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Sample records for apoptosis involves constitutive

  1. Propofol Treatment Inhibits Constitutive Apoptosis in Human Primary Neutrophils and Granulocyte-Differentiated Human HL60 Cells.

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    Chung-Hsi Hsing

    Full Text Available Apoptosis regulation is essential for neutrophil homeostasis. We previously demonstrated that a process involving glycