translation into action of basic rights protection by means of participation in procedures and the interpretation of the elementary (simple) Atomic Law by the Federal Constitutional Court with regard to the interpreation and application of the Atomic Energy Law in conformity with the Basic Law. Finally, he gives his opinion on the practical consequences the decision will have, and on its binding effects for current and future licensing procedures. (HSCH) [de

  9. HOW STAR WARS ILLUMINATES CONSTITUTIONAL LAW

    Directory of Open Access Journals (Sweden)

    Cass R. Sunstein

    2017-02-01

    Full Text Available Human beings often see coherence and planned design when neither exists. This is so in movies, literature, history, economics, and psychoanalysis – and constitutional law. Contrary to the repeated claims of George Lucas, its principal author, the Star Wars series was hardly planned in advance; it involved a great deal of improvisation and surprise, even to Lucas himself. Serendipity and happenstance, sometimes in the forms of eruptions of new thinking, play a pervasive and overlooked role in the creative imagination, certainly in single authored works, and even more in multi-authored ones extending over time. Serendipity imposes serious demands on the search for coherence in art, literature, history, and law. That search leads many people (including Lucas to misdescribe the nature of their own creativity and authorship. The misdescription appears to respond to a serious human need for sense-making and pattern-finding, but it is a significant obstacle to understanding and critical reflection. Whether Jedi or Sith, many authors of constitutional law are a lot like the author of Star Wars, disguising the essential nature of their own creative processes.

  10. Unborn children as constitutional persons.

    Science.gov (United States)

    Roden, Gregory J

    2010-01-01

    In Roe v. Wade, the state of Texas argued that "the fetus is a 'person' within the language and meaning of the Fourteenth Amendment." To which Justice Harry Blackmun responded, "If this suggestion of personhood is established, the appellant's case, of course, collapses, for the fetus' right to life would then be guaranteed specifically by the Amendment." However, Justice Blackmun then came to the conclusion "that the word 'person,' as used in the Fourteenth Amendment, does not include the unborn." In this article, it is argued that unborn children are indeed "persons" within the language and meaning of the Fourteenth and Fifth Amendments. As there is no constitutional text explicitly holding unborn children to be, or not to be, "persons," this argument will be based on the "historical understanding and practice, the structure of the Constitution, and thejurisprudence of [the Supreme] Court." Specifically, it is argued that the Constitution does not confer upon the federal government a specifically enumerated power to grant or deny "personhood" under the Fourteenth Amendment. Rather, the power to recognize or deny unborn children as the holders of rights and duties has been historically exercised by the states. The Roe opinion and other Supreme Court cases implicitly recognize this function of state sovereignty. The states did exercise this power and held unborn children to be persons under the property, tort, and criminal law of the several states at the time Roe was decided. As an effect of the unanimity of the states in holding unborn children to be persons under criminal, tort, and property law, the text of the Equal Protection Clause of the Fourteenth Amendment compels federal protection of unborn persons. Furthermore, to the extent Justice Blackmun examined the substantive law in these disciplines, his findings are clearly erroneous and as a whole amount to judicial error. Moreover, as a matter of procedure, according to the due process standards recognized in

  11. Apoptosis transcriptional mechanism of feline infectious peritonitis virus infected cells.

    Science.gov (United States)

    Shuid, Ahmad Naqib; Safi, Nikoo; Haghani, Amin; Mehrbod, Parvaneh; Haron, Mohd Syamsul Reza; Tan, Sheau Wei; Omar, Abdul Rahman

    2015-11-01

    Apoptosis has been postulated to play an important role during feline infectious peritonitis virus (FIPV) infection; however, its mechanism is not well characterized. This study is focused on apoptosis and transcriptional profiling of FIPV-infected cells following in vitro infection of CRFK cells with FIPV 79-1146 WSU. Flow cytometry was used to determine mode of cell death in first 42 h post infection (hpi). FIPV infected cells underwent early apoptosis at 9 hpi (p apoptosis at 12 hpi (p apoptosis cluster (80 down-regulated and 51 up-regulated) along with increase of apoptosis, p53, p38 MAPK, VEGF and chemokines/cytokines signaling pathways were probably involved in apoptosis process. Six of the de-regulated genes expression (RASSF1, BATF2, MAGEB16, PDCD5, TNFα and TRAF2) and TNFα protein concentration were analyzed by RT-qPCR and ELISA, respectively, at different time-points. Up-regulations of both pro-apoptotic (i.e. PDCD5) and anti-apoptotic (i.e. TRAF2) were detected from first hpi and continuing to deregulate during apoptosis process in the infected cells.

  12. Constitution of the Communication Field

    Directory of Open Access Journals (Sweden)

    José Luiz Braga

    2011-04-01

    Full Text Available The article seeks to clarify key points to characterize the field of communication studies – its possible formation as a discipline of knowledge, the question of interdisciplinarity; perspectives related to the objects of study, emphasizing the angle of “social interaction” and the theme of “media”; the problem of sharing the study of communication phenomena with other humanities and social sciences, the question of the constitution of the field, in its internal diversity, and the relationship between the phenomenon and sociocultural contexts. Each of these aspects is addressed in two stages – as perceived in the first article appeared, in 2001, and notes included now, seeking to clarify further perceptions occurring in the period.

  13. CONSTITUTIONAL LANDMARKS OF POLITICAL PLURALISM

    Directory of Open Access Journals (Sweden)

    ERHARD NICULESCU

    2013-05-01

    Full Text Available In order for democracy to result from freedom, the citizens’ participation in the creation and exercise of democratic power must be structured in a pluralist way. Art. 8(1 of the Romanian Constitution firstly imposes the organization of the company in parallel with the State’s organic structure as an indispensable requisite for the existence of democracy. In other words, there is no democracy without a civil society, distinct from the State. The organization of the civil society is necessary because the individual alone cannot determine a certain attitude of the political power: structuring gives weight to the action; the organization of citizens contributes to rendering their political participation more efficient. But the organization, structuring limits the freedom of people adhering to the structure.

  14. 7,12-Dimethylbenzanthracene induces apoptosis in RL95-2 human endometrial cancer cells: Ligand-selective activation of cytochrome P450 1B1

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ji Young [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Medical Research Science Center, Dong-A University, Busan 602-714 (Korea, Republic of); Lee, Seung Gee [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Chung, Jin-Yong [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Medical Research Science Center, Dong-A University, Busan 602-714 (Korea, Republic of); Kim, Yoon-Jae [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Park, Ji-Eun [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Medical Research Science Center, Dong-A University, Busan 602-714 (Korea, Republic of); Oh, Seunghoon [Department of Physiology, College of Medicine, Dankook University, Cheonan 330-714 (Korea, Republic of); Lee, Se Yong [Department of Obstetrics and Gynecology, Busan Medical Center, Busan 611-072 (Korea, Republic of); Choi, Hong Jo [Department of General Surgery, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Yoo, Young Hyun, E-mail: yhyoo@dau.ac.kr [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Medical Research Science Center, Dong-A University, Busan 602-714 (Korea, Republic of); and others

    2012-04-15

    7,12-Dimethylbenzanthracene (DMBA), a polycyclic aromatic hydrocarbon, exhibits mutagenic, carcinogenic, immunosuppressive, and apoptogenic properties in various cell types. To achieve these functions effectively, DMBA is modified to its active form by cytochrome P450 1 (CYP1). Exposure to DMBA causes cytotoxicity-mediated apoptosis in bone marrow B cells and ovarian cells. Although uterine endometrium constitutively expresses CYP1A1 and CYP1B1, their apoptotic role after exposure to DMBA remains to be elucidated. Therefore, we chose RL95-2 endometrial cancer cells as a model system for studying DMBA-induced cytotoxicity and cell death and hypothesized that exposure to DMBA causes apoptosis in this cell type following CYP1A1 and/or CYP1B1 activation. We showed that DMBA-induced apoptosis in RL95-2 cells is associated with activation of caspases. In addition, mitochondrial changes, including decrease in mitochondrial potential and release of mitochondrial cytochrome c into the cytosol, support the hypothesis that a mitochondrial pathway is involved in DMBA-induced apoptosis. Exposure to DMBA upregulated the expression of AhR, Arnt, CYP1A1, and CYP1B1 significantly; this may be necessary for the conversion of DMBA to DMBA-3,4-diol-1,2-epoxide (DMBA-DE). Although both CYP1A1 and CYP1B1 were significantly upregulated by DMBA, only CYP1B1 exhibited activity. Moreover, knockdown of CYP1B1 abolished DMBA-induced apoptosis in RL95-2 cells. Our data show that RL95-2 cells are susceptible to apoptosis by exposure to DMBA and that CYP1B1 plays a pivotal role in DMBA-induced apoptosis in this system. -- Highlights: ► Cytotoxicity-mediated apoptogenic action of DMBA in human endometrial cancer cells. ► Mitochondrial pathway in DMBA-induced apoptosis of RL95-2 endometrial cancer cells. ► Requirement of ligand-selective activation of CYP1B1 in DMBA-induced apoptosis.

  15. Fullerene and apoptosis

    Directory of Open Access Journals (Sweden)

    M. A. Orlova

    2013-01-01

    Full Text Available Fullerene derivatives superfamily attracts a serious attention as antiviral and anticancer agents and drug delivery carriers as well. A large number of such fullerene С60 derivatives obtained to date. However, there is an obvious deficit of information about causes and mechanisms of immediately and long-term consequences of their effects in vivo which is a true obstacle on the way leading to practical medical use of them. First, this concerns their impact on the proliferation, apoptosis and necrosis regulation. Fullerene nanoparticle functionalization type, their sizes and surface nanopathology are of great importance to further promoting of either cytoprotective or cytotoxic effects. This lecture provides modern concept analysis regarding fullerenes effects on apoptosis pathway in normal and tumor cells.

  16. Caspase Activation of p21-Activated Kinase 2 Occurs During Cisplatin-Induced Apoptosis of SH-SY5Y Neuroblastoma Cells and in SH-SY5Y Cell Culture Models of Alzheimer’s and Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Jerry W. Marlin

    2010-04-01

    Full Text Available p21-activated kinase 2 (PAK-2 appears to have a dual function in the regulation of cell survival and cell death. Activation of full-length PAK-2 by the p21 G-proteins Rac or Cdc42 stimulates cell survival. However, PAK-2 is unique among the PAK family because it is also activated through proteolytic cleavage by caspase 3 or similar caspases to generate the constitutively active PAK-2p34 fragment. Caspase activation of PAK-2 correlates with the induction of apoptosis in response to many stimuli and recombinant expression of PAK-2p34 has been shown to stimulate apoptosis in several human cell lines. Here, we show that caspase activation of PAK-2 also occurs during cisplatin-induced apoptosis of SH-SY5Y neuroblastoma cells as well as in SH-SY5Y cell culture models for Alzheimer’s and Parkinson’s disease. Inhibition of mitochondrial complex I or of ubiquitin/proteasome-mediated protein degradation, which both appear to be involved in Parkinson’s disease, induce apoptosis and caspase activation of PAK-2 in SH-SY5Y cells. Overexpression of the amyloid precursor protein, which results in accumulation and aggregation of β-amyloid peptide, the main component of β-amyloid plaques in Alzheimer’s disease, also induces apoptosis and caspase activation of PAK-2 in SH-SY5Y cells. Expression of the PAK-2 regulatory domain inhibits caspase-activated PAK-2p34 and prevents apoptosis in 293T human embryonic kidney cells, indicating that caspase activation of PAK-2 is directly involved in the apoptotic response. This is the first evidence that caspase activation of PAK-2 correlates with apoptosis in cell culture models of Alzheimer’s and Parkinson’s disease and that selective inhibition of caspase-activated PAK-2p34 could prevent apoptosis.

  17. Signaling Pathways in Cardiac Myocyte Apoptosis

    Science.gov (United States)

    Xia, Peng; Liu, Yuening

    2016-01-01

    Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation. PMID:28101515

  18. Analysis on constitution of American college republicans

    Directory of Open Access Journals (Sweden)

    Minghua Su

    2017-02-01

    Full Text Available This paper, based on internet survey and comparative analysis, according to the firsthand materials, comprehensively and systematically probes the formation of the constitution form and structure, and analyzes its contents of Constitution of American College Republicans among 15 colleges respectively, which includes the illustration of constitution, membership, personnel, meeting, financial amendment, etc. Finally, this essay analyzes the characteristics of constitution of college republicans and its advantages.

  19. Proliferation and apoptosis in infection with infectious bursal disease virus: a flow cytometric study.

    Science.gov (United States)

    Ojeda, F; Skardova, I; Guarda, M I; Ulloa, J; Folch, H

    1997-01-01

    Programmed cell death, or apoptosis, is involved in the normal physiology of many immunocompetent organs, including lymphocytes of the bursa of Fabricius in chickens. Involvement of apoptosis has also been described in some viral diseases such as AIDS. The purpose of this work was to study the potential role of apoptosis in the pathogenesis of Gumboro disease in the bursa of Fabricius. Our results show that 1-3 days after infection of young chickens with infectious bursal disease virus, the number of apoptotic cells increases and cellularity and proliferation decrease. Because of the dynamic nature of bursal lymphocyte populations and the involvement of apoptosis in lymphocyte cell physiology, the increased level of cells undergoing apoptosis may be due to an impairment in the withdrawal of apoptotic cells. A concomitant increase in macrophages in infected bursae and a dramatic decrease in cellularity suggest that an increase in apoptosis may be an important cause of cell depletion.

  20. Effects of Glucocorticoids on Apoptosis and Clearance of Apoptotic Cells

    Directory of Open Access Journals (Sweden)

    Aisleen McColl

    2007-01-01

    Full Text Available The glucocorticoid (GC drugs are one of the most commonly prescribed and effective anti-inflammatory agents used for the treatment of many inflammatory disorders through their ability to attenuate phlogistic responses. The glucocorticoid receptor (GCR primarily mediates GC actions via activation or repression of gene expression. GCs directly induce the expression of proteins displaying anti-inflammatory activities. However, the likely predominant effect of GCs is the repression of multiple inflammatory genes that invariably are overexpressed during nonresolving chronic inflammation. Although most GC actions are mediated through regulation of transcription, rapid nongenomic actions have also been reported. In addition, GCs modulate inflammatory cell survival, inducing apoptosis in immature thymocytes and eosinophils, while delaying constitutive neutrophil apoptosis. Importantly, GCs promote noninflammatory phagocytosis of apoptotic cell targets, a process important for the successful resolution of inflammation. Here, the effects and mechanisms of action of GC on inflammatory cell apoptosis and phagocytosis will be discussed.

  1. 118 CONSTITUTIONALISM AND GOOD GOVERNANCE IN NIGERIA

    African Journals Online (AJOL)

    Fr. Ikenga

    This paper attempts to analyse the constitutional development of Nigeria with a view to really determining at what point it can be said that Nigeria had a constitution. The various determinants of constitutionalism are to be x-rayed and juxtaposed with the activities of the government particularly the fourth and fifth republics.

  2. How Does the Constitution Secure Rights?

    Science.gov (United States)

    Goldwin, Robert A., Ed.; Schambra, William A., Ed.

    Third in a series designed to help prepare the nation for a thoughtful observance of the Constitutional bicentennial, this publication presents six essays addressing the issue of human rights and the Constitution. "How the Constitution Protects Our Rights: A Look at the Seminal Years" (Robert A. Rutland) focuses on James Madison's role…

  3. Teaching about Democratic Constitutionalism. ERIC Digest.

    Science.gov (United States)

    Patrick, John J.

    There are more than 100 democracies in the world today. All but three of them--Great Britain, Israel, and New Zealand --have written constitutions. This digest examines the importance of constitutions and constitutionalism and the teaching of these concepts through the use of comparisons. The primary objectives of civic education for democratic…

  4. State Constitutional Law: Teaching and Scholarship.

    Science.gov (United States)

    Williams, Robert F.

    1991-01-01

    State constitutional law is an emerging area for legal education, partly because of state supreme court decisions relying on state rather than federal constitutional law. Studying state constitutional law highlights similarities and diversity of legal and governmental systems. Interest in establishment of curricula and materials in state law is…

  5. Theoretical Issues of the Constitutional Regulation Mechanism

    Science.gov (United States)

    Zhussupova, Guldaray B.; Zhailyaubayev, Rassul T.; Ukin, Symbat K.; Shunayeva, Sylu M.; Nurmagambetov, Rachit G.

    2016-01-01

    The purpose of this research is to define the concept of "constitutional regulation mechanism." The definition of the concept of "constitutional regulation mechanism" will give jurists and legislators a theoretical framework for developing legal sciences, such as the constitutional law and the theory of state and law. The…

  6. The Constitution of the Republic of Estonia

    Index Scriptorium Estoniae

    2009-01-01

    Sisaldab ka: The Constitution of the Republic of Estonia Amendment Act. The Constitution of the Republic of Estonia Implementation Act. Act to Amend the Constitution of the Republic of Estonia for Election of Local Government Councils for Term of Four Years

  7. The Constitution of the Republic of Estonia

    Index Scriptorium Estoniae

    2005-01-01

    Raamat sisaldab ka: The Constitution of the Republic of Estonia amendment act ; The Constitution of the Republic of Estonia implementation act ; Act to amend the Constitution of the Republic of Estonia for election of local government councils for term of four years

  8. Ceramide-Induced Apoptosis in Renal Tubular Cells: A Role of Mitochondria and Sphingosine-1-Phoshate

    Science.gov (United States)

    Ueda, Norishi

    2015-01-01

    Ceramide is synthesized upon stimuli, and induces apoptosis in renal tubular cells (RTCs). Sphingosine-1 phosphate (S1P) functions as a survival factor. Thus, the balance of ceramide/S1P determines ceramide-induced apoptosis. Mitochondria play a key role for ceramide-induced apoptosis by altered mitochondrial outer membrane permeability (MOMP). Ceramide enhances oligomerization of pro-apoptotic Bcl-2 family proteins, ceramide channel, and reduces anti-apoptotic Bcl-2 proteins in the MOM. This process alters MOMP, resulting in generation of reactive oxygen species (ROS), cytochrome C release into the cytosol, caspase activation, and apoptosis. Ceramide regulates apoptosis through mitogen-activated protein kinases (MAPKs)-dependent and -independent pathways. Conversely, MAPKs alter ceramide generation by regulating the enzymes involving ceramide metabolism, affecting ceramide-induced apoptosis. Crosstalk between Bcl-2 family proteins, ROS, and many signaling pathways regulates ceramide-induced apoptosis. Growth factors rescue ceramide-induced apoptosis by regulating the enzymes involving ceramide metabolism, S1P, and signaling pathways including MAPKs. This article reviews evidence supporting a role of ceramide for apoptosis and discusses a role of mitochondria, including MOMP, Bcl-2 family proteins, ROS, and signaling pathways, and crosstalk between these factors in the regulation of ceramide-induced apoptosis of RTCs. A balancing role between ceramide and S1P and the strategy for preventing ceramide-induced apoptosis by growth factors are also discussed. PMID:25751724

  9. Constitutively activated ERK sensitizes cancer cells to doxorubicin ...

    Indian Academy of Sciences (India)

    2017-02-03

    Feb 3, 2017 ... Constitutively activated ERK sensitizes cancer cells to doxorubicin: Involvement of p53-EGFR-ERK pathway. RATNA KUMARI. 1,†. , SURBHI CHOUHAN. 1,†. , SNAHLATA SINGH. 1,†. , RISHI RAJ CHHIPA. 2. ,. AMRENDRA KUMAR AJAY. 3 and MANOJ KUMAR BHAT*. National Centre for Cell Science, ...

  10. CONSTITUTIONAL COMPLAINT DAN CONSTITUTIONAL QUESTION DAN PERLINDUNGAN HAK-HAK KONSTITUSIONAL WARGA NEGARA

    OpenAIRE

    Hamdan Zoelva

    2012-01-01

    The 1945 Constitution gives limitative authority to the Constitutional Court only to review of laws against the constitution, adjudicate dispute over state institution whose authorities are mandate by constitution, adjudicate dispute on the result of general election, dissolution of political parties and obliged to decide upon DPR’s opinion in the case of the impeachment of the President. In practice, many of the constitutional issues can not be resolved by the Constitutional Court because it...

  11. Constitutional Complaint Dan Constitutional Question Dan Perlindungan Hak-hak Konstitusional Warga Negara

    OpenAIRE

    Zoelva, Hamdan

    2012-01-01

    The 1945 Constitution gives limitative authority to the Constitutional Court only to review of laws against the constitution, adjudicate dispute over state institution whose authorities are mandate by constitution, adjudicate dispute on the result of general election, dissolution of political parties and obliged to decide upon DPR's opinion in the case of the impeachment of the President. In practice, many of the constitutional issues can not be resolved by the Constitutional Court because it...

  12. The significance of intestinal apoptosis

    International Nuclear Information System (INIS)

    Potten, C.S.

    1997-01-01

    Apoptosis occurs at a low level spontaneously in the small intestine (SI). The levels can be raised by a variety of cytotoxic agents including radiation. The apoptosis induced by radiation, and some drugs and the spontaneous apoptosis, show some specificity for the stem cells in the small intestinal crypt. In the colon, these agents target transit cells in the mid crypt. p53 expression is elevated at the same time as apoptosis in the SI but not in the cells undergoing apoptosis. The expression of bcl-2, a survival gene, is largely absent in the SI, but is expressed, albeit weakly, in the stem cells in the colon. Spontaneous apoptosis is observed in p53 null mice which also develop normally suggesting that spontaneous and developmental apoptosis are p53 independent and that spontaneous apoptosis is part of the homeostatic mechanisms maintaining stem cell numbers. Radiation induced apoptosis is completely absent at these early times post-irradiation in p53 nulls. In bel-2 null mice, the levels of spontaneous and radiation induced apoptosis are elevated in the colon. Bax, a death gene, is expressed on the villus and inter-crypt table in the colon suggesting that cells at the end of their lifespan initiate apoptosis. It has been suggested that apoptosis in the SI is a protective mechanism against carcinogenesis in the stem cells of the SI which rarely develops cancer. Cells that possess genetic damage detected. In the large bowel, this mechanism is not effective due to the action of bcl-2. Thus stem cells may persist in this tissue with genetic damage resulting in a higher cancer risk. Furthermore, the lack of spontaneous apoptosis in the colon may result in a gradual increase of the stem cells with time resulting in more ells at risk. (author)

  13. Dynamic Constitutive/Failure Models

    Science.gov (United States)

    1988-12-01

    concrete. Charvy Imiact Test: The Charpy Impact Test consists of a pendulum -type hammer striking a specimen, simulating either a cantilever beam or a...required for total fracture of the specimen. The energy required for fracture is evaluated from the travel of the pendulum after the impact. The measured...absorption capacity relative to unreinforced matrix. The next step involved the use of an instrumented hammer in the conventional Charpy test. Thus the

  14. Induction of Apoptosis and expression of Apoptosis-related gene products in response to radiation in murine tumors

    International Nuclear Information System (INIS)

    Seong, J. S.

    1997-01-01

    To analyze the involvement of apoptosis regulatory genes p53, p21 waf1/cip1 , bax and bcl-2 in induction of apoptosis by radiation in murine tumors. The radiation-sensitive ovarian carcinoma OCa-I and the radiation-resistant hepatocarcinoma HCa-I were used. Tumors, 8mm in diameter, were irradiated with 25Gy and at various times after irradiation, ranging from 1 to 48 h, were analyzed histologically for apoptosis and by western blot for alterations in the expression of these genes. The p53 status of the tumors were determined by the polymerase chain reaction-single strand conformation polymorphism assay. Both tumors were positive for wild-type p53. Radiation induced apoptosis in OCa-I but not in HCa-I. Apoptosis developed rapidly, peaked at 2 h after irradiation and returned to almost the background level at 48 h. In OCa-I radiation upregulated the expression of p53, p21 waf1/cip1 , and the bcl-2/bax ratio was decreased. In HCa-I radiation increased the expression of both p53 and p21 waf1/cip1 , although the increase of the latter was small. The bcl-2/bax ratio was greatly increased. In general the observed changes occurred within a few hours after irradiation, and either preceded or coincided with development of apoptosis. The development of apoptosis required upregulation of both p53 and p21 waf1/cip1 as well as a decrease in bcl-2/bax ratio. In contrast, an increase in bcl-2/bax ratio prevented apoptosis in the presence of upregulated p53 and p21 waf1/cip1 . These findings identified the involvement of multiple oncogenes in apoptosis regulation in vivo and demonstrate the complexity that may be associated with the use of a single oncogene assessment for predicting the outcome of cancer therapy with cytotoxic agents. (author)

  15. Induction of Apoptosis and expression of Apoptosis-related gene products in response to radiation in murine tumors

    Energy Technology Data Exchange (ETDEWEB)

    Seong, J. S. [Yonsei Univ., Seoul (Korea, Republic of). Coll. of Medicine; Hunter, N. R.; Milas, L. [Texas Univ., Houston, TX (United States)

    1997-09-01

    To analyze the involvement of apoptosis regulatory genes p53, p21{sup waf1/cip1}, bax and bcl-2 in induction of apoptosis by radiation in murine tumors. The radiation-sensitive ovarian carcinoma OCa-I and the radiation-resistant hepatocarcinoma HCa-I were used. Tumors, 8mm in diameter, were irradiated with 25Gy and at various times after irradiation, ranging from 1 to 48 h, were analyzed histologically for apoptosis and by western blot for alterations in the expression of these genes. The p53 status of the tumors were determined by the polymerase chain reaction-single strand conformation polymorphism assay. Both tumors were positive for wild-type p53. Radiation induced apoptosis in OCa-I but not in HCa-I. Apoptosis developed rapidly, peaked at 2 h after irradiation and returned to almost the background level at 48 h. In OCa-I radiation upregulated the expression of p53, p21{sup waf1/cip1}, and the bcl-2/bax ratio was decreased. In HCa-I radiation increased the expression of both p53 and p21{sup waf1/cip1}, although the increase of the latter was small. The bcl-2/bax ratio was greatly increased. In general the observed changes occurred within a few hours after irradiation, and either preceded or coincided with development of apoptosis. The development of apoptosis required upregulation of both p53 and p21{sup waf1/cip1} as well as a decrease in bcl-2/bax ratio. In contrast, an increase in bcl-2/bax ratio prevented apoptosis in the presence of upregulated p53 and p21{sup waf1/cip1}. These findings identified the involvement of multiple oncogenes in apoptosis regulation in vivo and demonstrate the complexity that may be associated with the use of a single oncogene assessment for predicting the outcome of cancer therapy with cytotoxic agents. (author).

  16. Change of position of constitutional judiciary

    Directory of Open Access Journals (Sweden)

    Orlović Slobodan P.

    2013-01-01

    Full Text Available Constitutional judiciary is the youngest branch of authority in the horizontal level of state power. Constitutional judiciary has, during its existence - during two centuries as an ordinary court and during one century as a special authority, changed its position, role and importance. Those characteristics of constitutional judiciary had an increasing way - the position became better, in political and law sense, its role has expanded and the importance has increased. Today, constitutional judiciary is an inevitable subject of constitutional regimes in huge number of states (between them are almost all federations but, in the same time, constitutional judiciary is an authority which is at least limited by the constitution. The constitution is "soft" to the constitutional judiciary because the judiciary interpreted the constitution in accordance to its political and law attitudes, hidden by the guise of protection. Different separation of power, a rise of executive power, requests for better protections of fundamental human rights, a changed role of state and executive power, altogether, have influenced to change of position of constitutional judiciary.

  17. Bax-induced apoptosis in Leber's congenital amaurosis: a dual role in rod and cone degeneration.

    Directory of Open Access Journals (Sweden)

    Séverine Hamann

    2009-08-01

    Full Text Available Pathogenesis in the Rpe65(-/- mouse model of Leber's congenital amaurosis (LCA is characterized by a slow and progressive degeneration of the rod photoreceptors. On the opposite, cones degenerate rapidly at early ages. Retinal degeneration in Rpe65(-/- mice, showing a null mutation in the gene encoding the retinal pigment epithelium 65-kDa protein (Rpe65, was previously reported to depend on continuous activation of a residual transduction cascade by unliganded opsin. However, the mechanisms of apoptotic signals triggered by abnormal phototransduction remain elusive. We previously reported that activation of a Bcl-2-dependent pathway was associated with apoptosis of rod photoreceptors in Rpe65(-/- mice during the course of the disease. In this study we first assessed whether activation of Bcl-2-mediated apoptotic pathway was dependent on constitutive activation of the visual cascade through opsin apoprotein. We then challenged the direct role of pro-apoptotic Bax protein in triggering apoptosis of rod and cone photoreceptors.Quantitative PCR analysis showed that increased expression of pro-apoptotic Bax and decreased level of anti-apoptotic Bcl-2 were restored in Rpe65(-/-/Gnat1(-/- mice lacking the Gnat1 gene encoding rod transducin. Moreover, photoreceptor apoptosis was prevented as assessed by TUNEL assay. These data indicate that abnormal activity of opsin apoprotein induces retinal cell apoptosis through the Bcl-2-mediated pathway. Following immunohistological and real-time PCR analyses, we further observed that decreased expression of rod genes in Rpe65-deficient mice was rescued in Rpe65(-/-/Bax(-/- mice. Histological and TUNEL studies confirmed that rod cell demise and apoptosis in diseased Rpe65(-/- mice were dependent on Bax-induced pathway. Surprisingly, early loss of cones was not prevented in Rpe65(-/-/Bax(-/- mice, indicating that pro-apoptotic Bax was not involved in the pathogenesis of cone cell death in Rpe65-deficient mice

  18. Identification of apoptosis-related PLZF target genes

    International Nuclear Information System (INIS)

    Bernardo, Maria Victoria; Yelo, Estefania; Gimeno, Lourdes; Campillo, Jose Antonio; Parrado, Antonio

    2007-01-01

    The PLZF gene encodes a BTB/POZ-zinc finger-type transcription factor, involved in physiological development, proliferation, differentiation, and apoptosis. In this paper, we investigate proliferation, survival, and gene expression regulation in stable clones from the human haematopoietic K562, DG75, and Jurkat cell lines with inducible expression of PLZF. In Jurkat cells, but not in K562 and DG75 cells, PLZF induced growth suppression and apoptosis in a cell density-dependent manner. Deletion of the BTB/POZ domain of PLZF abrogated growth suppression and apoptosis. PLZF was expressed with a nuclear speckled pattern distinctively in the full-length PLZF-expressing Jurkat clones, suggesting that the nuclear speckled localization is required for PLZF-induced apoptosis. By microarray analysis, we identified that the apoptosis-inducer TP53INP1, ID1, and ID3 genes were upregulated, and the apoptosis-inhibitor TERT gene was downregulated. The identification of apoptosis-related PLZF target genes may have biological and clinical relevance in cancer typified by altered PLZF expression

  19. Apoptosis and DNA Methylation

    International Nuclear Information System (INIS)

    Meng, Huan X.; Hackett, James A.; Nestor, Colm; Dunican, Donncha S.; Madej, Monika; Reddington, James P.; Pennings, Sari; Harrison, David J.; Meehan, Richard R.

    2011-01-01

    Epigenetic mechanisms assist in maintaining gene expression patterns and cellular properties in developing and adult tissues. The molecular pathology of disease states frequently includes perturbation of DNA and histone methylation patterns, which can activate apoptotic pathways associated with maintenance of genome integrity. This perspective focuses on the pathways linking DNA methyltransferases and methyl-CpG binding proteins to apoptosis, and includes new bioinformatic analyses to characterize the evolutionary origin of two G/T mismatch-specific thymine DNA glycosylases, MBD4 and TDG

  20. Thymocyte apoptosis induced by p53-dependent and independent pathways

    Energy Technology Data Exchange (ETDEWEB)

    Clarke, A.R.; Purdie, C.A.; Harrison, D.J.; Morris, R.G.; Bird, C.C.; Hooper, M.L.; Wyllie, A.H. (Edinburgh Univ. Medical School (United Kingdom). Dept. of Pathology)

    1993-04-29

    The authors studied the dependence of apoptosis on p53 expression in cells from the thymus cortex. Short-term thymocyte cultures were prepared from mice constitutively heterozygous or homozygous for a deletion in the p53 gene introduced into the germ line after gene targeting. Wild-type thymocytes readily undergo apoptosis after treatment with ionizing radiation, the glucocorticoid methylprednisolone, or etoposide (an inhibitor of topoisomerase II), or after Ca[sup 2+]-dependent activation by phorbol ester and a calcium ionophore. In contrast, homozygous null p53 thymocytes are resistant to induction of apoptosis by radiation or etoposide, but retain normal sensitivity to glucocorticoid and calcium. The time- dependent apoptosis that occurs in untreated cultures is unaffected by p53 status. Cells heterozygous for p53 deletion are partially resistant to radiation and etoposide. Results show that p53 exerts a significant and dose-dependent effect in the initiation of apoptosis, but only when it is induced by agents that cause DNA-strand breakage. (Author).

  1. Sphingolipids: Key Regulators of Apoptosis and Pivotal Players in Cancer Drug Resistance

    Directory of Open Access Journals (Sweden)

    Paola Giussani

    2014-03-01

    Full Text Available Drug resistance elicited by cancer cells still constitutes a huge problem that frequently impairs the efficacy of both conventional and novel molecular therapies. Chemotherapy usually acts to induce apoptosis in cancer cells; therefore, the investigation of apoptosis control and of the mechanisms used by cancer cells to evade apoptosis could be translated in an improvement of therapies. Among many tools acquired by cancer cells to this end, the de-regulated synthesis and metabolism of sphingolipids have been well documented. Sphingolipids are known to play many structural and signalling roles in cells, as they are involved in the control of growth, survival, adhesion, and motility. In particular, in order to increase survival, cancer cells: (a counteract the accumulation of ceramide that is endowed with pro-apoptotic potential and is induced by many drugs; (b increase the synthesis of sphingosine-1-phosphate and glucosylceramide that are pro-survivals signals; (c modify the synthesis and the metabolism of complex glycosphingolipids, particularly increasing the levels of modified species of gangliosides such as 9-O acetylated GD3 (αNeu5Ac(2-8αNeu5Ac(2-3βGal(1-4βGlc(1-1Cer or N-glycolyl GM3 (αNeu5Ac (2-3βGal(1-4βGlc(1-1Cer and de-N-acetyl GM3 (NeuNH(2βGal(1-4βGlc(1-1Cer endowed with anti-apoptotic roles and of globoside Gb3 related to a higher expression of the multidrug resistance gene MDR1. In light of this evidence, the employment of chemical or genetic approaches specifically targeting sphingolipid dysregulations appears a promising tool for the improvement of current chemotherapy efficacy.

  2. 76 FR 58705 - Constitution Day and Citizenship Day, Constitution Week, 2011

    Science.gov (United States)

    2011-09-21

    ... Day and Citizenship Day, Constitution Week, 2011 Proclamation 8715--National Employer Support of the... Constitution Day and Citizenship Day, Constitution Week, 2011 By the President of the United States of America... country stands for. Every year, thousands of candidates for citizenship commemorate Constitution Day and...

  3. Constitutional and Non-Constitutional Governments...Similarities and Differences throughout History. Resource Packet.

    Science.gov (United States)

    Pallasch, Brian Thomas

    This civic education resource packet is designed to provide teachers, community leaders, and other civic educators with an understanding of the differences between constitutional and non-constitutional governments. Six papers discussing the topic are included: "The Differences bewteen Constitutional and Non-Constitutional Governments" (John…

  4. State Constitutionalism: Completing the Interdisciplinary Study of Constitutional Law and Political Theory.

    Science.gov (United States)

    Williams, Robert F.

    1993-01-01

    Argues that a complete and accurate understanding of constitutional history and constitutional law requires the study of state constitutions. Maintains that state constitutions contain a coherent political theory that is, in important respects, at variance with the concept of federalism. (CFR)

  5. BIGH3 protein and macrophages in retinal endothelial cell apoptosis.

    Science.gov (United States)

    Mondragon, Albert A; Betts-Obregon, Brandi S; Moritz, Robert J; Parvathaneni, Kalpana; Navarro, Mary M; Kim, Hong Seok; Lee, Chi Fung; LeBaron, Richard G; Asmis, Reto; Tsin, Andrew T

    2015-01-01

    Diabetes is a pandemic disease with a higher occurrence in minority populations. The molecular mechanism to initiate diabetes-associated retinal angiogenesis remains largely unknown. We propose an inflammatory pathway of diabetic retinopathy in which macrophages in the diabetic eye provide TGFβ to retinal endothelial cells (REC) in the retinal microvasculature. In response to TGFβ, REC synthesize and secrete a pro-apoptotic BIGH3 (TGFβ-Induced Gene Human Clone 3) protein, which acts in an autocrine loop to induce REC apoptosis. Rhesus monkey retinal endothelial cells (RhREC) were treated with dMCM (cell media of macrophages treated with high glucose and LDL) and assayed for apoptosis (TUNEL), BIGH3 mRNA (qPCR), and protein (Western blots) expressions. Cells were also treated with ΤGFβ1 and 2 for BIGH3 mRNA and protein expression. Inhibition assays were carried out using antibodies for TGFβ1 and for BIGH3 to block apoptosis and mRNA expression. BIGH3 in cultured RhREC cells were identified by immunohistochemistry (IHC). Distribution of BIGH3 and macrophages in the diabetic mouse retina was examined with IHC. RhRECs treated with dMCM or TGFβ showed a significant increase in apoptosis and BIGH3 protein expression. Recombinant BIGH3 added to RhREC culture medium led to a dose-dependent increase in apoptosis. Antibodies (Ab) directed against BIGH3 and TGFβ, as well as TGFβ receptor blocker resulted in a significant reduction in apoptosis induced by either dMCM, TGFβ or BIGH3. IHC showed that cultured RhREC constitutively expressed BIGH3. Macrophage and BIGH3 protein were co-localized to the inner retina of the diabetic mouse eye. Our results support a novel inflammatory pathway for diabetic retinopathy. This pathway is initiated by TGFβ released from macrophages, which promotes synthesis and release of BIGH3 protein by REC and REC apoptosis.

  6. 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.

  7. Constitutional Amendment and Political Constitutionalism: The Potential Mitigation of Critiques on Judicial Review

    Directory of Open Access Journals (Sweden)

    Jairo Néia Lima

    2016-12-01

    Full Text Available The criticisms toward judicial review from Richard Bellamy and Jeremy Waldron’s political constitutionalism approach demonstrate that they do not exclude constitutional courts entirely, as they accept mechanisms of legislative responses, except constitutional amendments. This paper concludes that the high number of constitutional amendments in Brazil does not mitigate judicial review critiques. The extensive structure of the Brazilian Constitution imposes frequent changes, which do not modify its essence. Furthermore, the possibility of judicial review over constitutional amendments represents that constitutional court could overrule legislative response.

  8. Leukocyte apoptosis as a predictor of radiosensitivity in Fanconi anemia

    International Nuclear Information System (INIS)

    Petrovic, Sandra; Leskovac, Andreja; Joksic, Ivana; Filipovic, Jelena; Joksic, Gordana; Vujic, Dragana; Guc-Scekic, Marija

    2013-01-01

    Fanconi anemia (FA) is a rare cancer-prone genetic disease characterized by impaired oxygen metabolism and defects in DNA damage repair. Response of FA cells to ionizing radiation has been an issue intensively debated in the literature. To study in vitro radiosensitivity in patients suffering from FA and their parents (heterozygous carriers), we determined radiation-induced leukocyte apoptosis using flow cytometry. As TP53 gene is involved in the control of apoptosis, we studied its status in FA lymphocytes using dual colour fluorescence in situ hybridization (FISH). FA patients and female heterozygous carriers display radiosensitive response to ionizing radiation seen as abnormal elimination of cells via apoptosis. By employment of FISH, the TP53 allele loss in FA lymphocytes was not observed. In diseases related to oxidative stress, determination of radiation-induced apoptosis is the method of choice for testing the radiosensitivity. (author)

  9. Accelerated apoptosis of neutrophils in familial Mediterranean fever

    DEFF Research Database (Denmark)

    Manukyan, Gayane; Aminov, Rustam; Hakobyan, Gagik

    2015-01-01

    not revealed any conventional mechanisms contributing to the enhanced apoptotic rate of neutrophils in FMF. Although the exact molecular mechanisms of accelerated neutrophil apoptosis in FMF remain unknown, it may provide a protection against excessive inflammation and tissue damage due to a massive...... of systemic neutrophil apoptosis as well as the levels of proteins involved in apoptosis were investigated ex vivo in patients with FMF using flow cytometry and RT-qPCR. The freshly collected neutrophils from the patients in FMF remission displayed a significantly larger number of cells spontaneously entering...... apoptosis compared to control (6.27 ± 2.14 vs. 1.69 ± 0.18%). This elevated ratio was retained after 24 h incubation of neutrophils in the growth medium (32.4 ± 7.41 vs. 7.65 ± 1.32%). Correspondingly, the mRNA level for caspase-3 was also significantly increased under these conditions. In response...

  10. Role of the nucleus in apoptosis: signaling and execution.

    Science.gov (United States)

    Prokhorova, Evgeniia A; Zamaraev, Alexey V; Kopeina, Gelina S; Zhivotovsky, Boris; Lavrik, Inna N

    2015-12-01

    Since their establishment in the early 1970s, the nuclear changes upon apoptosis induction, such as the condensation of chromatin, disassembly of nuclear scaffold proteins and degradation of DNA, were, and still are, considered as the essential steps and hallmarks of apoptosis. These are the characteristics of the execution phase of apoptotic cell death. In addition, accumulating data clearly show that some nuclear events can lead to the induction of apoptosis. In particular, if DNA lesions resulting from deregulation during the cell cycle or DNA damage induced by chemotherapeutic drugs or viral infection cannot be efficiently eliminated, apoptotic mechanisms, which enable cellular transformation to be avoided, are activated in the nucleus. The functional heterogeneity of the nuclear organization allows the tight regulation of these signaling events that involve the movement of various nuclear proteins to other intracellular compartments (and vice versa) to initiate and govern apoptosis. Here, we discuss how these events are coordinated to execute apoptotic cell death.

  11. Reassessing apoptosis in plants.

    Science.gov (United States)

    Dickman, Martin; Williams, Brett; Li, Yurong; de Figueiredo, Paul; Wolpert, Thomas

    2017-10-01

    Cell death can be driven by a genetically programmed signalling pathway known as programmed cell death (PCD). In plants, PCD occurs during development as well as in response to environmental and biotic stimuli. Our understanding of PCD regulation in plants has advanced significantly over the past two decades; however, the molecular machinery responsible for driving the system remains elusive. Thus, whether conserved PCD regulatory mechanisms include plant apoptosis remains enigmatic. Animal apoptotic regulators, including Bcl-2 family members, have not been identified in plants but expression of such regulators can trigger or suppress plant PCD. Moreover, plants exhibit nearly all of the biochemical and morphological features of apoptosis. One difference between plant and animal PCD is the absence of phagocytosis in plants. Evidence is emerging that the vacuole may be key to removal of unwanted plant cells, and may carry out functions that are analogous to animal phagocytosis. Here, we provide context for the argument that apoptotic-like cell death occurs in plants.

  12. Bisphenol A induces spermatocyte apoptosis in rare minnow Gobiocypris rarus

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yingying; Cheng, Mengqian; Wu, Lang; Zhang, Guo; Wang, Zaizhao, E-mail: zzwang@nwsuaf.edu.cn

    2016-10-15

    Highlights: • Adult male G. rarus were exposed to 225 μg/L BPA for 7, 21 and 63 days. • BPA could induce spermatocyte apoptosis in rare minnow testis. • The mitochondrial apoptotic pathway participated in the germ cell apoptosis. • The spermatocyte apoptosis was likely initiated by BPA induced meiosis arrest. - Abstract: Bisphenol A (BPA) is an endocrine disruptor, and could induce germ cells apoptosis in the testis of mammals. But whether it could affect fish in the same mechanism has not’ been studied till now. In the present study, to investigate the influence of BPA on testis germ cells in fish, adult male rare minnow Gobiocypris rarus were exposed to 225 μg L{sup −1} (0.99 μM) BPA for 1, 3 and 9 weeks. Through TdT-mediated dUTP nick end labeling (TUNEL) and transmission electron microscope (TEM) analysis, we found that the amount of apoptotic spermatocytes significantly increased in a time dependent manner following BPA exposure. Western Blot results showed that the ratio of Bcl2/Bax, the important apoptosis regulators in intrinsic mitochondrial apoptotic pathway, was significantly decreased. qPCR showed that mRNA expression of several genes in mitochondrial apoptotic pathway including bcl2, bax, casp9, cytc and mcl1b were significantly changed following BPA exposure. In addition, mRNA expression of meiosis regulation genes (kpna7 and wee2), and genes involved in both apoptosis and meiosis (birc5, ccna1, and gsa1a) were also affected by BPA. Taken together, the present study demonstrated that BPA could induce spermatocytes apoptosis in rare minnow testis, and the apoptosis was probably under regulation of intrinsic mitochondrial apoptotic pathway. Moreover, the spermatocyte apoptosis was likely initiated by BPA induced meiosis arrest.

  13. Childrens' Rights in the South African Constitution

    Directory of Open Access Journals (Sweden)

    JA Robinson

    2003-10-01

    Full Text Available Children were in many respects defenceless victims of discriminatory practices in ‘apartheid South Africa’. In fact, discrimination on the basis of gender, race and other inequalities were inscribed in the social fabric of the previous constitutional dispensation. The constitutional dispensation that came into effect on the 27th April 1994 was therefore designed to innovate social, political and legal structures that would be radically different from those of the country’s past history.In this contribution the impact of the Constitution upon the rights of children are considered. In order to fathom the impact. a general overview of constitutional principles and provisions necessary for the comprehension of the rights of children is provided. Thereafter the rights of children expressly mentioned in the Constitution will be addressed. Attention is also paid to the equal protection and non-discrimination provisions of the Constitution, albeit only indirectly.

  14. "Not our constitution". Assessing the United Nations' assistance to the recent Somali constitution-making process.

    OpenAIRE

    Jørgensen, Hilde

    2013-01-01

    The UN increasingly provides assistance to constitution-making in war-torn countries as an element of larger peacebuilding operations. The underlying assumption is that constitution-making, if conducted in the right way, may contribute positively to peace in several ways. First, constitution-making can contribute to reconciliation by providing a platform for people to come together and agree on a common future for their state. Second, constitution-making can provide legitimacy to constitution...

  15. The Jurisdiction of The Constitutional Court In Controlling The Constitutionality of Criminal Judgments: Kosovo Case

    OpenAIRE

    BRAHA, Florentina Shala; BYTYQI, Vilard; VUNIQI, Dardan; Berisha, Fadil

    2016-01-01

    This paper will deal with individual requests that are submitted at the Constitutional Court in order to assess the constitutionality of criminal judicial decisions. The right to submit issues for assessing the constitutionality of criminal court decisions is a constitutionally guaranteed right. Many individuals who are dissatisfied with the decisions of the judicial instances use their right to oppose such a decision even at the Constitutional Court.Not all the cases submitted to the Court a...

  16. Autonomous Province of Vojvodina between the Constitution and the decision of the Constitutional court

    Directory of Open Access Journals (Sweden)

    Čiplić Svetozar

    2014-01-01

    Full Text Available The author deals individual assessments Constitutional court of the Competent in Law, as well as its different interpretation of constitutional and legal provisions. The author is of the opinion that the Constitutional Court amended the constitution and the law guaranteed the position of the Autonomous Province of Vojvodina and that the 'conservative interpretation of' diminished the rights of citizens by the constitution itself by.

  17. Complexities of Constitutional Change in the Philippines

    OpenAIRE

    Saunders, Cheryl; Yusingco, Michael Henry

    2018-01-01

    President Rodrigo Duterte assumed office in July 2016, His party, PDP-Laban, had campaigned under the slogan: “No to Drugs, Yes to Federalism”. Duterte thus is committed to shepherding the Philippines towards a federal form of government; an undertaking that would require an extensive overhaul of the country’s constitution. The future of constitutional change under Duterte in any event is uncertain for a series of constitutional and political reasons. Critically, some of the most pressing of ...

  18. Advanced glycation end products (AGEs) and their receptor (RAGE) induce apoptosis of periodontal ligament fibroblasts

    OpenAIRE

    Li,D.X.; Deng,T.Z.; Lv,J.; Ke,J.

    2014-01-01

    Diabetics have an increased prevalence of periodontitis, and diabetes is one of the causative factors of severe periodontitis. Apoptosis is thought to be involved in this pathogenic relationship. The aim of this study was to investigate apoptosis in human periodontal ligament (PDL) fibroblasts induced by advanced glycation end products (AGEs) and their receptor (RAGE). We examined the roles of apoptosis, AGEs, and RAGE during periodontitis in diabetes mellitus using cultured PDL fibroblasts t...

  19. Testing of constitutive models in LAME.

    Energy Technology Data Exchange (ETDEWEB)

    Hammerand, Daniel Carl; Scherzinger, William Mark

    2007-09-01

    Constitutive models for computational solid mechanics codes are in LAME--the Library of Advanced Materials for Engineering. These models describe complex material behavior and are used in our finite deformation solid mechanics codes. To ensure the correct implementation of these models, regression tests have been created for constitutive models in LAME. A selection of these tests is documented here. Constitutive models are an important part of any solid mechanics code. If an analysis code is meant to provide accurate results, the constitutive models that describe the material behavior need to be implemented correctly. Ensuring the correct implementation of constitutive models is the goal of a testing procedure that is used with the Library of Advanced Materials for Engineering (LAME) (see [1] and [2]). A test suite for constitutive models can serve three purposes. First, the test problems provide the constitutive model developer a means to test the model implementation. This is an activity that is always done by any responsible constitutive model developer. Retaining the test problem in a repository where the problem can be run periodically is an excellent means of ensuring that the model continues to behave correctly. A second purpose of a test suite for constitutive models is that it gives application code developers confidence that the constitutive models work correctly. This is extremely important since any analyst that uses an application code for an engineering analysis will associate a constitutive model in LAME with the application code, not LAME. Therefore, ensuring the correct implementation of constitutive models is essential for application code teams. A third purpose of a constitutive model test suite is that it provides analysts with example problems that they can look at to understand the behavior of a specific model. Since the choice of a constitutive model, and the properties that are used in that model, have an enormous effect on the results of an

  20. Health care for Micronesians and constitutional rights.

    Science.gov (United States)

    Shek, Dina; Yamada, Seiji

    2011-11-01

    Under the Compacts of Free Association (COFA), people from the Freely Associated States--the Republic of Palau (ROP), the Republic of the Marshall Islands (RMI), and the Federated States of Micronesia (FSM)--have been migrating to the United States in increasing numbers. In 1996, Congress passed broad welfare reform (Personal Responsibility and Work Opportunity Reconciliation Act) which limited certain federal benefits previously available to COFA migrants, including Medicaid benefits. Prior to July 2010, the State of Hawai'i had continued to include COFA migrants under its state-funded Medicaid program. In the face of budget constraints, the State removed these people from its Medicaid rolls. A challenge on the legal basis of the denial of equal protection of the laws, ie, the Fourteenth Amendment to the US Constitution, was successful in reinstating health care to the COFA migrants in December 2010. From the health worker's perspective, regardless of various social justice arguments that may have been marshaled in favor of delivering health care to the people, it was an appeal to the judicial system that succeeded. From the attorney's perspective, the legal victories are potentially limited to the four walls of the courtroom without community involvement and related social justice movements. Together, the authors propose that in order to better address the issue of health care access for Micronesian peoples, we must work together, as health and legal advocates, to define a more robust vision of both systems that includes reconciliation and community engagement.

  1. Sequential activation of proteases in radiation induced apoptosis

    International Nuclear Information System (INIS)

    Watters, D.; Waterhouse, N.

    1997-01-01

    Full text: Significant advances have been made in recent years in unraveling the molecular mechanisms of apoptosis particularly in relation to Fas- and TNF-mediated cell death, however there are considerable gaps in our knowledge of the processes involved in apoptosis induced by ionizing radiation. We have used the degradation of specific proteolytic targets in a pair of isogenic Burkitt's Iymphoma cells lines (BL30A, sensitive and BL30K resistant) to study the sequence of events in the execution of radiation-induced apoptosis. Fodrin can be cleaved to fragments of 150 kDa and 120 kDa. In the case of Fas-mediated apoptosis both cleavages are inhibited by the caspase inhibitor zVAD-fmk at 10 μM, a concentration which inhibits all the hallmarks of apoptosis. However in radiation-induced apoptosis, inhibition of the clevage of fodrin to the 150 kDa fragment requires 100 μM zVAD-fink while apoptosis itself is inhibited at 10 μM. This suggests that different enzymes are responsible for the generation of the 150 kDa fragment in the two models of apoptosis. Fodrin has been reported to be cleaved by μ-calpain to a 150 kDa fragment however, the involvement of μ-calpain in apoptosis has not yet been established. In murine fodrin there is a caspase cleavage site within 1 kDa of the calpain cleavage site. In vitro studies using purified enzymes showed that only caspase-3 and μ-calpain could cleave fodrin in untreated cell extracts to the same sized fragments as seen during apoptosis in vivo. We provide evidence for the early activation of μ-calpain after ionizing radiation in the sensitive BL30A cell line, and show that the time course of μ-calpain activation parallels that of the appearance of the 150 kDa fragment. Caspase-3 is activated much later and is likely to be responsible for the generation of the 120 kDa fragment. μ-Calpain was not activated in the resistant cell line. Based on these results we propose a model for the proteolytic cascade in radiation

  2. National Constitutional Avenues for Further EU Integration

    NARCIS (Netherlands)

    Besselink, L.F.M.; Claes, M.; Imamovic, Š.; Reestman, J.H.

    2014-01-01

    This study investigates national constitutional limits to further EU integration and explores ways to overcome them. It includes an in-depth examination of the constitutional systems of 12 Member States (Croatia, the Czech Republic, Estonia, Finland, France, Germany, Hungary, Ireland, Italy, the

  3. Constitutional provisions regarding juristic persons | Pienaar ...

    African Journals Online (AJOL)

    The interim Constitution of 1993 and the final Constitution of 1996 contain specific provisions applicable to juristic persons. Juristic persons are also entitled to the fundamental rights contained in the Bill of Rights to the extent that these rights are applicable to them. It must be kept in mind that juristic persons have peculiar ...

  4. Constitutional Government: The Soul of Modern Democracy.

    Science.gov (United States)

    Mansfield, Harvey C., Jr.

    1987-01-01

    Discusses the dilemma faced by constitutionalism today: limited, constitutional government requires that people and society be independent and distrustful of the state, but if the people are too independent and capable of ruling, they may wish to extend their powers and attempt to rule over others. (PS)

  5. Distinguishing Limitation on Constitutional Rights from Their ...

    African Journals Online (AJOL)

    Suspension of and limitation on fundamental rights and freedoms are justified violations of constitutional rights. Temporary suspension of some fundamental rights and freedoms can be made on the ground of a state of emergency. Since most constitutional rights are not absolute, they can be limited on basis of national ...

  6. PUMA mediates ER stress-induced apoptosis in portal hypertensive gastropathy

    Science.gov (United States)

    Tan, S; Wei, X; Song, M; Tao, J; Yang, Y; Khatoon, S; Liu, H; Jiang, J; Wu, B

    2014-01-01

    Mucosal apoptosis has been demonstrated to be an essential pathological feature in portal hypertensive gastropathy (PHG). p53-upregulated modulator of apoptosis (PUMA) was identified as a BH3-only Bcl-2 family protein that has an essential role in apoptosis induced by a variety of stimuli, including endoplasmic reticulum (ER) stress. However, whether PUMA is involved in mucosal apoptosis in PHG remains unclear, and whether PUMA induces PHG by mediating ER stress remains unknown. The aim of the study is to investigate whether PUMA is involved in PHG by mediating ER stress apoptotic signaling. To identify whether PUMA is involved in PHG by mediating ER stress, gastric mucosal injury and apoptosis were studied in both PHG patients and PHG animal models using PUMA knockout (PUMA-KO) and PUMA wild-type (PUMA-WT) mice. The induction of PUMA expression and ER stress signaling were investigated, and the mechanisms of PUMA-mediated apoptosis were analyzed. GES-1 and SGC7901 cell lines were used to further identify whether PUMA-mediated apoptosis was induced by ER stress in vitro. Epithelial apoptosis and PUMA were markedly induced in the gastric mucosa of PHG patients and mouse PHG models. ER stress had a potent role in the induction of PUMA and apoptosis in PHG models, and the apoptosis was obviously attenuated in PUMA-KO mice. Although the targeted deletion of PUMA did not affect ER stress, mitochondrial apoptotic signaling was downregulated in mice. Meanwhile, PUMA knockdown significantly ameliorated ER stress-induced mitochondria-dependent apoptosis in vitro. These results indicate that PUMA mediates ER stress-induced mucosal epithelial apoptosis through the mitochondrial apoptotic pathway in PHG, and that PUMA is a potentially therapeutic target for PHG. PMID:24625987

  7. Potential Roles of Humanin on Apoptosis in the Heart.

    Science.gov (United States)

    Charununtakorn, Savitree T; Shinlapawittayatorn, Krekwit; Chattipakorn, Siriporn C; Chattipakorn, Nipon

    2016-04-01

    The process of programmed cell death, or apoptosis, is known as a key player in the development and progression of cardiovascular disease. The proposed mechanism for apoptosis is the activation of two main apoptotic signaling pathways (the extrinsic and intrinsic pathways), which lead to cell death. As the rate and amount of cardiomyocyte loss is the most important determinant of patient morbidity and mortality, novel treatment strategies targeting apoptosis are crucial. Recently, Humanin has been shown to exert protective effects against cellular apoptosis in both experimental and clinical studies. The potential cardioprotective mechanisms of Humanin have been shown to involve both the extracellular and intracellular signaling pathways. In this review, the current knowledge and the mechanisms inhibiting cellular apoptosis by Humanin during cardiac injury are comprehensively summarized. In addition, both research and clinical findings regarding the effects of Humanin on the heart and vasculature are also presented and discussed. Currently available information suggests that Humanin may exert cardioprotective benefits and could potentially be used as a novel pharmacological intervention against cellular apoptosis during myocardial injury. © 2015 John Wiley & Sons Ltd.

  8. Gene expression profiling reveals two separate mechanisms regulating apoptosis in rectal carcinomas in vivo

    NARCIS (Netherlands)

    de Bruin, Elza C.; van de Pas, Simone; van de Velde, Cornelis J. H.; van Krieken, J. Han J. M.; Peltenburg, Lucy T. C.; Marijnen, Corrie A. M.; Medema, Jan Paul

    2007-01-01

    The level of apoptosis in rectal carcinomas of patients treated by surgery only predicts local failure; patients with intrinsically high-apoptotic tumors develop less local recurrences than patients with low levels of apoptosis. To identify genes involved in this intrinsic apoptotic process in vivo,

  9. CONSTITUTIONAL INTERPRETATION OF ROMANIA: POST MODERNITY

    Directory of Open Access Journals (Sweden)

    P. RATHNASWAMY

    2017-06-01

    Full Text Available Austria had in 1920 Constitutional Court followed by Italy in 1946, Germany in 1949, Romania in 1989, South Africa in 1991, and Ethiopia in 1995. Each Constitution has its provisions on the constitutional interpretation. Romania has its own provisions and it is considered here its legality and the best possible measures and recommendations for future. Judicial power is vested in judiciary to interpret constitution, laws, and actions of other organs of government. Judicial review is the function resulted upon judicial power. Political body joins through the appointment of its members in the judicial review and it limits the independence of judiciary. It also reduces the values of separation of powers. Challenges and opportunities of growth and development do influence the spirit of separation of powers and judicial independence. The principle of inherent judicial power in judiciary inducts upon the constitutional interpretation. Thus, the principles of constitutional interpretation are varying in Romania and other similar constitutional courts of Germany, Ethiopia, and Italy but not in South Africa.

  10. Closing in on the constitution of consciousness

    Science.gov (United States)

    Miller, Steven M.

    2014-01-01

    The science of consciousness is a nascent and thriving field of research that is founded on identifying the minimally sufficient neural correlates of consciousness. However, I have argued that it is the neural constitution of consciousness that science seeks to understand and that there are no evident strategies for distinguishing the correlates and constitution of (phenomenal) consciousness. Here I review this correlation/constitution distinction problem and challenge the existing foundations of consciousness science. I present the main analyses from a longer paper in press on this issue, focusing on recording, inhibition, stimulation, and combined inhibition/stimulation strategies, including proposal of the Jenga analogy to illustrate why identifying the minimally sufficient neural correlates of consciousness should not be considered the ultimate target of consciousness science. Thereafter I suggest that while combined inhibition and stimulation strategies might identify some constitutive neural activities—indeed minimally sufficient constitutive neural activities—such strategies fail to identify the whole neural constitution of consciousness and thus the correlation/constitution distinction problem is not fully solved. Various clarifications, potential objections and related scientific and philosophical issues are also discussed and I conclude by proposing new foundational claims for consciousness science. PMID:25452738

  11. MINISTERIAL LIABILITY IN THE ROMANIAN CONSTITUTIONAL SYSTEM

    Directory of Open Access Journals (Sweden)

    NICOLAE PAVEL

    2013-05-01

    Full Text Available What seems relevant to us for highlighting in this study is the approach of the ministerial liability within the Romanian constitutional and legal system starting with the first document of constitutional value, namely the Developing Statute of the Paris Convention of 1858 until today, that is the Constitution of Romania, revised in 2003 and republished. Having in view that this is a generous study topic covering over 150 years of constitutional and legal evolution of ministerial liability in Romania, it is necessary to specify from the very beginning the need of a diachronic approach of this topic by identifying all Romanian Constitutions that have regulated the constitutional system during this period of time. Moreover, we have to specify that, during this period of time, Romania has experienced several forms of governance, namely monarchy, people’s republic, socialist republic and semi-presidential republic. With this approach, the proposed study opens a complex and complete yet not exhaustive vision in the current scope of the ministerial liability. It is also the reason why the study begins with preliminary considerations in which the terminology used in the content of the study is justified. Following a key-scheme, there are successively examined the two major parts of the study, namely the general theory regarding the concepts of ministerial responsibility and liability and the Romanian constitutional, legal and doctrinaire milestones of the ministerial liability.

  12. Morphine withdrawal enhances constitutive μ-opioid receptor activity in the ventral tegmental area

    NARCIS (Netherlands)

    Meye, F.J.; van Zessen, R.; Smidt, M.P.; Adan, R.A.H.; Ramakers, G.M.J.

    2012-01-01

    μ-opioid receptors (MORs) in the ventral tegmental area (VTA) are pivotally involved in addictive behavior. While MORs are typically activated by opioids, they can also become constitutively active in the absence of any agonist. In the current study, we present evidence that MOR constitutive

  13. Competition And Antitrust Law In Ecuadorian Constitution

    Directory of Open Access Journals (Sweden)

    Marcelo Marín Sevilla

    2013-01-01

    Full Text Available This work allows us to establish the Economic Constitution and the Competition Law (C.L in the Constitution. Additionally, the paper analyzes whether the rules outlined in the C. L. and in doctrine are consistent and appropriate with the Constitution of Ecuador. The Competition and Antitrust Laws has rules for investigating and punishing the cartels, the abuses of power market (dominant position, the rules for merger control, the behaviors of Abuse of economic dependence, and unfair competition behaviors. Always the Antitrust Authority will analyze these behaviors in terms of welfare of both: the consumer and the market.

  14. The constitutional control system in Colombia

    Directory of Open Access Journals (Sweden)

    Luis Javier Moreno Ortiz

    2010-12-01

    Full Text Available The system of constitutional control in Colombia designed in the Legislative Act n.º 3 of 1910 is a milestone in a long and fruitful political and constitutional tradition owes much to his Hispanic roots and its American developments. Both the public action of unconstitutionality as the plea of unconstitutionality have clear precedents in the constitutionalism of Spain and the Colony were prepared by a Constituent Assembly acted with knowledge and faithfulness to that tradition and have been and are institutions of our capital social and democratic state of law.

  15. Avenanthramides Prevent Osteoblast and Osteocyte Apoptosis and Induce Osteoclast Apoptosis in Vitro in an Nrf2-Independent Manner

    Science.gov (United States)

    Pellegrini, Gretel G.; Morales, Cynthya C.; Wallace, Taylor C.; Plotkin, Lilian I.; Bellido, Teresita

    2016-01-01

    Oats contain unique bioactive compounds known as avenanthramides (AVAs) with antioxidant properties. AVAs might enhance the endogenous antioxidant cellular response by activation of the transcription factor Nrf2. Accumulation of reactive oxygen species plays a critical role in many chronic and degenerative diseases, including osteoporosis. In this disease, there is an imbalance between bone formation by osteoblasts and bone resorption by osteoclasts, which is accompanied by increased osteoblast/osteocyte apoptosis and decreased osteoclast apoptosis. We investigated the ability of the synthethic AVAs 2c, 2f and 2p, to 1-regulate gene expression in bone cells, 2-affect the viability of osteoblasts, osteocytes and osteoclasts, and the generation of osteoclasts from their precursors, and 3-examine the potential involvement of the transcription factor Nrf2 in these actions. All doses of AVA 2c and 1 and 5 µM dose of 2p up-regulated collagen 1A expression. Lower doses of AVAs up-regulated OPG (osteoprotegerin) in OB-6 osteoblastic cells, whereas 100 μM dose of 2f and all concentrations of 2c down-regulated RANKL gene expression in MLO-Y4 osteocytic cells. AVAs did not affect apoptosis of OB-6 osteoblastic cells or MLO-Y4 osteocytic cells; however, they prevented apoptosis induced by the DNA topoisomerase inhibitor etoposide, the glucocorticoid dexamethasone, and hydrogen peroxide. AVAs prevented apoptosis of both wild type (WT) and Nrf2 Knockout (KO) osteoblasts, demonstrating that AVAs-induced survival does not require Nrf2 expression. Further, KO osteoclast precursors produced more mature osteoclasts than WT; and KO cultures exhibited less apoptotic osteoclasts than WT cultures. Although AVAs did not affect WT osteoclasts, AVA 2p reversed the low apoptosis of KO osteoclasts. These in vitro results demonstrate that AVAs regulate, in part, the function of osteoblasts and osteocytes and prevent osteoblast/osteocyte apoptosis and increase osteoclast apoptosis; further

  16. Avenanthramides Prevent Osteoblast and Osteocyte Apoptosis and Induce Osteoclast Apoptosis in Vitro in an Nrf2-Independent Manner

    Directory of Open Access Journals (Sweden)

    Gretel G. Pellegrini

    2016-07-01

    Full Text Available Oats contain unique bioactive compounds known as avenanthramides (AVAs with antioxidant properties. AVAs might enhance the endogenous antioxidant cellular response by activation of the transcription factor Nrf2. Accumulation of reactive oxygen species plays a critical role in many chronic and degenerative diseases, including osteoporosis. In this disease, there is an imbalance between bone formation by osteoblasts and bone resorption by osteoclasts, which is accompanied by increased osteoblast/osteocyte apoptosis and decreased osteoclast apoptosis. We investigated the ability of the synthethic AVAs 2c, 2f and 2p, to 1-regulate gene expression in bone cells, 2-affect the viability of osteoblasts, osteocytes and osteoclasts, and the generation of osteoclasts from their precursors, and 3-examine the potential involvement of the transcription factor Nrf2 in these actions. All doses of AVA 2c and 1 and 5 µM dose of 2p up-regulated collagen 1A expression. Lower doses of AVAs up-regulated OPG (osteoprotegerin in OB-6 osteoblastic cells, whereas 100 μM dose of 2f and all concentrations of 2c down-regulated RANKL gene expression in MLO-Y4 osteocytic cells. AVAs did not affect apoptosis of OB-6 osteoblastic cells or MLO-Y4 osteocytic cells; however, they prevented apoptosis induced by the DNA topoisomerase inhibitor etoposide, the glucocorticoid dexamethasone, and hydrogen peroxide. AVAs prevented apoptosis of both wild type (WT and Nrf2 Knockout (KO osteoblasts, demonstrating that AVAs-induced survival does not require Nrf2 expression. Further, KO osteoclast precursors produced more mature osteoclasts than WT; and KO cultures exhibited less apoptotic osteoclasts than WT cultures. Although AVAs did not affect WT osteoclasts, AVA 2p reversed the low apoptosis of KO osteoclasts. These in vitro results demonstrate that AVAs regulate, in part, the function of osteoblasts and osteocytes and prevent osteoblast/osteocyte apoptosis and increase osteoclast

  17. Methylselenium and Prostate Cancer Apoptosis

    National Research Council Canada - National Science Library

    Lu, Junxuan

    2007-01-01

    The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of prostate cancer (PCa...

  18. Methylselenium and Prostate Cancer Apoptosis

    National Research Council Canada - National Science Library

    Lu, Junxuan

    2005-01-01

    The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of prostate cancer (PCa...

  19. Methylselenium and Prostate Cancer Apoptosis

    National Research Council Canada - National Science Library

    Lu, Junxuan

    2006-01-01

    The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of prostate cancer (PCa...

  20. Methylselenium and Prostate Cancer Apoptosis

    National Research Council Canada - National Science Library

    Lu, Junxuan

    2004-01-01

    The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of PCa cells by methyl selenium (Se)/selenol...

  1. Methylselenium and Prostate Cancer Apoptosis

    National Research Council Canada - National Science Library

    Lu, Junxuan

    2008-01-01

    The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of prostate cancer (PCa...

  2. Methylselenium and Prostate Cancer Apoptosis

    National Research Council Canada - National Science Library

    Lu, Junxuan

    2003-01-01

    The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of PCa cells by methyl selenium (Se...

  3. Dynamic constitutional frameworks for DNA biomimetic recognition.

    Science.gov (United States)

    Catana, Romina; Barboiu, Mihail; Moleavin, Ioana; Clima, Lilia; Rotaru, Alexandru; Ursu, Elena-Laura; Pinteala, Mariana

    2015-02-07

    Linear and cross-linked dynamic constitutional frameworks generated from reversibly interacting linear PEG/core constituents and cationic sites shed light on the dominant coiling versus linear DNA binding behaviours, closer to the histone DNA binding wrapping mechanism.

  4. Constitutive equation of concrete: Mesomechanical isotropic model

    Czech Academy of Sciences Publication Activity Database

    Kafka, Vratislav; Vokoun, David

    2005-01-01

    Roč. 1, č. 2 (2005), s. 183-193 ISSN 1573-6105 Institutional research plan: CEZ:AV0Z20710524 Keywords : plasticity * constitutive modeling * concrete * mesomechanics Subject RIV: JI - Composite Materials

  5. Structure and Calibration of Constitutive Equations for Granular Soils

    Directory of Open Access Journals (Sweden)

    Sawicki Andrzej

    2015-02-01

    Full Text Available The form of incremental constitutive equations for granular soils is discussed for the triaxial configuration. The classical elasto-plastic approach and the semi-empirical model are discussed on the basis of constitutive relations determined directly from experimental data. First, the general structure of elasto-plastic constitutive equations is presented. Then, the structure of semiempirical constitutive equations is described, and a method of calibrating the model is presented. This calibration method is based on a single experiment, performed in the triaxial apparatus, which also involves a partial verification of the model, on an atypical stress path. The model is shown to give reasonable predictions. An important feature of the semi-empirical incremental model is the definition of loading and unloading, which is different from that assumed in elasto-plasticity. This definition distinguishes between spherical and deviatoric loading/unloading. The definition of deviatoric loading/unloading has been subject to some criticism. It was therefore discussed and clarified in this paper on the basis of the experiment presented.

  6. Social rights constitutionalism: an antagonistic endorsement

    OpenAIRE

    Christodoulidis, Emilios

    2017-01-01

    The article discusses how we might understand solidarity as the organizing concept behind the institutionalization of social rights. I argue that writing solidarity into social rights constitutionalism carries productive tension into constitutional thinking because it disturbs the smooth passage from civil to political and finally to social rights. Marshall's influential argument that social rights are continuous to civil and political rights has become both the grounding assumption in consti...

  7. Constitutional rights and hypnotically elicited testimony.

    Science.gov (United States)

    Newman, A W; Thompson, J W

    1999-01-01

    Despite the former popularity of hypnosis as a way of "improving" eyewitness memory, many courts almost always regard the use of this testimony to be inadmissible, whereas others allow it only when strict procedural guidelines have been followed. Although the U.S. Supreme Court recognized a defendant's constitutional right to admit his own hypnotically elicited testimony, others have recognized a constitutional basis to exclude hypnotically elicited testimony in most other circumstances.

  8. On the constitutionality of dose limiting values

    International Nuclear Information System (INIS)

    Goetz, V.

    1976-01-01

    The fundamental right according to Art. 2 par. 2 sentence 1 of the German Constitution is relevant for the set-up and application of radiation protection law. Resulting from Art. 2 par. 2 sentence 1 of the Constitution it is a general obligation of the state to protect life (Federal Constitutional Court, judgment of 25th Feb., 1975, BVerfGE 39.1) and physical soundness. The subjective basic right of everybody to defend against official encroachments his personal integrity corresponds to the right of the individual within the framework of the official obligation for protection from the state (to ward off danger). The term of danger, as to the degree of its determination, corresponds to that of the encroachment. To speak of danger in a legal sense, the causal connection between a certain source of danger and certain damage must be ascertained and proved. Topical controversies as to the admissibility of activity discharges of low doses range in the field of risk reduction and thus in the field of the duty of the state to take precautionary steps against risks (Art. 2 par. 2 sentence 1 of the Constitution). The constitution, however, does not contain any basic right that every risk has to be avoided. On the other hand, the necessity of cautions valuation of radiation risks can be derived from the Constitution. The fixation of dose limits and their application in connection with general radiation protection principles (paragraph 28 E of the Radiation Protection Ordinance) do not contain any 'interference' with the basic right in the sense of Art. 2 par. 2 sentence 3 of the Constitution. Neither from aspects of the principle of the legal state nor from Art. 80 par. 1 of the Constitution can the use of the legal form of the Ordinance be doubted. (orig./HP) [de

  9. Effect of recombinant human erythropoietin expressions of apoptosis ...

    African Journals Online (AJOL)

    mechanisms underlying secondary brain damage following TBI are complex and involve two main stages: traumatic cerebral edema and delayed neuronal damage [1-3]. Delayed neuronal damage leads to irreversible necrosis or apoptosis of neurons, which could affect the long-term prognosis and quality of life in patients.

  10. Molecular interplay between ion channels and the regulation of apoptosis

    Directory of Open Access Journals (Sweden)

    MONA A RAZIK

    2002-01-01

    Full Text Available Apoptosis is the programmed and deliberate destruction of specific cells. This process occurs during normal development and maintains cellular homeostasis. Disruption or malfunction of apoptosis is implicated in diseases like cancer, AIDS as well as neurodegenerative disorders. The movement of monovalent ions appears to set the stage for the induction of the self-destruction machinery by creating an intracellular environment that favors activation and coordinated execution of the apoptotic program. Understanding the components and steps involved in this intricate process can further our insight to diseases and reveal new approaches for therapeutic treatment

  11. Recombinant vectors construction for cellobiohydrolase encoding gene constitutive expression

    Directory of Open Access Journals (Sweden)

    Leontina GURGU

    2012-12-01

    Full Text Available Cellobiohydrolases (EC 3.2.1.91 are important exo enzymes involved in cellulose hydrolysis alongside endoglucanases (EC 3.2.1.4 and β-glucosidases (EC 3.2.1.21. Heterologous cellobiohydrolase gene expression under constitutive promoter control using Saccharomyces cerevisiae as host system is of great importance for a successful SSF process. From this point of view, the main objective of the work was to use Yeplac181 expression vector as a recipient for cellobiohdrolase - cbhB encoding gene expression under the control of the actin promoter, in Saccharomyces cerevisiae. Two hybridvectors, YEplac-Actp and YEplac-Actp-CbhB, were generated usingEscherichia coli XLI Blue for the cloning experiments. Constitutive cbhB gene expression was checked by proteine gel electrophoresis (SDS-PAGE after insertion of these constructs into Saccharomyces cerevisiae.

  12. A thermomechanical crystal plasticity constitutive model for ultrasonic consolidation

    KAUST Repository

    Siddiq, Amir

    2012-01-01

    We present a micromechanics-based thermomechanical constitutive model to simulate the ultrasonic consolidation process. Model parameters are calibrated using an inverse modeling approach. A comparison of the simulated response and experimental results for uniaxial tests validate and verify the appropriateness of the proposed model. Moreover, simulation results of polycrystalline aluminum using the identified crystal plasticity based material parameters are compared qualitatively with the electron back scattering diffraction (EBSD) results reported in the literature. The validated constitutive model is then used to simulate the ultrasonic consolidation process at sub-micron scale where an effort is exerted to quantify the underlying micromechanisms involved during the ultrasonic consolidation process. © 2011 Elsevier B.V. All rights reserved.

  13. Loading method of core constituting elements

    International Nuclear Information System (INIS)

    Kasai, Shigeo

    1976-01-01

    Purpose: To provide a remote-controlled replacing method for core constituting elements in a liquid-metal cooling fast breeder, wherein particularly, the core constituting elements are prevented from being loaded on the core position other than as designated. Constitution: The method comprises a first step which determines a position of a suitable neutron shielding body in order to measure a reference level of complete insertion of the core constituting elements, a second step which inserts a gripper for a fuel exchanger, a third step which decides stroke dimensions of the complete insertion, and a fourth step which discriminates the core constituting elements to begin handling of fuel rods. The method further comprises a fifth step which determines a loading position of fuel rod, and a sixth step which inserts and loads fuel rods into the core. The method still further comprises a seventh step which compares and judges the dimension of loading stroke and the dimension of complete inserting stroke so that when coincided, loading is completed, and when not coincided, loading is not completed and then the cycle of the fourth step is repeated. (Kawakami, Y.)

  14. A constitutive theory of reacting electrolyte mixtures

    Science.gov (United States)

    Costa Reis, Martina; Wang, Yongqi; Bono Maurizio Sacchi Bassi, Adalberto

    2013-11-01

    A constitutive theory of reacting electrolyte mixtures is formulated. The intermolecular interactions among the constituents of the mixture are accounted for through additional freedom degrees to each constituent of the mixture. Balance equations for polar reacting continuum mixtures are accordingly formulated and a proper set of constitutive equations is derived with basis in the Müller-Liu formulation of the second law of thermodynamics. Moreover, the non-equilibrium and equilibrium responses of the reacting mixture are investigated in detail by emphasizing the inner and reactive structures of the medium. From the balance laws and constitutive relations, the effects of molecular structure of constituents upon the fluid flow are studied. It is also demonstrated that the local thermodynamic equilibrium state can be reached without imposing that the set of independent constitutive variables is time independent, neither spatially homogeneous nor null. The resulting constitutive relations presented throughout this work are of relevance to many practical applications, such as swelling of clays, developing of bio and polymeric membranes, and use of electrorheological fluids in industrial processes. The first author acknowledges financial support from National Counsel of Technological and Scientific Development (CNPq) and German Academic Exchange Service (DAAD).

  15. Health care law versus constitutional law.

    Science.gov (United States)

    Hall, Mark A

    2013-04-01

    National Federation of Independent Business v. Sebelius, the Supreme Court's ruling on the Patient Protection and Affordable Care Act, is a landmark decision - both for constitutional law and for health care law and policy. Others will study its implications for constitutional limits on a range of federal powers beyond health care. This article considers to what extent the decision is also about health care law, properly conceived. Under one view, health care law is the subdiscipline that inquires how courts and government actors take account of the special features of medicine that make legal or policy issues especially problematic - rather than regarding health care delivery and finance more generically, like most any other economic or social enterprise. Viewed this way, the opinions from the Court's conservative justices are mainly about general constitutional law principles. In contrast, Justice Ruth Bader Ginsburg's dissenting opinion for the four more liberal justices is just as much about health care law as it is about constitutional law. Her opinion gives detailed attention to the unique features of health care finance and delivery in order to inform her analysis of constitutional precedents and principles. Thus, the Court's multiple opinions give a vivid depiction of the compelling contrasts between communal versus individualistic conceptions of caring for those in need, and between health care and health insurance as ordinary commodities versus ones that merit special economic, social, and legal status.

  16. Nuclear energy and the constitutional state

    International Nuclear Information System (INIS)

    Saladin, P.

    1984-01-01

    This article puts the main emphasis on the problems of the constitutional principles of democracy, federalism, peaceful living together of peoples and constitutional state, i.e. problems caused by the development of nuclear energy. The fact that these problems are explained by way of the example of Switzerland, does not reduce the validity of the findings also for the German constitutional system, since the problems are identical and comparable. A long-term goal is a state theory which helps to define the aims and tasks of the state under technical, social, economic and cultural conditions of the end of the 20th and perhaps of the 21st century. Nuclear technology challenges the modern Western state and puts to the test the firmness of its legitimacy basis and the efficiency of its principles. It was conceived in a time which is separated from the present by technological revolutions. Safeguarding of humanity is aim and obligation of the modern constitutional state; the constitutional state stipulates the rules of conduct and, if the state remains true to its claim, it sets the procedures and the organization which give due priority order to the development of modern technology. (orig./HSCH) [de

  17. Transforming Growth Factor-β Directly Induces p53-up-regulated Modulator of Apoptosis (PUMA) during the Rapid Induction of Apoptosis in Myc-driven B-cell Lymphomas*

    Science.gov (United States)

    Spender, Lindsay C.; Carter, Matthew J.; O'Brien, Darren I.; Clark, Louise J.; Yu, Jian; Michalak, Ewa M.; Happo, Lina; Cragg, Mark S.; Inman, Gareth J.

    2013-01-01

    c-Myc transformed human Burkitt's lymphoma (BL) cells are highly sensitive to TGF-β-induced apoptosis. Previously we demonstrated that TGF-β-mediated cell death in BL cells is regulated via the mitochondrial intrinsic apoptosis pathway, which is dependent on the activation of BAX and/or BAK. TGF-β directly induces transcription of the BH3-only protein BIK and represses expression of the pro-survival factor BCL-XL but has no effect on the direct BAX/BAK “activators” BIM or BID (tBID). Here we show that TGF-β induces the BH3-only activator PUMA to aid induction of the intrinsic cell death pathway. TGF-β also induced PUMA in normal germinal center CD77-positive centroblasts isolated from human tonsil tissue. PUMA was a direct TGF-β target gene in B-cells, and we identify a putative Smad-binding region within the human PUMA promoter that recruits Smad3 and Smad4 in cells in response to TGF-β signaling. Constitutive activity of the isolated Smad-binding region in luciferase reporter assays was dependent on Smad consensus sequences and was partially dependent on endogenous TGF-β signaling and Smad4. Knockdown of PUMA in BL cells using lentiviral shRNA resulted in slower kinetics of the TGF-β-mediated apoptotic response. Analysis of Eμ-Myc cell lines demonstrated that c-myc-driven murine lymphomas are also sensitive to TGF-β-mediated apoptosis. Moreover, Puma−/− Eμ-Myc lines demonstrated significantly delayed kinetics of the apoptotic response when compared with wild type lymphomas. TGF-β therefore induces a polygenic response in Myc-driven lymphomas involving transcription of PUMA, which is necessary for the rapid induction of cell death. PMID:23243310

  18. Aβ induces PUMA activation: a new mechanism for Aβ-mediated neuronal apoptosis.

    Science.gov (United States)

    Feng, Jie; Meng, Chengbo; Xing, Da

    2015-02-01

    p53 upregulated modulator of apoptosis (PUMA) is a promising tumor therapy target because it elicits apoptosis and profound sensitivity to radiation and chemotherapy. However, inhibition of PUMA may be beneficial for curbing excessive apoptosis associated with neurodegenerative disorders. Alzheimer's disease (AD) is a representative neurodegenerative disease in which amyloid-β (Aβ) deposition causes neurotoxicity. The regulation of PUMA during Aβ-induced neuronal apoptosis remains poorly understood. Here, we reported that PUMA expression was significantly increased in the hippocampus of transgenic mice models of AD and hippocampal neurons in response to Aβ. PUMA knockdown protected the neurons against Aβ-induced apoptosis. Furthermore, besides p53, PUMA transactivation was also regulated by forkhead box O3a through p53-independent manner following Aβ treatment. Notably, PUMA contributed to neuronal apoptosis through competitive binding of apoptosis repressor with caspase recruitment domain to activate caspase-8 that cleaved Bid into tBid to accelerate Bax mitochondrial translocation, revealing a novel pathway of Bax activation by PUMA to mediate Aβ-induced neuronal apoptosis. Together, we demonstrated that PUMA activation involved in Aβ-induced apoptosis, representing a drug target to antagonize AD progression. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Genetically Encoded Fluorescent Probe for Imaging Apoptosis in Vivo with Spontaneous GFP Complementation.

    Science.gov (United States)

    Nasu, Yusuke; Asaoka, Yoichi; Namae, Misako; Nishina, Hiroshi; Yoshimura, Hideaki; Ozawa, Takeaki

    2016-01-05

    Apoptosis plays a pivotal role in development and tissue homeostasis in multicellular organisms. Dysfunction of apoptosis is involved in many fatal diseases such as cancer. Visualization of apoptosis in living animals is necessary to understand the mechanism of apoptosis-related diseases. Here, we describe a genetically encoded fluorescent probe for imaging apoptosis in living multicellular organisms, based on spontaneous complementation of two fragments of a green fluorescent protein (GFP) variant (GFP OPT). The probe is designed for detection of mitochondria-mediated apoptosis during which a mitochondrial protein of Smac is released into cytosol. The Smac is connected with a carboxy-terminal fragment of GFP OPT (GFP11), whereas the remainder of GFP OPT (GFP(1-10)) is located in the cytosol. Under an apoptotic condition, the Smac is released from mitochondria into cytosol, allowing complementation of the GFP-OPT fragments and the emission of fluorescence. Live-cell imaging demonstrates that the probe enables detection of apoptosis in living cells with a high signal-to-background ratio. We applied the probe to living zebrafish, in which apoptotic cells were visualized with fluorescence. The technique provides a useful tool for the study of apoptosis in living animals, facilitating elucidation of the mechanisms of apoptosis-related diseases.

  20. Molecular Imaging of Apoptosis: From Micro to Macro

    Science.gov (United States)

    Zeng, Wenbin; Wang, Xiaobo; Xu, Pengfei; Liu, Gang; Eden, Henry S.; Chen, Xiaoyuan

    2015-01-01

    Apoptosis, or programmed cell death, is involved in numerous human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer, and is often confused with other types of cell death. Therefore strategies that enable visualized detection of apoptosis would be of enormous benefit in the clinic for diagnosis, patient management, and development of new therapies. In recent years, improved understanding of the apoptotic machinery and progress in imaging modalities have provided opportunities for researchers to formulate microscopic and macroscopic imaging strategies based on well-defined molecular markers and/or physiological features. Correspondingly, a large collection of apoptosis imaging probes and approaches have been documented in preclinical and clinical studies. In this review, we mainly discuss microscopic imaging assays and macroscopic imaging probes, ranging in complexity from simple attachments of reporter moieties to proteins that interact with apoptotic biomarkers, to rationally designed probes that target biochemical changes. Their clinical translation will also be our focus. PMID:25825597

  1. Renal cell apoptosis in human lupus nephritis: a histological study

    DEFF Research Database (Denmark)

    Faurschou, M; Penkowa, Milena; Andersen, C B

    2009-01-01

    Nuclear autoantigens from apoptotic cells are believed to drive the immunological response in systemic lupus erythematosus (SLE). Conflicting data exist as to the possible renal origin of apoptotic cells in SLE patients with nephritis. We assessed the level of renal cell apoptosis in kidney...... biopsies from 35 patients with lupus nephritis by means of terminal deoxynucleotidyl-transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-digoxigenin nick end labeling (TUNEL). Five samples of normal kidney tissue served as control specimens. We did not observe apoptotic glomerular cells in any...... cells constitute a quantitatively important source of auto-antibody-inducing nuclear auto-antigens in human lupus nephritis....

  2. Constitutional Fundamentals of Conscription and Some Aspects of the Ordinary Legal Regulation of Constitutionality

    Directory of Open Access Journals (Sweden)

    Kenstavičienė Kristina

    2015-12-01

    Full Text Available Article 139 of the Constitution of the Republic of Lithuania is one of the constitutional fundamentals of state defense and stipulates the defense of the state as the right of citizens on the one hand and the duty on the other. This article of the Constitution gives the legislative power the right of discretion to detail by law the order of the implementation of citizens’ duty to perform military or alternative country defense service. Due to the reorganization of the armed forces into a professional and volunteer army, the issue of some ordinary regulation rules concerning the constitutionality of nationwide conscription, though at present suspended but not abolished, is becoming urgent. Though the Constitutional Court of the Republic of Lithuania presented their ruling on the constitutionality of the suspension of military conscription, it does not mean that all problems related to conscription have been settled. The aim of this article is to analyze the constitutional basis of nationwide conscription as well as the constitutionality of some ordinary regulation provisions related to nationwide conscription. Therefore, the issue to be analyzed is whether nationwide conscription, if it were to be implemented, complies with the constitutional principles of human equality and military justice1. Consequently, the question is posed how the constitutional objective of ensuring the defense of the state determines conscription. Because of the growing employment of the army abroad, yet the dwindling demand for conscripts, it should be explored whether the suspension of the nationwide conscription as a part of the defense reform is further feasible in order to guarantee the defense of the state. In answering the raised questions, the author will analyze the abundant and long-lasting constitutional doctrine of Germany which provides clarifications of the Basic Law, as the legal act of the establishing power, which can doubtless be of assistance in

  3. The Trials and Tribulations of Constitutionalism and the Constitution Making Process in Zimbabwe

    OpenAIRE

    Mapuva, Jephias

    2015-01-01

    Constitutionalism in Zimbabwe has been characterised by controversy with citizens getting a raw deal. The colonial era was characterised by deprivation of basic rights and civil liberties. A plethora of constitutions were established to try and create a semblance of black representativity. The post-colonial era was informed by governance structures provided by the Lancaster House Constitutional document which was a surrender document that brought the protracted liberation struggle to an end. ...

  4. A survey of unified constitutive theories

    Science.gov (United States)

    Chan, K. S.; Lindholm, U. S.; Bodner, S. R.; Walker, K. P.

    1985-01-01

    The state of the art of time temperature dependent elastic viscoplastic constitutive theories which are based on the unified approach werre assessed. This class of constitutive theories is characterized by the use of kinetic equations and internal variables with appropriate evolutionary equations for treating all aspects of inelastic deformation including plasticity, creep, and stress relaxation. More than 10 such unified theories which are shown to satisfy the uniqueness and stability criteria imposed by Drucker's postulate and Ponter's inequalities are identified. The theories are compared for the types of flow law, kinetic equation, evolutionary equation of the internal variables, and treatment of temperature dependence. The similarities and differences of these theories are outlined in terms of mathematical formulations and illustrated by comparisons of theoretical calculations with experimental results which include monotonic stress-strain curves, cyclic hysteresis loops, creep and stress relaxation rates, and thermomechanical loops. Numerical methods used for integrating these stiff time temperature dependent constitutive equations are reviewed.

  5. Butyrate down regulates BCL-XL and sensitizes human fibroblasts to radiation and chemotherapy induced apoptosis

    International Nuclear Information System (INIS)

    Chung, Diana H.; Ljungman, Mats; Zhang Fenfen; Chen Feng; McLaughlin, William P.

    1997-01-01

    Purpose/Objective: Butyrate is a short chain fatty acid that has been implicated in the induction of cell cycle arrest, cell differentiation and apoptosis. The purpose of this study was to determine if butyrate treatment sensitizes cells to radiation or chemotherapy induced apoptosis. Materials and Methods: Normal neonatal human diploid fibroblasts were used throughout this study. Apoptosis was scored and quantified using three different methods. First, cell morphology using propidium iodide and fluorescence microscopy was used to qualitatively determine apoptosis and to quantify the percentage of cells undergoing apoptosis. Second, apoptosis induced DNA degradation was scored by quantifying the amount of cells appearing in a sub-G1 peak using fixed and PI-stained cells and flow cytometry. Third, apoptosis-induced DNA degradation was examined by using an assay involving direct lysis of cells in the wells of agarose gels followed by conventional gel electrophoresis. Western blotting was used to quantify the cellular levels of the apoptosis regulators, Bcl-2, Bcl-XL and Bax. Results: Human diploid fibroblasts, which were resistant to radiation induced apoptosis, were found to undergo massive apoptosis when radiation was combined with butyrate treatment. Sensitization was obtained when butyrate was added before or after radiation although the combination of both pre and post-treatment was the most effective. Butyrate was also found to enhance UV light and cisplatin-induced apoptosis. These findings correlated with a reduction of the apoptosis antagonist Bcl-XL. Bcl-XL levels significantly dropped in a time and dose dependent manner. In addition, butyrate effectively blocked UV-induced accumulation of p53. Conclusion: Our results suggest that butyrate may be an attractive agent to use in combination with radiation or chemotherapy to lower the apoptotic threshold of tumor cells, regardless of the p53 status of the tumor cells

  6. Csk regulates angiotensin II-induced podocyte apoptosis.

    Science.gov (United States)

    Zhang, Lu; Ren, Zhilong; Yang, Qian; Ding, Guohua

    2016-07-01

    Increasing data have shown that angiotensin II (Ang II) perpetuates podocyte injury and promotes progression to end-stage kidney disease. The mechanism underlying Ang II-induced podocyte apoptosis has not been established. C-terminal Src kinase (Csk) is a cytoplasmic kinase that interacts with scaffolding proteins involved in cell growth, adhesion, and polarization, and the role of Csk in regulating cellular apoptosis has gradually attracted attention. This study evaluates the role of Csk in Ang II-induced podocyte apoptosis. In vivo, Wistar rats were randomly subjected to a normal saline or Ang II infusion. In vitro, we exposed differentiated mouse podocytes to Ang II. Ang II increased Csk expression and induced podocyte apoptosis, stimulated Csk translocation and binding to Caveolin-1, and stimulated decreased Fyn pY416, increased Fyn pY529, and nephrin dephosphorylation. Csk knockdown prevented Ang II-induced podocyte apoptosis, reduced Fyn kinase inactivation, and increased the interaction between nephrin and the activated form of Fyn, accompanied by a reduced interaction between Csk and Caveolin-1. These findings indicate that Ang II induces podocyte injury via a Csk-dependent pathway.

  7. Beyond annexin V: fluorescence response of cellular membranes to apoptosis.

    Science.gov (United States)

    Demchenko, Alexander P

    2013-03-01

    Dramatic changes in the structure of cell membranes on apoptosis allow easy, sensitive and non-destructive analysis of this process with the application of fluorescence methods. The strong plasma membrane asymmetry is present in living cells, and its loss on apoptosis is commonly detected with the probes interacting strongly and specifically with phosphatidylserine (PS). This phospholipid becomes exposed to the cell surface, and the application of annexin V labeled with fluorescent dye is presently the most popular tool for its detection. Several methods have been suggested recently that offer important advantages over annexin V assay with the ability to study apoptosis by spectroscopy of cell suspensions, flow cytometry and confocal or two-photon microscopy. The PS exposure marks the integrated changes in the outer leaflet of cell membrane that involve electrostatic potential and hydration, and the attempts are being made to provide direct probing of these changes. This review describes the basic mechanisms underlying the loss of membrane asymmetry during apoptosis and discusses, in comparison with the annexin V-binding assay, the novel fluorescence techniques of detecting apoptosis on cellular membrane level. In more detail we describe the detection method based on smart fluorescent dye F2N12S incorporated into outer leaflet of cell membrane and reporting on apoptotic cell transformation by easily detectable change of the spectral distribution of fluorescent emission. It can be adapted to any assay format.

  8. Globalisation, the development of constitutionalism and the individual employer

    Directory of Open Access Journals (Sweden)

    K Calitz

    2007-11-01

    Full Text Available To establish which legal system will govern the relationship between parties involved in an international employment contract, the rules of private international law (or conflict of laws must be applied. Each country has its own rules of private international law and each country’s courts will apply its own rules if the court is seized with a matter that involves foreign elements. There may be conflict between the potentially applicable legal systems of countries in terms of the level of protection afforded to employees who are parties to international employment contracts. South Africa has constitutionalised the right to fair labour practices and the question is whether this right is applicable to South African employees working in other countries, or to foreigners working in South Africa who originate from countries where this right is not protected. The answer to this question is to be found in the influence of the Constitution on the rules of private international law as applied by South African courts. It is evident from recent judgments of the Labour Court that the Court will readily assume jurisdiction and will furthermore readily hold that the proper law of the contract is South African law in order to protect the constitutional rights of employees involved in international employment contracts. Had the Labour Court held that the place of performance was still the decisive connecting factor, (as previously decided in most South African cases on this aspect the law of the other countries involved in the international employment relationship could have left employees in a worse position than under South African law. This possibility seems to be one of the important underlying reasons for the Labour Court’s willingness to assume jurisdiction and to hold that the proper law was in fact South African law. In the globalisation context the Labour Court has contributed to the advancement of constitutionalism by developing South Africa

  9. A Federal Constitution for the European Union

    DEFF Research Database (Denmark)

    Sweeney, Richard J.

    2003-01-01

    A constitution is more likely to be accepted if it federalizes those issues that arewidely seen as needing complete harmonization. A constitution is more likely to endure if thefederal government does not have powers that are not vital to it but which may alienate somemember states to the point...... within and across member statesthat severely weaken the Union, conceivably contributing to eventual collapse. Insisting onharmonization of commercial codes does not have the destructive potential of attemptingcompletely to harmonize defense and foreign policies; it may, however, lead to needlessconflict...

  10. Catholic Modernity and the Italian Constitution

    DEFF Research Database (Denmark)

    Thomassen, Bjørn; Forlenza, Rosario

    2016-01-01

    project for the new Constitution had a considerable impact on modern Italian culture and politics and on the building of a modern mass democracy and welfare state. During the crucial historical juncture that followed the collapse of Fascism, Catholic politicians and intellectuals sought to interpret......This article analyzes the Catholic contribution to the Italian republican and democratic Constitution of 1948. The focus is on the specific way in which the Italian citizen became symbolically coded as a ‘person’ and not as an ‘individual’, inspired by Catholic social philosophy. The Catholic...

  11. generalized constitutive model for stabilized quick clay

    African Journals Online (AJOL)

    QUICK CLAY. PANCRAS MUGISHAGWE BUJULU AND GUSTAV GRIMSTAD. ABSTRACT. An experimentally-based two yield surface constitutive model for cemented quick clay has been ... Clay Model, the Koiter Rule and two Mapping Rules. .... models, where a mobilization formulation is used, this is independent of q.

  12. The Anatomy of a Constitutional Tort.

    Science.gov (United States)

    Horner, Jeffrey J.

    1988-01-01

    Given state law barriers to recovery for the negligence of public officials, redress is often sought in federal courts. Discusses the concept of "constitutional tort" and analyzes the various components and the elements that must be satisfied before recovery is allowed. (MLF)

  13. generalized constitutive model for stabilized quick clay

    African Journals Online (AJOL)

    An experimentally-based two yield surface constitutive model for cemented quick clay has been developed at NTNU, Norway, to reproduce the mechanical behavior of the stabilized quick clay in the triaxial p'-q stress space. The model takes into account the actual mechanical properties of the stabilized material, such as ...

  14. Constitution 200: A Bicentennial Collection of Essays.

    Science.gov (United States)

    Hepburn, Mary A., Ed.; And Others

    Constitutional essays which formed the basis of public assemblies throughout three states are compiled in this book. The first three essays consider the U.S. government principles of federalism, judicial review, and the separation of powers. Michael L. Benedict proposes that the question of ultimate sovereignty has been answered differently by…

  15. Ethnicity and constitutionalism in contemporary Ethiopia

    NARCIS (Netherlands)

    Abbink, G.J.

    1997-01-01

    According to the policy of the government of the Ethiopian Peoples' Revolutionary Democratic Front (EPRDF), ethnic identity is the ideological basis of Ethiopia's political organization and administration and as such has been enshrined in the Federal Constitution of December 1994. Yet the

  16. Between availability and entitlement: The Constitution, Grootboom ...

    African Journals Online (AJOL)

    Between availability and entitlement: The Constitution, Grootboom and the right to food. Danie Brand. Abstract. No Abstract. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians ...

  17. Optimizing culture medium for debittering constitutive enzyme ...

    African Journals Online (AJOL)

    STORAGESEVER

    2010-08-02

    Aug 2, 2010 ... The objective of this study was to investigate nutrient requirements for extracellular constitutive naringinase production by Aspergillus oryzae JMU316. The one-factor-at-a-time method was used to determine the impact of different carbon and nitrogen sources on naringinase production. Naringin exhibited ...

  18. Crushed-salt constitutive model update

    Energy Technology Data Exchange (ETDEWEB)

    Callahan, G.D.; Loken, M.C.; Mellegard, K.D. [RE/SPEC Inc., Rapid City, SD (United States); Hansen, F.D. [Sandia National Labs., Albuquerque, NM (United States)

    1998-01-01

    Modifications to the constitutive model used to describe the deformation of crushed salt are presented in this report. Two mechanisms--dislocation creep and grain boundary diffusional pressure solutioning--defined previously but used separately are combined to form the basis for the constitutive model governing the deformation of crushed salt. The constitutive model is generalized to represent three-dimensional states of stress. New creep consolidation tests are combined with an existing database that includes hydrostatic consolidation and shear consolidation tests conducted on Waste Isolation Pilot Plant and southeastern New Mexico salt to determine material parameters for the constitutive model. Nonlinear least-squares model fitting to data from the shear consolidation tests and a combination of the shear and hydrostatic consolidation tests produced two sets of material parameter values for the model. The change in material parameter values from test group to test group indicates the empirical nature of the model but demonstrates improvement over earlier work with the previous models. Key improvements are the ability to capture lateral strain reversal and better resolve parameter values. To demonstrate the predictive capability of the model, each parameter value set was used to predict each of the tests in the database. Based on the fitting statistics and the ability of the model to predict the test data, the model appears to capture the creep consolidation behavior of crushed salt quite well.

  19. Constitutive behavior of reconsolidating crushed salt

    Energy Technology Data Exchange (ETDEWEB)

    Callahan, G.D.; Mellegard, K.D. [RE/SPEC, Inc., Rapid City, SD (United States); Hansen, F.D. [Sandia National Labs., Carlsbad, NM (United States)

    1998-02-01

    The constitutive model used to describe deformation of crushed salt is presented in this paper. Two mechanisms--dislocation creep and grain boundary diffusional pressure solutioning--are combined to form the basis for the constitutive model governing deformation of crushed salt. The constitutive model is generalized to represent three-dimensional states of stress. Recently completed creep consolidation tests are combined with an existing database that includes hydrostatic consolidation and shear consolidation tests conducted on Waste Isolation Pilot Plant (WIPP) and southeastern New Mexico salt to determine material parameters for the constitutive model. Nonlinear least-squares model fitting to data from shear consolidation tests and a combination of shear and hydrostatic tests produces two sets of material parameter values for the model. Changes in material parameter values from test group to test group indicate the empirical nature of the model but show significant improvement over earlier work. To demonstrate the predictive capability of the model, each parameter value set was used to predict each of the tests in the database. Based on fitting statistics and ability of the model to predict test data, the model appears to capture the creep consolidation behavior of crushed salt quite well.

  20. A hypoplastic constitutive model for clays

    Czech Academy of Sciences Publication Activity Database

    Mašín, David

    2005-01-01

    Roč. 29, č. 4 (2005), s. 311-336 ISSN 0363-9061 Institutional research plan: CEZ:AV0Z20710524 Keywords : clay * constitutive model * hypoplasticity Subject RIV: JM - Building Engineering Impact factor: 0.590, year: 2005

  1. Constitutive equations for two-phase flows

    International Nuclear Information System (INIS)

    Boure, J.A.

    1974-12-01

    The mathematical model of a system of fluids consists of several kinds of equations complemented by boundary and initial conditions. The first kind equations result from the application to the system, of the fundamental conservation laws (mass, momentum, energy). The second kind equations characterize the fluid itself, i.e. its intrinsic properties and in particular its mechanical and thermodynamical behavior. They are the mathematical model of the particular fluid under consideration, the laws they expressed are so called the constitutive equations of the fluid. In practice the constitutive equations cannot be fully stated without reference to the conservation laws. Two classes of model have been distinguished: mixture model and two-fluid models. In mixture models, the mixture is considered as a single fluid. Besides the usual friction factor and heat transfer correlations, a single constitutive law is necessary. In diffusion models, the mixture equation of state is replaced by the phasic equations of state and by three consitutive laws, for phase change mass transfer, drift velocity and thermal non-equilibrium respectively. In the two-fluid models, the two phases are considered separately; two phasic equations of state, two friction factor correlations, two heat transfer correlations and four constitutive laws are included [fr

  2. Optimizing culture medium for debittering constitutive enzyme ...

    African Journals Online (AJOL)

    The objective of this study was to investigate nutrient requirements for extracellular constitutive naringinase production by Aspergillus oryzae JMU316. The one-factor-at-a-time method was used to determine the impact of different carbon and nitrogen sources on naringinase production. Naringin exhibited the highest ...

  3. Constitutive modelling of sandvik 1RK91

    NARCIS (Netherlands)

    Datta, K.; Datta, K.; Hommes, M.; Post, J.; Geijselaers, Hubertus J.M.; Huetink, Han; Beyer, J.; Onate, E; Owen, D.R.J

    2003-01-01

    A physically based constitutive equation is being developed for the maraging stainless steel Sandvik 1RK91. The steel is used to make precision parts. These parts are formed through multistage forming operations and heat treatments from cold rolled and annealed sheets. The specific alloy is designed

  4. POSITION AND STRATEGIC LEITMOTIVS IN CONSTITUTIONAL ...

    African Journals Online (AJOL)

    Information Technology

    novel rigorously interrogating issues of identity and difference. A resoluteness not to repeat the injustices of ... to mind in this regard are National Coalition for Gay and Lesbian Equality v Minister of Justice43 (the ... Lesbian and Gay Equality Project v Minister of Home Affairs,48 the Constitutional. Court judgment in which the ...

  5. globalisation, the development of constitutionalism and the ...

    African Journals Online (AJOL)

    Dr Tanya du Plessis

    is important because labour law systems differ among countries. There may be ... international law and each country's courts will apply its own rules if the court is ..... evidence about the Mozambican constitution or the protection of human rights in that country. What is significant is that the court was prepared to assume.

  6. Great Constitutional Ideas: Justice, Equality, and Property.

    Science.gov (United States)

    Starr, Isidore

    1987-01-01

    Examines the ideas of justice, equality, and property as they are represented in the Declaration of Independence, the U.S. Constitution and the Bill of Rights. Discusses how these ideas affect the way public schools operate and the lessons educators teach or don't teach about our society. Includes ideas for classroom activities. (JDH)

  7. Constitutive laws, tensorial invariance and chocolate cake

    Science.gov (United States)

    Rundle, John B.; Passman, S. L.

    1982-04-01

    Although constitutive modeling is a well-established branch of mathematics which has found wide industrial application, geophysicists often do not take full advantage of its known results. We present a synopsis of the theory of constitutive modeling, couched in terms of the ‘simple material’, which has been extensively studied and is complex enough to include most of the correct models proposed to describe the behavior of geological materials. Critical in the development of the theory are various invariance requirements, the principal ones being coordinate invariance, peer group invariance (isotropy), and frame-indifference. Each places distinet restrictions on constitutive equations. A noncomprehensive list of properly invariant and commonly used constitutive equations is given. To exemplify use of the equations, we consider two problems in detail: steady extension, which models the commonly performed constant strain rate triaxial test, and simple shearing. We note that each test is so restricted kinematically that only the most trivial aspects of material behavior are manifested in these tests, no matter how complex the material. Furthermore, the results of one test do not generally determine the results of the other.

  8. Crushed-salt constitutive model update

    International Nuclear Information System (INIS)

    Callahan, G.D.; Loken, M.C.; Mellegard, K.D.; Hansen, F.D.

    1998-01-01

    Modifications to the constitutive model used to describe the deformation of crushed salt are presented in this report. Two mechanisms--dislocation creep and grain boundary diffusional pressure solutioning--defined previously but used separately are combined to form the basis for the constitutive model governing the deformation of crushed salt. The constitutive model is generalized to represent three-dimensional states of stress. New creep consolidation tests are combined with an existing database that includes hydrostatic consolidation and shear consolidation tests conducted on Waste Isolation Pilot Plant and southeastern New Mexico salt to determine material parameters for the constitutive model. Nonlinear least-squares model fitting to data from the shear consolidation tests and a combination of the shear and hydrostatic consolidation tests produced two sets of material parameter values for the model. The change in material parameter values from test group to test group indicates the empirical nature of the model but demonstrates improvement over earlier work with the previous models. Key improvements are the ability to capture lateral strain reversal and better resolve parameter values. To demonstrate the predictive capability of the model, each parameter value set was used to predict each of the tests in the database. Based on the fitting statistics and the ability of the model to predict the test data, the model appears to capture the creep consolidation behavior of crushed salt quite well

  9. Does the Constitution Protect the Despised?

    Science.gov (United States)

    Roe, Richard L; And Others

    1984-01-01

    Presented is the history of the Scottsboro case, in which eight Black men were found guilty and sentenced to death for raping two White women in Alabama. At the heart of the Scottsboro trials was the issue of whether the U.S. Constitution established standards of justice in state criminal trials. (RM)

  10. income tax assignment under the ethiopian constitution

    African Journals Online (AJOL)

    eliasn

    Constitution from an income tax point of view. And finally, the article ends with some concluding remarks. 1. Theories of Fiscal Federalism In Income Tax Assignment. Few countries pursue the course of decentralization on grounds of its perceived economic efficiency or equity. Political, social, cultural or historical forces are.

  11. Constitutive and ligand-induced TCR degradation

    DEFF Research Database (Denmark)

    von Essen, Marina; Bonefeld, Charlotte Menné; Siersma, Volkert

    2004-01-01

    divergent models for TCR down-regulation and degradation have been suggested. The aims of this study were to determine the rate constants for constitutive and ligand-induced TCR degradation and to determine whether the TCR subunits segregate or are processed as an intact unit during TCR down...

  12. Constitutional protection against discrimination of homosexuals.

    Science.gov (United States)

    Waaldijk, K

    A brief review of equality for homosexuals prior to 1983 is presented followed by the introduction and explanation of the relevant section of the revised edition of the Dutch Constitution (enacted in 1983). The possible impact of this section on the abolishment of discrimination based on sex and sexual orientation is discussed.

  13. Notes: Constitutionalism | Bazezew | Mizan Law Review

    African Journals Online (AJOL)

    Mizan Law Review. Journal Home · ABOUT · Advanced Search · Current Issue · Archives · Journal Home > Vol 3, No 2 (2009) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register. Notes: Constitutionalism. M Bazezew. Abstract. (No abstract). Full Text: EMAIL FREE ...

  14. 1 HUMAN DIGNITY - OUR SUPREME CONSTITUTIONAL VALUE ...

    African Journals Online (AJOL)

    Administrator

    There can be little doubt that, as far as constitutional interpretation and statutory interpretation in general is concerned, South Africa is undergoing a transformation from a formal, positivistic vision of law to a substantive, natural law vision of law.4 And the single most significant factor in this transformation is the existence of ...

  15. Language question and the constitutional challenges of ...

    African Journals Online (AJOL)

    to the analogy of the Tower of Babel_ a linguistic confusion. This paper puts multilingualism in its proper perspective as a blessing, which must be accorded a full constitutional recognition, rather than a curse; an asset, rather than a liability. While making Nigeria a focal point of reference, especially the language component ...

  16. Constitutional Provisions And Administrative Disciplinary Powers ...

    African Journals Online (AJOL)

    The Medical and Dental Practitioners Disciplinary Tribunal is empowered to deal with all cases of professional discipline under the Medical and Dental Practitioners Act. This process of administrative adjudication is examined against the background of constitutional provision that affects the exercise of the powers of the ...

  17. The parameters of constitutional conflict after Melloni

    NARCIS (Netherlands)

    Besselink, L.F.M.

    2014-01-01

    The judgment of the Court of Justice of the EU in Melloni makes clear that primacy of EU law is not about citizens’ rights: even the core of their constitutional rights under national law has to be set aside in favour of the "primacy, unity and effectiveness" of EU law. Melloni extends the duty to

  18. The Constitution of a Transnational Policy Field

    DEFF Research Database (Denmark)

    Højbjerg, Erik; Frankel, Christian

    is dependent on an inter-organizational coordination between the EU and ESO. Applying the analytical concept of a `policy field' the analysis shows how the completion of the internal market fundamentally challenges institutionalized conceptions of the role of politics in constituting markets.Keywords: Internal...... market, policy field, technical standards, transnationalization, new approach harmonization, private product policy...

  19. LEGAL AND CONSTITUTIONAL EVALUATION OF THE NIGERIAN ...

    African Journals Online (AJOL)

    sets such as stocks, bonds, real estate, or other financial in- struments funded by foreign exchange assets. These assets can include: balance of payments ...... national agency or programme with the funds meant for the three tiers of government which is dealt with in section 162(3) of the 1999 Constitution. It is important to ...

  20. Culture (and religion) in constitutional adjudication | Rautenbach ...

    African Journals Online (AJOL)

    The faculty of law of the Potchefstroom University for Christian Higher Education in corroboration with the Konrad-Adenauer-Stifttung embarked on a study on Politics, Socio-Economic Issues and Culture in Constitutional Adjudication. The aim of the project is twofold. The first aim is to analyse the influence of political, ...

  1. Rapping the 27 Amendments to the Constitution

    Science.gov (United States)

    Knaresborough, Adam

    2009-01-01

    Early in the year, the students of history and government at Mountain View High School in Stafford, Virginia, began to devise hand motions to help memorize the 27 amendments to the Constitution for government class. Three students in the school who are interested in hip hop music then suggested composing a rap song about the topic. Working with…

  2. Constitutive behavior of reconsolidating crushed salt

    International Nuclear Information System (INIS)

    Callahan, G.D.; Mellegard, K.D.; Hansen, F.D.

    1998-02-01

    The constitutive model used to describe deformation of crushed salt is presented in this paper. Two mechanisms--dislocation creep and grain boundary diffusional pressure solutioning--are combined to form the basis for the constitutive model governing deformation of crushed salt. The constitutive model is generalized to represent three-dimensional states of stress. Recently completed creep consolidation tests are combined with an existing database that includes hydrostatic consolidation and shear consolidation tests conducted on Waste Isolation Pilot Plant (WIPP) and southeastern New Mexico salt to determine material parameters for the constitutive model. Nonlinear least-squares model fitting to data from shear consolidation tests and a combination of shear and hydrostatic tests produces two sets of material parameter values for the model. Changes in material parameter values from test group to test group indicate the empirical nature of the model but show significant improvement over earlier work. To demonstrate the predictive capability of the model, each parameter value set was used to predict each of the tests in the database. Based on fitting statistics and ability of the model to predict test data, the model appears to capture the creep consolidation behavior of crushed salt quite well

  3. School Choice and State Constitutions' Religion Clauses

    Science.gov (United States)

    Komer, Richard D.

    2009-01-01

    After the U.S. Supreme Court's decision in "Zelman v. Simmons-Harris," only state religion clauses represent a potential constitutional bar to the inclusion of religious options in properly designed school choice programs. The two most significant are compelled support clauses and Blaine Amendments. Both are frequently misinterpreted by state…

  4. religious freedom in South African constitutional jurisprudence

    African Journals Online (AJOL)

    Irma Kroeze

    does not combine easily, and if we ignore the effect of language on understanding we will no ... the ways in which the South African Constitutional Court has dealt with the question of religious freedom as an .... recognises both the dependence of politics on social and economic conditions and the dependence of these ...

  5. The U.S. Constitution in Today's World.

    Science.gov (United States)

    Patrick, John J.

    A comparative study of constitutions and governments in world history is a key to deeper understanding of the U.S. Constitution. While many countries have constitutions, the United States is among a minority of nations in today's world that has a constitutional government. Many nations' constitutions truly guarantee few protections of individual…

  6. 77 FR 57981 - Constitution Day and Citizenship Day, Constitution Week, 2012

    Science.gov (United States)

    2012-09-18

    ... Day and Citizenship Day, Constitution Week, 2012 #0; #0; #0; Presidential Documents #0; #0; #0;#0... Citizenship Day, Constitution Week, 2012 By the President of the United States of America A Proclamation Today... the candidates for citizenship who will commemorate this day by joining our American family. For more...

  7. Institute of constitutional revision in the Constitution of the Republic of Albania, comparative view

    Directory of Open Access Journals (Sweden)

    Makbule Çeço

    2014-07-01

    Full Text Available In its very dynamic essence, a democratic society bears the need for continuous reformation and perfection, and that is why the application of reforms represents an inseparable feature for this type of society. The consolidation of the rule of law, the institutional independence, and the cause of justice itself comprise, inter alia, the need for constitutional revision. This study puts forward a theoretical-historical comparative view of the relevant and dynamic issue of the institute of constitutional revision in the framework of the Constitution of the Republic of Albania, as a complex process accompanied by limitations on constitutional revision. The historical evolution of constitutional drafting, modern constitutions, relevant issues, political and social circumstances as well as drafting and adoption procedures, dynamism of constitutions to cope with the course of time achieved by revisions for the purpose of their stability as well as consolidation of the role of constitutions as a factor that facilitates and precedes social development, comprise the pillar of this study addressed in a comparative point of view.

  8. The Franco-German constitutional divide: reflections on national and constitutional identity

    NARCIS (Netherlands)

    Reestman, J.H.

    2009-01-01

    German Constitutional Court decision of 30 June 2009 on the compatibility of the Lisbon Treaty with the German Constitution - ‘Identity’ key word of the Lissabon-Urteil - The national identity clause in the current Union Treaty - Nation: people and state; diachronic and synchronic identity -

  9. Parameters of constitutional development: The fiscal compact in between EU and member state constitutions

    NARCIS (Netherlands)

    Besselink, L.F.M.; Rossi, L.S.; Casolari, F.

    2014-01-01

    The answer to the questions whether the Lisbon Treaty is a quasi-constitutional framework to be revised, and whether the crisis is a matter for amending or just completing the Lisbon Treaty, depends on our understanding of what constitutional change is and entails. In this chapter, the boundaries of

  10. A geometric rationale for invariance, covariance and constitutive relations

    Science.gov (United States)

    Romano, Giovanni; Barretta, Raffaele; Diaco, Marina

    2018-01-01

    There are, in each branch of science, statements which, expressed in ambiguous or even incorrect but seemingly friendly manner, were repeated for a long time and eventually became diffusely accepted. Objectivity of physical fields and of their time rates and frame indifference of constitutive relations are among such notions. A geometric reflection on the description of frame changes as spacetime automorphisms, on induced push-pull transformations and on proper physico-mathematical definitions of material, spatial and spacetime tensor fields and of their time-derivatives along the motion, is here carried out with the aim of pointing out essential notions and of unveiling false claims. Theoretical and computational aspects of nonlinear continuum mechanics, and especially those pertaining to constitutive relations, involving material fields and their time rates, gain decisive conceptual and operative improvement from a proper geometric treatment. Outcomes of the geometric analysis are frame covariance of spacetime velocity, material stretching and material spin. A univocal and frame-covariant tool for evaluation of time rates of material fields is provided by the Lie derivative along the motion. The postulate of frame covariance of material fields is assessed to be a natural physical requirement which cannot interfere with the formulation of constitutive laws, with claims of the contrary stemming from an improper imposition of equality in place of equivalence.

  11. Aniline Induces Oxidative Stress and Apoptosis of Primary Cultured Hepatocytes

    Directory of Open Access Journals (Sweden)

    Yue Wang

    2016-11-01

    Full Text Available The toxicity and carcinogenicity of aniline in humans and animals have been well documented. However, the molecular mechanism involved in aniline-induced liver toxicity and carcinogenesis remains unclear. In our research, primary cultured hepatocytes were exposed to aniline (0, 1.25, 2.50, 5.0 and 10.0 μg/mL for 24 h in the presence or absence of N-acetyl-l-cysteine (NAC. Levels of reactive oxygen species (ROS, malondialdehyde (MDA, and glutathione (GSH, activities of superoxide dismutase (SOD and catalase (CAT, mitochondrial membrane potential, DNA damage, cell viability, and apoptosis were detected. Levels of ROS and MDA were significantly increased and levels of GSH and CAT, activity of SOD, and mitochondrial membrane potential in hepatocytes were significantly decreased by aniline compared with the negative control group. The tail moment and DNA content of the tail in exposed groups were significantly higher than those in the negative control group. Cell viability was reduced and apoptotic death was induced by aniline in a concentration-dependent manner. The phenomena of ROS generation, oxidative damage, loss of mitochondrial membrane potential, DNA damage and apoptosis could be prevented if ROS inhibitor NAC was added. ROS generation is involved in the loss of mitochondrial membrane potential and DNA injury, which may play a role in aniline-induced apoptosis in hepatocytes. Our study provides insight into the mechanism of aniline-induced toxicity and apoptosis of hepatocytes.

  12. Apoptosis activation in human carious dentin. An immunohistochemical study

    Directory of Open Access Journals (Sweden)

    C. Loreto

    2015-07-01

    Full Text Available The exact mechanisms and enzymes involved in caries progression are largely unclear. Apoptosis plays a key role in dentin remodelling related to damage repair; however, it is unclear whether apoptosis in decayed teeth is activated through the extrinsic or the intrinsic pathway. This ex vivo immunohistochemical study explored the localization of TRAIL, DR5, Bcl-2 and Bax, the main proteins involved in apoptosis, in teeth with advanced caries. To evaluate TRAIL, DR5, Bcl-2 and Bax immunoexpressions twelve permanent carious premolars were embedded in paraffin and processed for immunohistochemistry. The results showed that TRAIL and DR5 were overexpressed in dentin and in pulp vessels and mononuclear cells; strong Bax immunostaining was detected in dilated dentinal tubules close to the lesion, and Bcl-2 staining was weak in some dentin areas under the cavity or altogether absent. These findings suggest that both apoptosis pathways are activated in dental caries. Further studies are required to gain insights into its biomolecular mechanisms. 

  13. Molecular Mechanisms Regulating Ocular Apoptosis in Zebrafish gdf6a Mutants

    DEFF Research Database (Denmark)

    Pant, Sameer D.; March, Lindsey D.; Famulski, Jakub K.

    2013-01-01

    PURPOSE. To characterize the molecular mechanisms underlying retinal apoptosis induced by loss of Gdf6, a TGF beta ligand. METHODS. The role of Gdf6 in regulating apoptosis was studied using a zebrafish gdf6a(-/-) mutant, which encodes a truncated, nonfunctional protein. To investigate whether...... intrinsic or extrinsic apoptotic mechanisms were involved, morpholino antisense oligonucleotides targeting baxa, baxb, and p53 were employed. Caspase-3 immunohistochemistry (IHC) was performed to assay apoptosis. Pharmacologic inhibition (using SB203580) and IHC were used to investigate the role of p38...... mitogen activated protein (MAP) kinase activation in gdf6a(-/-) induced apoptosis. To assess the role of Gdf6a in transcriptional regulation of TGF beta signal transducers, in situ hybridization (ISH) was performed using probes to smad1, 5, 7, and 8. RESULTS. Results indicate maximal ocular apoptosis...

  14. Apoptosis detection in histological sections

    Czech Academy of Sciences Publication Activity Database

    Matalová, Eva; Dubská, Lenka; Míšek, Ivan

    2003-01-01

    Roč. 72, č. 7 (2003), s. 18-19 ISSN 0001-7213. [Congress of the European Association of Veterinary Anatomists/24./. 21.07.2002-25.07.2002, Brno] R&D Projects: GA ČR GP204/02/P112 Institutional research plan: CEZ:AV0Z5045916 Keywords : apoptosis Subject RIV: FF - HEENT, Dentistry

  15. An anisotropic elastoplastic constitutive formulation generalised for orthotropic materials

    Science.gov (United States)

    Mohd Nor, M. K.; Ma'at, N.; Ho, C. S.

    2018-03-01

    This paper presents a finite strain constitutive model to predict a complex elastoplastic deformation behaviour that involves very high pressures and shockwaves in orthotropic materials using an anisotropic Hill's yield criterion by means of the evolving structural tensors. The yield surface of this hyperelastic-plastic constitutive model is aligned uniquely within the principal stress space due to the combination of Mandel stress tensor and a new generalised orthotropic pressure. The formulation is developed in the isoclinic configuration and allows for a unique treatment for elastic and plastic orthotropy. An isotropic hardening is adopted to define the evolution of plastic orthotropy. The important feature of the proposed hyperelastic-plastic constitutive model is the introduction of anisotropic effect in the Mie-Gruneisen equation of state (EOS). The formulation is further combined with Grady spall failure model to predict spall failure in the materials. The proposed constitutive model is implemented as a new material model in the Lawrence Livermore National Laboratory (LLNL)-DYNA3D code of UTHM's version, named Material Type 92 (Mat92). The combination of the proposed stress tensor decomposition and the Mie-Gruneisen EOS requires some modifications in the code to reflect the formulation of the generalised orthotropic pressure. The validation approach is also presented in this paper for guidance purpose. The \\varvec{ψ} tensor used to define the alignment of the adopted yield surface is first validated. This is continued with an internal validation related to elastic isotropic, elastic orthotropic and elastic-plastic orthotropic of the proposed formulation before a comparison against range of plate impact test data at 234, 450 and {895 ms}^{-1} impact velocities is performed. A good agreement is obtained in each test.

  16. Coronavirus infection, ER stress and Apoptosis

    Directory of Open Access Journals (Sweden)

    TO SING eFUNG

    2014-06-01

    Full Text Available The replication of coronavirus, a family of important animal and human pathogens, is closely associated with the cellular membrane compartments, especially the endoplasmic reticulum (ER. Coronavirus infection of cultured cells was previously shown to cause ER stress and induce the unfolded protein response (UPR, a process that aims to restore the ER homeostasis by global translation shutdown and increasing the ER folding capacity. However under prolonged ER stress, UPR can also induce apoptotic cell death. Accumulating evidence from recent studies has shown that induction of ER stress and UPR may constitute a major aspect of coronavirus-host interaction. Activation of the three branches of UPR modulates a wide variety of signaling pathways, such as mitogen-activated protein (MAP kinases activation, autophagy, apoptosis and innate immune response. ER stress and UPR activation may therefore contribute significantly to the viral replication and pathogenesis during coronavirus infection. In this review, we summarize current knowledge on coronavirus-induced ER stress and UPR activation, with emphasis on their cross-talking to apoptotic signaling.

  17. Clinical application of traditional Chinese medicine constitution theory in diagnosis and treatment of chronic hepatitis B

    Directory of Open Access Journals (Sweden)

    XUN Yunhao

    2016-04-01

    Full Text Available The traditional Chinese medicine (TCM constitution theory is an important means to reveal the host′s genetic characteristics from the perspective of TCM. The types of constitution can influence liver pathological changes and the prognosis of disease in patients with chronic hepatitis B virus infection, and to a certain degree, they are associated with the polymorphisms of genes involved in immunoregulation, for example, human leukocyte antigen(HLA class Ⅱ gene. Yin-deficiency constitution is associated with various adverse clinical outcomes, as well as the genotypes of genes including HLA-DQA1*0501. Preliminary data also show that the chronic hepatitis B (CHB patients with yin-deficiency constitution have a poor response to interferon therapy. This article reviews the current application of TCM constitution theory in the diagnosis and treatment of CHB, its potential value, and existing problems.

  18. CAN THE MUSLIM WORLD BORROW FROM INDONESIAN CONSTITUTIONAL REFORM? A Comparative Constitutional Approach

    Directory of Open Access Journals (Sweden)

    Nadirsyah Hosen

    2007-06-01

    Full Text Available This paper attempts to analytically examine the possibility of constitutional borrowing for the Muslim world regardless the differences in history, system, culture, language, and cha­racteristics. It discusses this issue by looking at the arguments put forth by the oppo­nents of comparative cons­titutional interpre­tation and their counter arguments. It will consider materials from Canada, USA, South Africa, Singapore, Malaysia, and Hungary, taking the position that constitutional borrowing can be justified. The paper argues that the 1999-2002 Indonesian constitutional reform should be taken into account by other Muslim countries in undertaking their constitutional reform. The substantive approach of the Shari‘ah that has been used in Indonesia has shown that Muslim world can reform its constitutions without the “assistance” of Western foreign policy. Indo­nesian constitutional reform has demonstrated that Islamic constitutionalism comes from within Islamic teaching and the Islamic community itself; it is a home grown product.

  19. Technical risks as a constitutional problem

    International Nuclear Information System (INIS)

    Murswiek, D.

    1991-01-01

    Between the constitutional duty to protect, and the limits of protecting powers lies a domain where governmental bodies are empowered, but not obligated, to control and plan technical development and risks. Thus there is political responsibility for the way technical matters are handled, and a constitutional perspetive for accepting technical risks. As long as there has been general consent for technical progress, politicians were able to let the progress process take its course. Now they are asked to intervene. The transformation of living conditions through technical innovation has a greater significance for the individual and the State as a whole than most of the other matters of political decision-making. It would be irresponsible therefore to leave technical development to its own dynamics, and not continuously assess impacts of new technologies, weight up possible advantages and disadvantages, and change the course if necessary. (orig./HWCH) [de

  20. The Constitution of a Transnational Policy Field

    DEFF Research Database (Denmark)

    Højbjerg, Erik; Frankel, Christian

    The EU internal market has predominantly been studied in terms of changes in delegation of authority and division of labor between EU institutions and member states. However, this EU internal focus ignores that already in 1987 the completion of the internal market was substantially left...... outside EU political and administrative control - in the constitution of the internal market. Second, the delegation raises important analytical questions concerning the identification of the institutional locus of European integration, when the realization of the political goals with the internal market...... is dependent on an inter-organizational coordination between the EU and ESO. Applying the analytical concept of a `policy field' the analysis shows how the completion of the internal market fundamentally challenges institutionalized conceptions of the role of politics in constituting markets.Keywords: Internal...

  1. A Federal Constitution for the European Union

    DEFF Research Database (Denmark)

    Sweeney, Richard J.

    2003-01-01

    that the federal government loses legitimacy. It appears vital tohave trade policy at the European Union level; for euro countries, monetary policy is alreadyfederalized. It is not clear that common foreign and defense policies are needed; insisting oncommon foreign and defense policies may lead to conflicts...... within and across member statesthat severely weaken the Union, conceivably contributing to eventual collapse. Insisting onharmonization of commercial codes does not have the destructive potential of attemptingcompletely to harmonize defense and foreign policies; it may, however, lead to needlessconflict......A constitution is more likely to be accepted if it federalizes those issues that arewidely seen as needing complete harmonization. A constitution is more likely to endure if thefederal government does not have powers that are not vital to it but which may alienate somemember states to the point...

  2. Sirt1 protects against oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression

    International Nuclear Information System (INIS)

    Hasegawa, Kazuhiro; Wakino, Shu; Yoshioka, Kyoko; Tatematsu, Satoru; Hara, Yoshikazu; Minakuchi, Hitoshi; Washida, Naoki; Tokuyama, Hirobumi; Hayashi, Koichi; Itoh, Hiroshi

    2008-01-01

    NAD + -dependent protein deacetylase Sirt1 regulates cellular apoptosis. We examined the role of Sirt1 in renal tubular cell apoptosis by using HK-2 cells, proximal tubular cell lines with or without reactive oxygen species (ROS), H 2 O 2 . Without any ROS, Sirt1 inhibitors enhanced apoptosis and the expression of ROS scavenger, catalase, and Sirt1 overexpression downregulated catalase. When apoptosis was induced with H 2 O 2 , Sirt1 was upregulated with the concomitant increase in catalase expression. Sirt1 overexpression rescued H 2 O 2 -induced apoptosis through the upregulation of catalase. H 2 O 2 induced the nuclear accumulation of forkhead transcription factor, FoxO3a and the gene silencing of FoxO3a enhanced H 2 O 2 -induced apoptosis. In conclusion, endogenous Sirt1 maintains cell survival by regulating catalase expression and by preventing the depletion of ROS required for cell survival. In contrast, excess ROS upregulates Sirt1, which activates FoxO3a and catalase leading to rescuing apoptosis. Thus, Sirt1 constitutes a determinant of renal tubular cell apoptosis by regulating cellular ROS levels

  3. Constitutive relations for multiphase flow modeling

    Energy Technology Data Exchange (ETDEWEB)

    Jacobs, H.; Vaeth, L.; Thurnay, K. [Forschungszentrum Karlsruhe GmbH Technik und Umwelt (Germany). Inst. fuer Neutronenphysik und Reaktortechnik

    1998-01-01

    The constitutive relations that are used in the three-field fluid dynamics code IVA-KA for determining the drag in three-phase mixtures and the heat transferred by radiation are described together with some comparisons of calculational results with experiments. In these experiments (QUEOS), large quantities of solid particles are injected into water. Potential deficiencies of the present drag model are discussed. (author)

  4. National simple: Constitutionality Analysis of Exclusions Sectorial

    OpenAIRE

    Mendes, Guilherme Adolfo dos Santos

    2016-01-01

     The Constitution defines the favored legal treatment for small businesses without making any explicit exception, including and especially for tax obligations. Nevertheless, all the laws, which have introduced tax benefits guided by this higher provision, have discriminated small companies due to the economic sector of activity. Known as “National Simple” and introduced by the Complementary Law No. 123/06, the current legislation did not extend its benefits to small production units of a numb...

  5. Excretory-secretory product of newly excysted metacercariae of Paragonimus westermani directly induces eosinophil apoptosis

    Science.gov (United States)

    2000-01-01

    Eosinophils are important effector cells in host defense against parasites. Excretory-secretory product (ESP) produced by helminthic worms plays important roles in the uptake of nutrients, migration in the host tissue, and in immune modulation. However, little is known about the ability of the ESP to directly trigger eosinophil apoptosis. This study investigated whether the ESP of newly excysted metacercariae of Paragonimus westermani could induce apoptosis in human eosinophils. Apoptosis was assayed by staining the cells with FITC-annexin V, and the cells were analyzed by flow cytometry. It was found that the ESP of newly excysted metacercariae of P. westermani induced a direct time- and concentration-dependent increase in the rate of constitutive apoptosis in mature human eosinophils. Eosinophil apoptosis was first apparent 3 hr after treatment with the ESP and continued to increase after 6 hr of incubation with respect to the cells cultured in the absence of the ESP. While only 2.8% of the eosinophils incubated in the medium for 3 hr were apoptotic, 7.6%, 10.9% and 22.6% of the eosinophils treated with 10, 30 and 100 µg/ml ESP were apoptotic, respectively. This result suggests that the ESP of newly excysted metacercariae of P. westermani directly induce eosinophil apoptosis, which may be important for the survival of the parasites and the reduction of eosinophilic inflammation in vivo. PMID:10743354

  6. Inositol Hexakisphosphate Mediates Apoptosis in Human Breast Adenocarcinoma MCF-7 Cell Line via Intrinsic Pathway

    Science.gov (United States)

    Agarwal, Rakhee; Ali, Nawab

    2010-04-01

    Inositol polyphosphates (InsPs) are naturally occurring compounds ubiquitously present in plants and animals. Inositol hexakisphosphate (InsP6) is the most abundant among all InsPs and constitutes the major portion of dietary fiber in most cereals, legumes and nuts. Certain derivatives of InsPs also regulate cellular signaling mechanisms. InsPs have also been shown to reduce tumor formation and induce apoptosis in cancerous cells. Therefore, in this study, the effects of InsPs on apoptosis were studied in an attempt to investigate their potential anti-cancer therapeutic application and understand their mechanism of action. Acridine orange and ethidium bromide staining suggested that InsP6 dose dependently induced apoptosis in human breast adenocarcinoma MCF-7 cells. Among InsPs tested (InsP3, InsP4, InsP5, and InsP6), InsP6 was found to be the most effective in inducing apoptosis. Furthermore, effects of InsP6 were found most potent inducing apoptosis. Etoposide, the drug known to induce apoptosis in both in vivo and in vitro, was used as a positive control. Western blotting experiments using specific antibodies against known apoptotic markers suggested that InsP6 induced apoptotic changes were mediated via an intrinsic apoptotic pathway.

  7. INOSITOL HEXAKISPHOSPHATE MEDIATES APOPTOSIS IN HUMAN BREAST ADENOCARCINOMA MCF-7 CELL LINE VIA INTRINSIC PATHWAY

    International Nuclear Information System (INIS)

    Agarwal, Rakhee; Ali, Nawab

    2010-01-01

    Inositol polyphosphates (InsP s ) are naturally occurring compounds ubiquitously present in plants and animals. Inositol hexakisphosphate (InsP 6 ) is the most abundant among all InsP s and constitutes the major portion of dietary fiber in most cereals, legumes and nuts. Certain derivatives of InsP s also regulate cellular signaling mechanisms. InsP s have also been shown to reduce tumor formation and induce apoptosis in cancerous cells. Therefore, in this study, the effects of InsPs on apoptosis were studied in an attempt to investigate their potential anti-cancer therapeutic application and understand their mechanism of action. Acridine orange and ethidium bromide staining suggested that InsP 6 dose dependently induced apoptosis in human breast adenocarcinoma MCF-7 cells. Among InsP s tested (InsP 3 , InsP 4 , InsP 5 , and InsP 6 ), InsP 6 was found to be the most effective in inducing apoptosis. Furthermore, effects of InsP 6 were found most potent inducing apoptosis. Etoposide, the drug known to induce apoptosis in both in vivo and in vitro, was used as a positive control. Western blotting experiments using specific antibodies against known apoptotic markers suggested that InsP 6 induced apoptotic changes were mediated via an intrinsic apoptotic pathway.

  8. Implicit constitutive relations for nonlinear magnetoelastic bodies.

    Science.gov (United States)

    Bustamante, R; Rajagopal, K R

    2015-03-08

    Implicit constitutive relations that characterize the response of elastic bodies have greatly enhanced the arsenal available at the disposal of the analyst working in the field of elasticity. This class of models were recently extended to describe electroelastic bodies by the present authors. In this paper, we extend the development of implicit constitutive relations to describe the behaviour of elastic bodies that respond to magnetic stimuli. The models that are developed provide a rational way to describe phenomena that have hitherto not been adequately described by the classical models that are in place. After developing implicit constitutive relations for magnetoelastic bodies undergoing large deformations, we consider the linearization of the models within the context of small displacement gradients. We then use the linearized model to describe experimentally observed phenomena which the classical linearized magnetoelastic models are incapable of doing. We also solve several boundary value problems within the context of the models that are developed: extension and shear of a slab, and radial inflation and extension of a cylinder.

  9. A constitutive law for degrading bioresorbable polymers.

    Science.gov (United States)

    Samami, Hassan; Pan, Jingzhe

    2016-06-01

    This paper presents a constitutive law that predicts the changes in elastic moduli, Poisson's ratio and ultimate tensile strength of bioresorbable polymers due to biodegradation. During biodegradation, long polymer chains are cleaved by hydrolysis reaction. For semi-crystalline polymers, the chain scissions also lead to crystallisation. Treating each scission as a cavity and each new crystal as a solid inclusion, a degrading semi-crystalline polymer can be modelled as a continuum solid containing randomly distributed cavities and crystal inclusions. The effective elastic properties of a degrading polymer are calculated using existing theories for such solid and the tensile strength of the degrading polymer is predicted using scaling relations that were developed for porous materials. The theoretical model for elastic properties and the scaling law for strength form a complete constitutive relation for the degrading polymers. It is shown that the constitutive law can capture the trend of the experimental data in the literature for a range of biodegradable polymers fairly well. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Investigating the evolution of apoptosis in malaria parasites: the importance of ecology

    Directory of Open Access Journals (Sweden)

    Pollitt Laura C

    2010-11-01

    Full Text Available Abstract Apoptosis is a precisely regulated process of cell death which occurs widely in multicellular organisms and is essential for normal development and immune defences. In recent years, interest has grown in the occurrence of apoptosis in unicellular organisms. In particular, as apoptosis has been reported in a wide range of species, including protozoan malaria parasites and trypanosomes, it may provide a novel target for intervention. However, it is important to understand when and why parasites employ an apoptosis strategy before the likely long- and short-term success of such an intervention can be evaluated. The occurrence of apoptosis in unicellular parasites provides a challenge for evolutionary theory to explain as organisms are expected to have evolved to maximise their own proliferation, not death. One possible explanation is that protozoan parasites undergo apoptosis in order to gain a group benefit from controlling their density as this prevents premature vector mortality. However, experimental manipulations to examine the ultimate causes behind apoptosis in parasites are lacking. In this review, we focus on malaria parasites to outline how an evolutionary framework can help make predictions about the ecological circumstances under which apoptosis could evolve. We then highlight the ecological considerations that should be taken into account when designing evolutionary experiments involving markers of cell death, and we call for collaboration between researchers in different fields to identify and develop appropriate markers in reference to parasite ecology and to resolve debates on terminology.

  11. Dissection of pathways leading to antigen receptor-induced and Fas/CD95-induced apoptosis in human B cells

    NARCIS (Netherlands)

    Lens, S. M.; den Drijver, B. F.; Pötgens, A. J.; Tesselaar, K.; van Oers, M. H.; van Lier, R. A.

    1998-01-01

    To dissect intracellular pathways involved in B cell Ag receptor (BCR)-mediated and Fas-induced human B cell death, we isolated clones of the Burkitt lymphoma cell line Ramos with different apoptosis sensitivities. Selection for sensitivity to Fas-induced apoptosis also selected for clones with

  12. The Causes of Failure of the European Constitution From the Perspective of the Constitution-Making Process

    OpenAIRE

    Robert Podolnjak

    2006-01-01

    The basic argument of the article is that the main causes of failure of the European Constitution stem from an inadequate preparation and implementation of a complex procedure of constitution-making for a federation of countries on a continental scale. This process includes the issues of temporal aspects of constitutionmaking, the subject of constitution-making, the text of the constitution, the strategy of constitutional ratifi cation and the constitution-makers themselves. The principal cau...

  13. The European Parliament in the 2000 IGC and the Constitutional Treaty negotiations: from loser to winner

    DEFF Research Database (Denmark)

    Beach, Derek

    2007-01-01

      Abstract           Why did two rounds of EU constitutional reform held within a five year period yield very different results? The 2000 IGC resulted in the modest Treaty of Nice, whereas the 2002-04 round drafted the Constitutional Treaty, which although it did not involve major substantive...... changes, did mark a major symbolic step forward. This article argues that the change in outcomes can to a large degree be explained by the change in negotiating structure due to the use of a convention that drafted most of the Constitutional Treaty's text, creating a context which privileged MEPs. While...

  14. Influence of vitamin D on cell cycle, apoptosis, and some apoptosis related molecules in systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Nafise Tabasi

    2015-11-01

    Full Text Available Objective(s:Genetic and environmental factors are involved in the pathogenesis of systemic lupus erythematosus (SLE. Autoreactive lymphocytes are cleared through apoptosis and any disturbance in the apoptosis or clearance of apoptotic cells may disturb tolerance and lead to autoimmunity. Vitamin D has anti-proliferative effects and controls cell cycle progression. In this study we investigated the effects of vitamin D on cell cycle and apoptosis induction in lupus patients. Materials and Methods:Isolated peripheral blood mononuclear cells (PBMCs from 25 SLE patients were cultured in the presence of 50 nM of 1,25(OH2D3; then one part of the cells were stained with FITC labeled Annexin V and PI and were analyzed for apoptosis determination. For gene expression assessment of FasL, Bcl-2 and Bax, RNA was extracted from one another part of the cells, cDNA was synthesized and gene expression analysis was performed using Real time PCR. An additional part of the cells were treated with PI and the cell cycle was analyzed using flowcytometer. Results: The mean number of early apoptotic cells in vitamin D treated cells decreased significantly (18.48±7.9% compared to untreated cells (22.02±9.4% (P=0.008. Cell cycle analysis showed a significant increase in G1 phase in vitamin D treated cells (67.33±5.2% compared to non treated ones (60.77±5.7% (P =0.02. Vitamin D up-regulated the expression levels of Bcl-2 by (18.87 fold increase, and down-regulated expression of Bax (23% and FasL (25%. Conclusion:Vitamin D has regulatory effects on cell cycle progression, apoptosis and apoptosis related molecules in lupus patients.

  15. Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis

    Science.gov (United States)

    Aguiló, N; Uranga, S; Marinova, D; Martín, C; Pardo, J

    2014-01-01

    Mycobacterium tuberculosis, the causative agent of tuberculosis, induces apoptosis in infected macrophages in vitro and in vivo. However, the molecular mechanism controlling this process is not known. In order to study the involvement of the mitochondrial apoptotic pathway in M. tuberculosis-induced apoptosis, we analysed cell death in M. tuberculosis-infected embryonic fibroblasts (MEFs) derived from different knockout mice for genes involved in this route. We found that apoptosis induced by M. tuberculosis is abrogated in the absence of Bak and Bax, caspase 9 or the executioner caspases 3 and 7. Notably, we show that MEF deficient in the BH3-only BCL-2-interacting mediator of cell death (Bim) protein were also resistant to this process. The relevance of these results has been confirmed in the mouse macrophage cell line J774, where cell transfection with siRNA targeting Bim impaired apoptosis induced by virulent mycobacteria. Notably, only infection with a virulent strain, but not with attenuated ESX-1-defective strains, such as Bacillus Calmette-Guerin and live-attenuated M. tuberculosis vaccine strain MTBVAC, induced Bim upregulation and apoptosis, probably implicating virulence factor early secreted antigenic target 6-kDa protein in this process. Our results suggest that Bim upregulation and apoptosis is mediated by the p38MAPK-dependent pathway. Our findings show that Bim is a master regulator of apoptosis induced by M. tuberculosis. PMID:25032866

  16. Apoptosis in oral epithelial dysplastic lesions and oral squamous cell carcinoma: A prognostic marker.

    Science.gov (United States)

    Nambiar, Shwetha; Hegde, Veda

    2016-01-01

    Apoptotic index (AI) using light microscopy as an indirect measure to assess the significance of apoptosis as a proliferative marker in dysplastic lesions and malignant epithelial lesions of the oral cavity. (1) To quantify the apoptotic bodies/cells in oral epithelial dysplastic (OED) lesions and oral squamous cell carcinoma (OSCC). (2) To measure AI in OED and OSCC. (3) To compare AI in OED and OSCC. The proposed laboratory-based retrospective study involved the use of hematoxylin and eosin (H and E)-stained slides of previously diagnosed OED lesions and OSCC from institutional archives. This study constituted 50 cases, each of H and E-stained slides of previously diagnosed cases of OED and OSCC. AI was calculated as the number of apoptotic bodies/cells expressed as a percentage of the total number of nonapoptotic tumor/dysplastic cells counted in each case. Nonparametric tests such as Kruskal-Wallis test and Mann-Whitney test were used. There was a statistically significant increase in AI from OED to OSCC (P = 0.000). Further studies need to be undertaken to detect and understand the apoptotic mechanisms in the progression from OED to OSCC.

  17. Apoptosis in oral epithelial dysplastic lesions and oral squamous cell carcinoma: A prognostic marker

    Directory of Open Access Journals (Sweden)

    Shwetha Nambiar

    2016-01-01

    Full Text Available Background: Apoptotic index (AI using light microscopy as an indirect measure to assess the significance of apoptosis as a proliferative marker in dysplastic lesions and malignant epithelial lesions of the oral cavity. Aims: (1 To quantify the apoptotic bodies/cells in oral epithelial dysplastic (OED lesions and oral squamous cell carcinoma (OSCC. (2 To measure AI in OED and OSCC. (3 To compare AI in OED and OSCC. Settings and Design: The proposed laboratory-based retrospective study involved the use of hematoxylin and eosin (H and E-stained slides of previously diagnosed OED lesions and OSCC from institutional archives. Materials and Methods: This study constituted 50 cases, each of H and E-stained slides of previously diagnosed cases of OED and OSCC. AI was calculated as the number of apoptotic bodies/cells expressed as a percentage of the total number of nonapoptotic tumor/dysplastic cells counted in each case. Statistical Analysis Used: Nonparametric tests such as Kruskal–Wallis test and Mann–Whitney test were used. Results: There was a statistically significant increase in AI from OED to OSCC (P = 0.000. Conclusions: Further studies need to be undertaken to detect and understand the apoptotic mechanisms in the progression from OED to OSCC.

  18. Global Survey of National Constitutions: Mapping Constitutional Commitments to Sexual and Reproductive Health and Rights.

    Science.gov (United States)

    Pizzarossa, Lucía Berro; Perehudoff, Katrina

    2017-12-01

    General Comment No. 22, issued in 2016 by the Committee on Economic, Social and Cultural Rights (CESCR), clarifies states' legal duties to respect, protect, and fulfill the right to sexual and reproductive health (SRH). Our study analyzes domestic constitutions around the world to investigate whether and to what extent the right to sexual and reproductive health is respected, protected, and fulfilled; to what extent these provisions are inclusive and non-discriminatory; and to what degree the interlinkages between this and other human rights are acknowledged. Of the 195 constitutions accessed, 27 enshrine sexual and/or reproductive health, and seven adopt restrictive approaches to this right. In the 27 constitutions, provisions most frequently enshrine respect of one's sexual health and family planning decisions, the protection of sexual health, and the provision of reproductive health care and family planning services (fulfillment). Most of the 27 constitutions fail to adequately respect reproductive health rights; to protect reproductive health, family planning, and abortion services from third-party interference; and to fulfill all dimensions of sexual health and access to abortion. Three of the 27 constitutions enshrine a universal right to SRH, and additional constitutions protect specific vulnerable groups (such as women, children) and/or restrict the scope of rights holders to couples. Among the 27 constitutions, nine explicitly link the right to sexual and reproductive health to the rights to education, science, and/or to make autonomous decisions about sexuality and reproduction. Our results can serve as a baseline measure to track constitutional reforms in pursuit of the realization of sexual and reproductive health and rights, and as building blocks for future lawmakers committed to realizing these rights through domestic legal reform.

  19. Interference of Apoptosis by Hepatitis B Virus.

    Science.gov (United States)

    Lin, Shaoli; Zhang, Yan-Jin

    2017-08-18

    Hepatitis B virus (HBV) causes liver diseases that have been a consistent problem for human health, leading to more than one million deaths every year worldwide. A large proportion of hepatocellular carcinoma (HCC) cases across the world are closely associated with chronic HBV infection. Apoptosis is a programmed cell death and is frequently altered in cancer development. HBV infection interferes with the apoptosis signaling to promote HCC progression and viral proliferation. The HBV-mediated alteration of apoptosis is achieved via interference with cellular signaling pathways and regulation of epigenetics. HBV X protein (HBX) plays a major role in the interference of apoptosis. There are conflicting reports on the HBV interference of apoptosis with the majority showing inhibition of and the rest reporting induction of apoptosis. In this review, we described recent studies on the mechanisms of the HBV interference with the apoptosis signaling during the virus infection and provided perspective.

  20. Interference of Apoptosis by Hepatitis B Virus

    Science.gov (United States)

    2017-01-01

    Hepatitis B virus (HBV) causes liver diseases that have been a consistent problem for human health, leading to more than one million deaths every year worldwide. A large proportion of hepatocellular carcinoma (HCC) cases across the world are closely associated with chronic HBV infection. Apoptosis is a programmed cell death and is frequently altered in cancer development. HBV infection interferes with the apoptosis signaling to promote HCC progression and viral proliferation. The HBV-mediated alteration of apoptosis is achieved via interference with cellular signaling pathways and regulation of epigenetics. HBV X protein (HBX) plays a major role in the interference of apoptosis. There are conflicting reports on the HBV interference of apoptosis with the majority showing inhibition of and the rest reporting induction of apoptosis. In this review, we described recent studies on the mechanisms of the HBV interference with the apoptosis signaling during the virus infection and provided perspective. PMID:28820498

  1. Role of apoptosis in common variable immunodeficiency and selective immunoglobulin A deficiency.

    Science.gov (United States)

    Yazdani, Reza; Fatholahi, Maryam; Ganjalikhani-Hakemi, Mazdak; Abolhassani, Hassan; Azizi, Gholamreza; Hamid, Kabir Magaji; Rezaei, Nima; Aghamohammadi, Asghar

    2016-03-01

    Common variable immunodeficiency (CVID) and selective IgA deficiency (SIgAD) are the most common primary immunodeficiencies in human. Both diseases share clinical manifestation and molecular defects. Increased apoptosis may be one of the mechanisms involved in the pathogenesis of CVID and SIgAD. Elevated apoptosis in this disorder leads to defective long-term survival of B-cells, reduced antibody production, decreased lymphocyte proliferation and defective cytokine secretion. For the first time, we reviewed the role of apoptosis in CVID and SIgAD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Apoptosis Gene Hunting Using Retroviral Expression Cloning: Identification of Vacuolar ATPase Subunit E

    Directory of Open Access Journals (Sweden)

    Claire L. Anderson

    2003-01-01

    Full Text Available Over the past 10-15 years there has been an explosion of interest in apoptosis. The delayed realisation that cell death is an essential part of life for any multicellular organism has meant that, despite the recent and rapid developments of the last decade, the precise biochemical pathways involved in apoptosis remain incomplete and potentially novel genes may, as yet, remain undiscovered. The hunt is therefore on to bridge the remaining gaps in our knowledge. Our contribution to this research effort utilises a functional cloning approach to isolate important regulatory genes involved in apoptosis. This mini-review focuses on the use and advantages of a retroviral expression cloning strategy and describes the isolation and identification of one such potential apoptosis regulatory gene, namely that encoding vacuolar ATPase subunit E.

  3. Spironolactone induces apoptosis and inhibits NF-kappaB independent of the mineralocorticoid receptor

    DEFF Research Database (Denmark)

    Sønder, Søren Ulrik Salling; Woetmann, Anders; Odum, Niels

    2006-01-01

    mononuclear cells (MNC). To elucidate the mechanism behind SPIR's apoptotic effect, we investigated the relation between apoptosis and cytokine suppression for SPIR along with the apoptosis-inducing and antiinflammatory drug sulfasalazine (SFZ). Using human MNC, we found that SPIR and SFZ, at concentrations...... 10 and 1000 muM, respectively, significantly increased both apoptosis and cell death. Production of inflammatory cytokines was significantly reduced by 3 to 30 muM SPIR and by 300 to 1000 muM SFZ. We also found that 0.4 muM SPIR and 300 muM SFZ significantly reduced the activity of NF......-kappaB, a transcription factor involved in both apoptosis and immunoinflammation. ALDO, the MR antagonist, eplerenone, and the SPIR metabolite, 7alpha-thiomethyl-spironolactone, slightly reduced NF-kappaB activity, but they did not interfere with SPIR's effect, showing that MR binding is not involved in SPIR...

  4. Iodinated contrast media induce neutrophil apoptosis through a mitochondrial and caspase mediated pathway.

    LENUS (Irish Health Repository)

    Fanning, N F

    2012-02-03

    Iodinated contrast media (ICM) can induce apoptosis (programmed cell death) in renal, myocardial and endothelial cells. Following intravascular injection, circulating immune cells are exposed to high concentrations of ICM. As neutrophils constitutively undergo apoptosis we hypothesized that ICM may adversely affect neutrophil survival. Our aim was to investigate the effect of ICM on neutrophil apoptosis. Neutrophils were isolated from healthy subjects and cultured in vitro with ionic (diatrizoate and ioxaglate) and non-ionic (iohexol and iotrolan) ICM. The effect of ICM on neutrophil apoptosis in both unstimulated and lipopolysaccharide-stimulated neutrophils was determined by annexin V flow cytometry. The influence of physicochemical properties of the different ICM on apoptosis of neutrophils was also studied. We further investigated the effects of ICM on key intracellular signal pathways, including p38 mitogen-activated protein kinase (MAPK) by Western blotting, and mitochondrial depolarization and caspase activity by flow cytometry. Isoiodine concentrations (20 mg ml(-1)) of ionic (diatrizoate 69.6+\\/-2.9%; ioxaglate 58.9+\\/-2.0%) and non-ionic (iohexol 57.3+\\/-2.9%; iotrolan 57.1+\\/-2.6%) ICM significantly induced neutrophil apoptosis over control levels (47.7+\\/-1.4%). The apoptotic effect of ICM was influenced by their chemical structure, with ionic ICM having a more significant (p<0.01) apoptotic effect than non-ionic ICM (p<0.05). Furthermore, ICM reversed the anti-apoptotic effect of lipopolysaccharide (1000 ng ml(-1)) treated neutrophils to control levels (23.0+\\/-3.5% to 61.2+\\/-5.3%; n=4; p<0.05). These agents induce apoptosis through a p38 MAPK independent pathway that results in mitochondrial depolarization, and is dependent on caspase activation. As neutrophils play a central role in host response to infection and injury, ICM, through induction of neutrophil apoptosis, could have a significant deleterious effect on host immune defence and

  5. The cephalostatin way of apoptosis.

    Science.gov (United States)

    Rudy, Anita; López-Antón, Nancy; Dirsch, Verena M; Vollmar, Angelika M

    2008-03-01

    The cephalostatins, bis-steroidal natural products from the marine tube worm Cephalodiscus gilchristi, were isolated by Dr. G. R. Pettit and his group. These compounds show a unique cytotoxicity profile in the in vitro screen of the National Cancer Institute, suggesting a novel mechanism of action. Indeed, cephalostatin 1 ( 1) is an extremely powerful agent that acts via an unusual apoptosis pathway. It induces selective Smac/DIABLO, but no cytochrome c release from mitochondria. Nevertheless, caspase-9 is required for apoptosis induction. Interestingly, caspase-9 is activated without the participation of the apoptosome, leading to the question of its mechanism of activation. We found that endoplasmic reticulum stress-associated caspase-4 contributes to nonclassical cephalostatin-mediated caspase-9 activation, additionally pointing out the unusual pathway used by this substance. Cephalostatin 1 ( 1), therefore, provides a very good tool to discover novel apoptotic pathways, which might be important in the understanding and treatment of chemo-resistant cancer.

  6. Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma

    Directory of Open Access Journals (Sweden)

    Dimberg Lina Y

    2012-07-01

    Full Text Available Abstract Background Multiple myeloma (MM is at present an incurable malignancy, characterized by apoptosis-resistant tumor cells. Interferon (IFN treatment sensitizes MM cells to Fas-induced apoptosis and is associated with an increased activation of Signal transducer and activator of transcription (Stat1. The role of Stat1 in MM has not been elucidated, but Stat1 has in several studies been ascribed a pro-apoptotic role. Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM. Methods To delineate the role of Stat1 in IFN mediated sensitization to apoptosis, sub-lines of the U-266-1970 MM cell line with a stable expression of the active mutant Stat1C were utilized. The influence of Stat1C constitutive transcriptional activation on endogenous Stat3 expression and activation, and the expression of apoptosis-related genes were analyzed. To determine whether Stat1 alone would be an important determinant in sensitizing MM cells to apoptosis, the U-266-1970-Stat1C cell line and control cells were exposed to high throughput compound screening (HTS. Results To explore the role of Stat1 in IFN mediated apoptosis sensitization of MM, we established sublines of the MM cell line U-266-1970 constitutively expressing the active mutant Stat1C. We found that constitutive nuclear localization and transcriptional activity of Stat1 was associated with an attenuation of IL-6-induced Stat3 activation and up-regulation of mRNA for the pro-apoptotic Bcl-2 protein family genes Harakiri, the short form of Mcl-1 and Noxa. However, Stat1 activation alone was not sufficient to sensitize cells to Fas-induced apoptosis. In a screening of > 3000 compounds including bortezomib, dexamethasone, etoposide, suberoylanilide hydroxamic acid (SAHA, geldanamycin (17-AAG, doxorubicin and thalidomide, we found that the drug response and IC50 in cells constitutively expressing active Stat1 was mainly unaltered. Conclusion We conclude that Stat1 alters IL-6

  7. Methylselenium and Prostate Cancer Apoptosis

    Science.gov (United States)

    2003-02-01

    miethylselenol generated in cell-culture medium by described previously [12,15]. All cell-culture workwas performed without antibiotics . L-methionine-cL-deamino...Thompson HJ. Effect of 16. Datta SR, Brunet A, Greenberg ME. Cellular survival: A play an aqueous extract of selenium enriched garlic on in vitro in three... garlic on in vitro markers and relationship to caspase-mediated apoptosis execution. The in vivo efficacy in cancer prevention. Carcinogenesis (Lond.), 17

  8. Habermas on European Constitution and European Identity

    Directory of Open Access Journals (Sweden)

    Éva Biró-Kaszás

    2010-12-01

    Full Text Available For the last two decades or so philosophers have been reflecting on a set of practical and political concerns in connection with the new political structural arrangements beyond the nation-state. In this article two essays by Jürgen Habermas shall be examined. An attempt shall be made to tackle Habermas’ philosophical concepts of personal and collective identity as well as the role that a constitution may play in building the post-national constellation. It has been shown that Habermas has normative answers. Firstly, according to him, the fragile balance between the legal order and the particular cultures and traditions of a community has to be protected by the constitutional state. For that reason the political culture has to be “decoupled” from the majority culture. Secondly, the democratically structured attempt to achieve shared meaning has to find the delicate balance between the context-transcending universal normative claims and the claims of particular individual and collective life. Thirdly, it is possible to expand legally mediated civil solidarity trans-nationally, across Europe – we may recognize this development as the emergence of European identity –, since the process of democratic will-formation of citizens may get loose from the structures provided by the state if both shared democratic political cultures as well as a European-wide public sphere exist. The European Constitution may have a catalytic function in materialization of these conditions. It has been shown that in his deliberations Habermas tried to find a reflective equilibrium between the normative and the empirical.

  9. The Constitutional Deficiencies of the German 'Rechtsgutslehre'

    Directory of Open Access Journals (Sweden)

    Carl-Friedrich Stuckenberg

    2013-01-01

    Full Text Available This paper questions the theoretical merits and constitutional validity of the “Rechtsgutslehre” (doctrine of the protection of legal goods, a widely held doctrine about the limits of legitimate criminalization in Germany and some other jurisdictions. The immediate cause for this reassessment is a recent decision of the German constitutional court which upheld the German incest prohibition and simultaneously rejected the traditional “Rechtsgutslehre” as constitutionally irrelevant, thereby stirring up considerable controversy among academic criminal lawyers. The paper tries to show why the court’s view is correct by pointing out the main deficiencies of the doctrine and what criteria a better theory must fulfil. Este artículo cuestiona los méritos teóricos y la validez constitucional de la "Rechtsgutslehre" (doctrina de la protección de los bienes jurídicos, una doctrina muy extendida acerca de los límites de la criminalización legítima en Alemania y algunas otras jurisdicciones. La causa inmediata de esta nueva valoración es una decisión reciente del Tribunal Constitucional alemán que ratificó la prohibición del incesto en Alemania y al mismo tiempo rechazó el tradicional "Rechtsgutslehre" por ser constitucionalmente irrelevante, lo que provocó una considerable controversia entre la comunidad académica de abogados criminalistas. El artículo trata de mostrar por qué la decisión de la corte es correcta, señalando las deficiencias principales de la doctrina y los criterios que una teoría más adecuada debe cumplir. DOWNLOAD THIS PAPER FROM SSRN: http://ssrn.com/abstract=2200870

  10. A constitutive law for dense granular flows.

    Science.gov (United States)

    Jop, Pierre; Forterre, Yoël; Pouliquen, Olivier

    2006-06-08

    A continuum description of granular flows would be of considerable help in predicting natural geophysical hazards or in designing industrial processes. However, the constitutive equations for dry granular flows, which govern how the material moves under shear, are still a matter of debate. One difficulty is that grains can behave like a solid (in a sand pile), a liquid (when poured from a silo) or a gas (when strongly agitated). For the two extreme regimes, constitutive equations have been proposed based on kinetic theory for collisional rapid flows, and soil mechanics for slow plastic flows. However, the intermediate dense regime, where the granular material flows like a liquid, still lacks a unified view and has motivated many studies over the past decade. The main characteristics of granular liquids are: a yield criterion (a critical shear stress below which flow is not possible) and a complex dependence on shear rate when flowing. In this sense, granular matter shares similarities with classical visco-plastic fluids such as Bingham fluids. Here we propose a new constitutive relation for dense granular flows, inspired by this analogy and recent numerical and experimental work. We then test our three-dimensional (3D) model through experiments on granular flows on a pile between rough sidewalls, in which a complex 3D flow pattern develops. We show that, without any fitting parameter, the model gives quantitative predictions for the flow shape and velocity profiles. Our results support the idea that a simple visco-plastic approach can quantitatively capture granular flow properties, and could serve as a basic tool for modelling more complex flows in geophysical or industrial applications.

  11. Constitutionalism and good governance in Nigeria (1999-2014 ...

    African Journals Online (AJOL)

    While the country, at present, has a written constitution which in reality, was derived from a military decree, there has been constant debate as to whether what the country has is really a constitution and whether the subsequent civilian regimes are constitutional governments. This paper attempts to analyse the constitutional ...

  12. An Integrated Theory of Constitutionalism in World Society

    DEFF Research Database (Denmark)

    Kjær, Poul F.

    both been regarded a indicating a triumph as well as a failure of constitutionalism. This article circumvents this standoff by questioning the very foundation of constitutional theory in the public/private and the national/transnational distinctions. It is argued that the object of constitutions...... for compatibility between orders through constitutionalisation and the idea of constitutionalism as a way of approaching the future....

  13. Ubuntu versus the core values of the South African Constitution ...

    African Journals Online (AJOL)

    At the dawn of South Africa's new era of constitutionalism the Constitutional Court introduced “African law and legal thinking” and ubuntu to South African jurisprudence as part of the Constitution's source of democratic values. Whereas the Constitutional Court averred on the one hand that African law sustains firmly ...

  14. 1 CHILDREN'S RIGHTS IN THE SOUTH-AFRICAN CONSTITUTION ...

    African Journals Online (AJOL)

    Administrator

    1994-04-27

    Apr 27, 1994 ... In order to fathom the impact of the Constitution upon the rights of children, a general overview of constitutional principles and provisions necessary for the comprehension of the rights of children in the Constitution will be given. .... terms of section 8(2) entitles a court to read constitutional rights into the.

  15. Sensitization for Anticancer Drug-Induced Apoptosis by Betulinic Acid

    Directory of Open Access Journals (Sweden)

    Simone Fulda

    2005-02-01

    Full Text Available We previously described that betulinic acid (BetA, a naturally occurring pentacyclic triterpenoid, induces apoptosis in tumor cells through the mitochondrial pathway. Here, for the first time, we provide evidence that BetA cooperated with anticancer drugs to induce apoptosis and to inhibit clonogenic survival of tumor cells. Combined treatment with BetA and anticancer drugs acted in concert to induce loss of mitochondrial membrane potential and the release of cytochrome c and Smac from mitochondria, resulting in activation of caspases and apoptosis. Overexpression of Bcl-2, which blocked mitochondrial perturbations, also inhibited the cooperative effect of BetA and anticancer drugs, indicating that cooperative interaction involved the mitochondrial pathway. Notably, cooperation of BetA and anticancer drugs was found for various cytotoxic compounds with different modes of action (e.g., doxorubicin, cisplatin, Taxol, VP16, or actinomycin D. Importantly, BetA and anticancer drugs cooperated to induce apoptosis in different tumor cell lines, including p53 mutant cells, and also in primary tumor cells, but not in human fibroblasts indicating some tumor specificity. These findings indicate that using BetA as sensitizer in chemotherapy-based combination regimens may be a novel strategy to enhance the efficacy of anticancer therapy, which warrants further investigation.

  16. Induction of apoptosis by eugenol in human breast cancer cells

    International Nuclear Information System (INIS)

    Vidhya, N.; Niranjali Devaraj, S.

    2011-01-01

    In the present study, potential anticancer effect of eugenol on inhibition of cell proliferation and induction of apoptosis in human MCF-7 breast cancer cells was investigated. Induction of cell death by eugenol was evaluated following MTT assay and monitoring lactate dehydrogenase released into the culture medium for cell viability and cytotoxicity, giemsa staining for morphological alterations, fluorescence microscopy analysis of cells using ethidium bromide and acridine orange and quantitation of DNA fragments for induction of apoptosis. Effect of eugenol on intracellular redox status of the human breast cancer cells was assessed by determining the level of glutathione and lipid peroxidation products (TBARS). Eugenol treatment inhibited the growth and proliferation of human MCF-7 breast cancer cells through induction of cell death, which was dose and time dependent. Microscopic examination of eugenol treated cells showed cell shrinkage, membrane blebbing and apoptotic body formation. Further, eugenol treatment also depleted the level of intracellular glutathione and increased the level of lipid peroxidation. The dose dependent increase in the percentage of apoptotic cells and DNA fragments suggested that apoptosis was involved in eugenol induced cell death and apoptosis might have played a role in the chemopreventive action of eugenol. (author)

  17. Apple polysaccharides induce apoptosis in colorectal cancer cells.

    Science.gov (United States)

    Zhang, Dian; Sun, Yang; Yue, Zhenggang; Li, Qian; Meng, Jin; Liu, Junajuan; Hekong, Xiang; Jiang, Fengliang; Mi, Man; Liu, Li; Mei, Qibing

    2012-07-01

    Certain components of apples have been shown to prevent cancer growth and impede cancer progression. We hypothesized that extracted apple polysaccharides (APs) might, therefore, have anticancer effects, through a mechanism involving the induction of apoptosis in cancer cells, partly via the NF-κB pathway. Two human colorectal cancer (CRC) cell lines, HT-29 and SW620, were exposed to different concentrations of APs (0.01, 0.1 or 1 mg/ml). Cell apoptosis was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay by flow cytometry and incorporation of 5'-bromodeoxyuridine (BrdU) into DNA to identify the proliferating cell fraction, using fluorescence microscopy in vitro. The protein levels of NF-κB/p65, I-κBα, pI-κBα, Bax, Bcl-xl and Bcl-2 were evaluated by western blotting. The target sites of APs on CRC cells were assessed by flow cytometry. At concentrations of 0.1 and 1 mg/ml, APs showed apoptosis-inducing effects, increased expressions of Bax, nuclear p65 and cytoplasmic pI-κBα, and decreased expressions of Bcl-2, Bcl-xl and cytoplasmic I-κBα. APs induced apoptosis by slightly activating the NF-κB pathway; the AP target site could be the Toll-like receptor 4 on the cell membrane. These results demonstrate the potential of APs as agents for clinical prevention and treatment of CRC.

  18. Xylodiol from Xylopia langsdorfiana induces apoptosis in HL60 cells

    Directory of Open Access Journals (Sweden)

    Marianna Vieira S. Castello-Branco

    2011-08-01

    Full Text Available An atisane diterpene was isolated from Xylopia langsdorfiana St. Hilaire & Tulasne, Annonaceae, leaves, ent-atisane-7α,16α-diol (xylodiol. Preliminary study showed that xylodiol was cytotoxic and induced differentiation on human leukemia cell lines. However, the molecular mechanisms of xylodiol-mediated cytotoxicity have not been fully defined. Thus, we investigated the anti-tumor effect of xylodiol in human leukemia HL60 cell line. Xylodiol induced apoptosis and necrosis. HL60 cells treated with xylodiol showed biochemical changes characteristic of apoptosis, including caspases-8, -9 and -3 activation and loss of mitochondrial transmembrane potential (∆ Ψm. However, there was a condensation rather than swelling of mitochondria. Moreover, the formation of condensed mitochondria and the loss of ∆ Ψm occurred downstream of caspase activation. Cyclosporine A did not protect HL60 cells from the cytotoxic effects of xylodiol, suggesting that the loss of ∆ Ψm is a late event in xylodiol-induced apoptosis. Oxidative stress was involved in xylodiol-induced apoptosis. Thus, we conclude that activated caspases cleave cellular proteins resulting in mitochondrial damage leading to mitochondrial condensation, loss of ∆ Ψm and ROS release from the mitochondria. ROS can further induce and maintain a collapse of ∆ Ψm leading to cellular damage through oxidation of lipids and proteins resulting in apoptotic cell death.

  19. Keratocyte loss in Acanihamoeba Keratitis: Phagocytosis, necrosis or apoptosis?

    Directory of Open Access Journals (Sweden)

    Vemuganti Geeta

    2000-01-01

    Full Text Available Purpose: Pathogenesis of Acanthamoeba keratitis involves breakdown of epithelial barrier, stromal invasion by Acanthamoeba, loss of keratocytes, inflammatory response and finally stromal necrosis. The loss of keratocytes, believed to be due to the phagocytic activity of the parasite, occurs disproportionate to and independent of the parasite load, thereby suggesting additional modes of cell loss. To test our hypothesis that the loss of keratocytes in Acanthamoeba keratitis is due to apoptosis, we did both histology and histochemistry on the corneal tissues. Methods: Routine Haematoxylin and Eosin, Gomori′s Methenamine Silver and Periodic acid Schiff stained sections of five corneal tissues from penetrating keratoplasty and eviscerated eyes were reviewed. TUNEL staining was done for morphological detection of apoptosis in three cases, using formalin-fixed, paraffin-processed tissues. Results: Histological changes were epithelial ulceration, loss of keratocytes in all layers, inflammation in anterior two-thirds of the stroma with necrosis, and deeper quiet stroma. Acanthamoeba trophozoites were found in the anterior stroma while the cysts were more in the deeper stroma, with minimal or no inflammatory response. TUNEL staining was positive in keratocytic nuclei in all layers. Conclusions: This study demonstrates that one of the modes of keratocyte loss in Acanthamoeba keratitis is by apoptosis, possibly in addition to the necrotic process and phagocytic activity of the parasite. The death of inflammatory cells also appears to be mediated by apoptosis.

  20. Evaluation of constitutive models for crushed salt

    Energy Technology Data Exchange (ETDEWEB)

    Callahan, G.D.; Loken, M.C. [RE/SPEC, Inc., Rapid City, SD (United States); Hurtado, L.D.; Hansen, F.D.

    1996-05-01

    Three constitutive models are recommended as candidates for describing the deformation of crushed salt. These models are generalized to three-dimensional states of stress to include the effects of mean and deviatoric stress and modified to include effects of temperature, grain size, and moisture content. A database including hydrostatic consolidation and shear consolidation tests conducted on Waste Isolation Pilot Plant (WIPP) and southeastern New Mexico salt is used to determine material parameters for the models. To evaluate the capability of the models, parameter values obtained from fitting the complete database are used to predict the individual tests. Finite element calculations of a WIPP shaft with emplaced crushed salt demonstrate the model predictions.

  1. Validation of constitutive equations for steel

    International Nuclear Information System (INIS)

    Valentin, T.; Magain, P.; Quik, M.; Labibes, K.; Albertini, C.

    1997-01-01

    High strain rate mechanical properties are a major concern for each steel manufacturer, especially with respect to thin sheet steel used in the automotive branch. We began to study this topic by starting a project with the following goals: acquiring reliable experimental data, understanding in depth the energy absorption in thin sheet steel and finding the right constitutive material equation. The first part of the project has been presented in. In this paper we present data computation and comparison with the existing material model theories to exploit the experimental data. (orig.)

  2. Ritual Slaughter in the Modern Constitutional State

    DEFF Research Database (Denmark)

    Afsah, Ebrahim

    In this proposed presentation I intend to give a historical overview of the political and constitutional debates in selected European countries – including Germany, France, Great Britain, Holland and Scandinavia – from the nineteenth century to the present day, paying special attention to the shi....... Similar in nature if not necessarily in intensity to questions of forced and/or underage marriage, male circumcision and female genital mutilation, the commitment of the secular state to animal welfare cannot summarily be rejected by demands for religious freedom....

  3. The EU and Constitutionalism in Egypt

    DEFF Research Database (Denmark)

    Seeberg, Peter

    2013-01-01

    surprising development in the region. This article analyses how strategic relations between the EU and Egypt are being challenged by constitutional changes in Egypt following the political development since early 2011. Initially the article describes European-Egyptian relations prior to the fall of President...... of the unrest in Egypt followed by an analysis of the European-Egyptian relationship over the last two years divided in three parts: Egypt and the ENP-UfM complex, the Muslim Brotherhood and the Egyptian political transformation process seen in a European perspective and finally the migration issue...

  4. What Constitutes 'Failure to Notify' National Measures?

    DEFF Research Database (Denmark)

    Gáspár-Szilágyi, Szilárd

    2013-01-01

    “The inclusion of article 260(3) TFEU adopted as part of the Lisbon Treaty changed the landscape of infringement proceedings. The provision grants the Commission the power to propose monetary sanctions already during the initial Court litigation against a Member State that ‘failed to notify...... and is prone to lead to judicial uncertainty. It further increases the already heavily criticized Commission discretion. Furthermore, the lack of proper guidelines of what constitutes ‘failure to notify’ can lead to the arbitrary launching of non-communication proceedings as well as further complicate...

  5. Engineering and the constitution. Technik und Verfassung

    Energy Technology Data Exchange (ETDEWEB)

    Herzog, R.

    1988-01-01

    We can see at every turn how instruments once used for the good of mankind become blunt right before our very eyes. They still serve their purpose, but each further step brings about less additional benefit ('residual benefit'). This is a fundamental problem rather than a detail problem, as it is the self-concept, reliability and stability of our public order that is at risk. 'Constitution' in this sense is more than just the legal basis of the state; as used by the author it refers to the laws governing a society's life. (orig./HSCH).

  6. Programmed cell death-10 enhances proliferation and protects malignant T cells from apoptosis

    DEFF Research Database (Denmark)

    Lauenborg, Britt; Kopp, Katharina; Krejsgaard, Thorbjørn

    2010-01-01

    The programmed cell death-10 (PDCD10; also known as cerebral cavernous malformation-3 or CCM3) gene encodes an evolutionarily conserved protein associated with cell apoptosis. Mutations in PDCD10 result in cerebral cavernous malformations, an important cause of cerebral hemorrhage. PDCD10...... of cutaneous T-cell lymphoma (Sezary syndrome) patients. PDCD10 is associated with protein phosphatase-2A, a regulator of mitogenesis and apoptosis in malignant T cells. Inhibition of oncogenic signal pathways [Jak3, Notch1, and nuclear factor-¿B (NF-¿B)] partly inhibits the constitutive PDCD10 expression......, whereas an activator of Jak3 and NF-¿B, interleukin-2 (IL-2), enhances PDCD10 expression. Functional data show that PDCD10 depletion by small interfering RNA induces apoptosis and decreases proliferation of the sensitive cells. To our knowledge, these data provide the first functional link between PDCD10...

  7. The Scottish Constitutional Tradition: A Very British Radicalism?

    Directory of Open Access Journals (Sweden)

    Bulmer W. Elliot

    2015-11-01

    Full Text Available This paper discusses recent developments in Scottish nationalist constitutional thought during the period of 2002 to 2014, showing how the Scottish constitutional conversation has diverged from, but continues to be influenced by, the UK-wide constitutional conversation at Westminster. It presents Scottish nationalist constitutional thought as a ‘very British radicalism’, which is characterised by certain constitutional forms and ideas that are radical in a British context (such as popular sovereignty, proportional representation, a written constitution, and a commitment to covenantal socio-economic and environmental provisions while at the same time retaining a persistent ‘Britishness’ in terms of specific institutional proposals and ambivalence towards the principles of constitutional government. Finally, I will discuss possible designs of a future constitutional settlement in Scotland and the United Kingdom. Notably, I will explore how far the Scottish constitutional tradition might impact on the constitutional shape of the United Kingdom.

  8. Ide Mengakomodasi Constitutional Complain sebagai Kewenangan Baru Mahkamah Konstitusi Indonesia

    OpenAIRE

    Taruna, Bayu Lesmana

    2010-01-01

    Constitutional Courts presence in the Indonesian state administration system in, order to reform state affairs which menutut law enforcement in a fair and democratic about the constitution. In general, society or justitiabellen who feel their human rights have been violated by the law expect to benefit by the existence of the Constitutional Court. Further development of the Constitutional Court has managed to provide protection for the constitutional rights of citizens from any violation of l...

  9. Penile apoptosis in association with p53 under lack of testosterone.

    Science.gov (United States)

    Yamamoto, Hiroto; Sasaki, Shoichi; Tatsura, Hiroyuki; Umemoto, Yukihiro; Kubota, Hiroki; Kamiya, Hiroyuki; Kawai, Tetsuya; Kang, Kiho; Kohri, Kenjiro

    2004-02-01

    It is known that testosterone deficiency induces apoptosis in the prostate and that p53 protein is involved in this apoptosis. Therefore, p53 protein may also be involved in apoptosis induction in a testosterone-deficient state in the penis. In this study, we investigated whether castration and chemical castration induce apoptosis at penile tissue in rats, and whether p53 protein is involved in this apoptosis. Male SD rats aged 8 weeks were divided into four groups: 1) the Control group; 2) the Castration group; 3) the Estrogen group, in which rats received betaestradiol 17-(beta-D-glucuronide) injection of 500 microg/body/day; and 4) the LH-RH group, in which rats received LH-RH analogue (leuprorelin acetate) injection of 2 mg/kg. The rats were sacrificed after treatment on days 1, 3, 5, 14, and 28 by cervical dislocation. Apoptotic cells and p53 protein-positive cells were observed on the 5th day after treatment and thereafter in all castration, estrogen, and LH-RH groups. These findings showed that both castration and chemical castration induced p53 protein in vascular endothelial cells in the corpus cavernosus during the process of losing testosterone. It was also suggested that in such states, apoptosis is induced in vascular endotherial cells in the corpus cavernosus.

  10. The Eurozone Crisis: A Constitutional Analysis

    Directory of Open Access Journals (Sweden)

    Anna Sting

    2015-08-01

    Full Text Available “Every power comes through crisis” has long been a motif of European integration. The financial and sovereign debt crises, which have shaken the European Union (EU in recent years, are at first glance no different. Treaty reforms, intergovernmental treaties such as the Fiscal Compact and the Treaty Establishing a European Stability Mechanism (ESM Treaty have significantly altered the constitutional landscape of the EU and its Member States. The crisis has also inspired many European legal scholars to critically analyse the EU’s system of economic governance, as have other events throughout the history of the European Union, from the Empty Chair Crisis to the referenda in the aftermath of the Treaty of Maastricht and the failure of the Constitution for the European Union. What does seem to be different is the way in which scholars approach the issue of the Eurozone crisis. Instead of a purely legal perspective on economic governance, European legal scholars have realised that in order to understand and analyse the euro crisis, interdisciplinarity is the word of the moment.

  11. National simple: Constitutionality Analysis of Exclusions Sectorial

    Directory of Open Access Journals (Sweden)

    Guilherme Adolfo dos Santos Mendes

    2016-06-01

    Full Text Available The Constitution defines the favored legal treatment for small businesses without making any explicit exception, including and especially for tax obligations. Nevertheless, all the laws, which have introduced tax benefits guided by this higher provision, have discriminated small companies due to the economic sector of activity. Known as “National Simple” and introduced by the Complementary Law No. 123/06, the current legislation did not extend its benefits to small production units of a number of industries, such as the automotive industry, the passenger transport industry, the energy industry and the industry of manufacture of weapons, beverages and tobacco products. By demonstrating the mistakes of the arguments in favor of such exclusions, the article holds up that none of these provisions meets constitutional standards. Furthermore, based on a critical analysis of the Positive Law, it is shown that the hidden desire behind the exclusions was to keep the economic sectors of high profitability under control of big corporations to the detriment of smaller initiatives.

  12. Constitutional moments in governing science and technology.

    Science.gov (United States)

    Jasanoff, Sheila

    2011-12-01

    Scholars in science and technology studies (STS) have recently been called upon to advise governments on the design of procedures for public engagement. Any such instrumental function should be carried out consistently with STS's interpretive and normative obligations as a social science discipline. This article illustrates how such threefold integration can be achieved by reviewing current US participatory politics against a 70-year backdrop of tacit constitutional developments in governing science and technology. Two broad cycles of constitutional adjustment are discerned: the first enlarging the scope of state action as well as public participation, with liberalized rules of access and sympathetic judicial review; the second cutting back on the role of the state, fostering the rise of an academic-industrial complex for technology transfer, and privatizing value debates through increasing delegation to professional ethicists. New rules for public engagement in the United Sates should take account of these historical developments and seek to counteract some of the anti-democratic tendencies observable in recent decades.

  13. Constitutive model for coupled inelasticity and damage

    International Nuclear Information System (INIS)

    Kawai, M.

    1995-01-01

    A constitutive model to describe a coupling between deformation and damage due to creep of polycrystalline metallic materials is developed from phenomenological and continuum mechanics points of view. The constitutive modeling is based on the irreversible thermodynamics for internal state variable theories, where the thermodynamic potentials, i.e., free energy and dissipation energy functions, are defined using hardening and damage variables. The material damage is assumed to be isotropic. We first derive a damage coupled kinematic-hardening model in the invariant form on the basis of the Malinin-Khadjinsky model. Then, an isotropic-hardening model which includes a coupling with damage is formulated by assuming a particular representation of the kinematic hardening variable. The evolution equation of the hardening variable is prescribed by the Bailey-Orowan format which includes the effect of damage. The damage rate is governed by the magnitude of the assumed strain hardening variable. These models can describe a transition from primary to tertiary creep stages, and it is applicable to variable loading conditions. In a particular case the expression for the creep rupture time has a similar form to the Kachanov-Rabotnov type, although it depends on the time and damage at the instant of a hardening saturation under the applied stress condition. (author)

  14. Preliminary Test for Constitutive Models of CAP

    International Nuclear Information System (INIS)

    Choo, Yeon Joon; Hong, Soon Joon; Hwang, Su Hyun; Lee, Keo Hyung; Kim, Min Ki; Lee, Byung Chul; Ha, Sang Jun; Choi, Hoon

    2010-01-01

    The development project for the domestic design code was launched to be used for the safety and performance analysis of pressurized light water reactors. As a part of this project, CAP (Containment Analysis Package) code has been developing for the containment safety and performance analysis side by side with SPACE. The CAP code treats three fields (vapor, continuous liquid and dispersed drop) for the assessment of containment specific phenomena, and is featured by assessment capabilities in multi-dimensional and lumped parameter thermal hydraulic cell. Thermal hydraulics solver was developed and has a significant progress now. Implementation of the well proven constitutive models and correlations are essential in other for a containment code to be used with the generalized or optimized purposes. Generally, constitutive equations are composed of interfacial and wall transport models and correlations. These equations are included in the source terms of the governing field equations. In order to develop the best model and correlation package of the CAP code, various models currently used in major containment analysis codes, such as GOTHIC, CONTAIN2.0 and CONTEMPT-LT are reviewed. Several models and correlations were incorporated for the preliminary test of CAP's performance and test results and future plans to improve the level of execution besides will be discussed in this paper

  15. Preliminary Test for Constitutive Models of CAP

    Energy Technology Data Exchange (ETDEWEB)

    Choo, Yeon Joon; Hong, Soon Joon; Hwang, Su Hyun; Lee, Keo Hyung; Kim, Min Ki; Lee, Byung Chul [FNC Tech., Seoul (Korea, Republic of); Ha, Sang Jun; Choi, Hoon [Korea Electric Power Research Institute, Daejeon (Korea, Republic of)

    2010-05-15

    The development project for the domestic design code was launched to be used for the safety and performance analysis of pressurized light water reactors. As a part of this project, CAP (Containment Analysis Package) code has been developing for the containment safety and performance analysis side by side with SPACE. The CAP code treats three fields (vapor, continuous liquid and dispersed drop) for the assessment of containment specific phenomena, and is featured by assessment capabilities in multi-dimensional and lumped parameter thermal hydraulic cell. Thermal hydraulics solver was developed and has a significant progress now. Implementation of the well proven constitutive models and correlations are essential in other for a containment code to be used with the generalized or optimized purposes. Generally, constitutive equations are composed of interfacial and wall transport models and correlations. These equations are included in the source terms of the governing field equations. In order to develop the best model and correlation package of the CAP code, various models currently used in major containment analysis codes, such as GOTHIC, CONTAIN2.0 and CONTEMPT-LT are reviewed. Several models and correlations were incorporated for the preliminary test of CAP's performance and test results and future plans to improve the level of execution besides will be discussed in this paper

  16. Micromechanics of Composite Materials Governed by Vector Constitutive Laws

    Science.gov (United States)

    Bednarcyk, Brett A.; Aboudi, Jacob; Arnold, Steven M.

    2017-01-01

    The high-fidelity generalized method of cells micromechanics theory has been extended for the prediction of the effective property tensor and the corresponding local field distributions for composites whose constituents are governed by vector constitutive laws. As shown, the shear analogy, which can predict effective transverse properties, is not valid in the general three-dimensional case. Consequently, a general derivation is presented that is applicable to both continuously and discontinuously reinforced composites with arbitrary vector constitutive laws and periodic microstructures. Results are given for thermal and electric problems, effective properties and local field distributions, ordered and random microstructures, as well as complex geometries including woven composites. Comparisons of the theory's predictions are made to test data, numerical analysis, and classical expressions from the literature. Further, classical methods cannot provide the local field distributions in the composite, and it is demonstrated that, as the percolation threshold is approached, their predictions are increasingly unreliable. XXXX It has been observed that the bonding between the fibers and matrix in composite materials can be imperfect. In the context of thermal conductivity, such imperfect interfaces have been investigated in micromechanical models by Dunn and Taya (1993), Duan and Karihaloo (2007), Nan et al. (1997) and Hashin (2001). The present HFGMC micromechanical method, derived for perfectly bonded composite materials governed by vector constitutive laws, can be easily generalized to include the effects of weak bonding between the constituents. Such generalizations, in the context of the mechanical micromechanics problem, involve introduction of a traction-separation law at the fiber/matrix interface and have been presented by Aboudi (1987), Bednarcyk and Arnold (2002), Bednarcyk et al. (2004) and Aboudi et al. (2013) and will be addressed in the future.

  17. Spred2 is involved in imatinib-induced cytotoxicity in chronic myeloid leukemia cells

    International Nuclear Information System (INIS)

    Liu, Xiao-Yun; Yang, Yue-Feng; Wu, Chu-Tse; Xiao, Feng-Jun; Zhang, Qun-Wei; Ma, Xiao-Ni; Li, Qing-Fang; Yan, Jun; Wang, Hua; Wang, Li-Sheng

    2010-01-01

    Spreds, a recently established class of negative regulators of the Ras-ERK (extracellular signal-regulated kinase) pathway, are involved in hematogenesises, allergic disorders and tumourigenesis. However, their role in hematologic neoplasms is largely unknown. Possible effects of Spreds on other signal pathways closely related to Ras-ERK have been poorly investigated. In this study, we investigated the in vitro effects of Spred2 on chronic myeloid leukemia (CML) cells. In addition to inhibiting the well-established Ras-ERK cascade, adenovirus-mediated Spred2 over-expression inhibits constitutive and stem cell factor (SCF)-stimulated sphingosine kinase-1 (SPHK1) and Mcl-1 expression, as well as inhibiting proliferation and inducing apoptosis in CML cells. In K562 cells and primary CML cells, imatinib induces endogenous Spred2 expression. Spred2 silencing by stable RNA interference partly protects K562 cells against imatinib-induced apoptosis. Together, these data implicate Spred2 in imatinib-induced cytotoxicity in CML cells, possibly by inhibiting the Ras-ERK cascade and the pro-survival signaling molecules SPHK1 and Mcl-1. These findings reveal potential targets for selective therapy of CML.

  18. Spred2 is involved in imatinib-induced cytotoxicity in chronic myeloid leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xiao-Yun; Yang, Yue-Feng; Wu, Chu-Tse; Xiao, Feng-Jun; Zhang, Qun-Wei [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Ma, Xiao-Ni [Lanzhou University of Technology, Lanzhou 730050 (China); Li, Qing-Fang; Yan, Jun [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Wang, Hua, E-mail: wanghualjh@gmail.com [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Wang, Li-Sheng, E-mail: wangls@nic.bmi.ac.cn [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China)

    2010-03-19

    Spreds, a recently established class of negative regulators of the Ras-ERK (extracellular signal-regulated kinase) pathway, are involved in hematogenesises, allergic disorders and tumourigenesis. However, their role in hematologic neoplasms is largely unknown. Possible effects of Spreds on other signal pathways closely related to Ras-ERK have been poorly investigated. In this study, we investigated the in vitro effects of Spred2 on chronic myeloid leukemia (CML) cells. In addition to inhibiting the well-established Ras-ERK cascade, adenovirus-mediated Spred2 over-expression inhibits constitutive and stem cell factor (SCF)-stimulated sphingosine kinase-1 (SPHK1) and Mcl-1 expression, as well as inhibiting proliferation and inducing apoptosis in CML cells. In K562 cells and primary CML cells, imatinib induces endogenous Spred2 expression. Spred2 silencing by stable RNA interference partly protects K562 cells against imatinib-induced apoptosis. Together, these data implicate Spred2 in imatinib-induced cytotoxicity in CML cells, possibly by inhibiting the Ras-ERK cascade and the pro-survival signaling molecules SPHK1 and Mcl-1. These findings reveal potential targets for selective therapy of CML.

  19. Activator protein 1 promotes gemcitabine-induced apoptosis in pancreatic cancer by upregulating its downstream target Bim.

    Science.gov (United States)

    Ren, Xiaoxia; Zhao, Wenjing; Du, Yongxing; Zhang, Taiping; You, Lei; Zhao, Yupei

    2016-12-01

    Gemcitabine is a commonly used chemotherapy drug in pancreatic cancer. The function of activator protein 1 (AP-1) is cell-specific, and its function depends on the expression of other complex members. In the present study, we added gemcitabine to the media of Panc-1 and SW1990 cells at clinically achieved concentrations (10 µM). Compared with constitutive c-Fos expression, c-Jun expression increased in a dose-dependent manner upon gemcitabine treatment. c-Jun overexpression increased gemcitabine-induced apoptosis through Bim activation, while cell apoptosis and Bim expression decreased following c-Jun knockdown. Furthermore, gemcitabine-induced apoptosis and Bim levels decreased when c-Jun phosphorylation was blocked by SP600125. Our findings suggest that c-Jun, which is a member of the AP-1 complex, functions in gemcitabine-induced apoptosis by regulating its downstream target Bim in pancreatic cancer cells.

  20. Creep mechanisms and constitutive relations in pure metals

    International Nuclear Information System (INIS)

    Nix, W.D.

    1979-01-01

    The mechanisms of creep of pure metals is briefly reviewed and divided into two parts: steady state flow mechanisms, and non-steady state flow mechanisms and constitutive relations. Creep by diffusional flow is now reasonably well understood, with theory and experiment in good agreement. The closely related phenomenon of Harper--Dorn creep can also be understood in terms of diffusion between dislocations. Power law creep involves the climb of edge disloctions controlled by lattice self diffusion. Theoretical treatments of this process invariably give a power law exponent of 3. This natural creep law is compared with the data for FCC and BCC metals. It is suggested that diffusion controlled climb is the controlling process in BCC metals at very high temperatures. Stacking fault energy effects may preclude the possibility that creep is controlled entirely by lattice self diffusion in some FCC metals. The subject of power law breakdown is presented as a natural consequence of the transition to low temperature flow phenomena. The role of core diffusion in this transition is briefly discussed. The mechanisms are presented by which pure metals creep at elevated temperatures. While most of this review deals with the mechanisms of steady state flow, some discussion is devoted to creep flow under non-steady state conditions. This topic is discussed in connection with the development of constitutive equations for describing plastic flow in metals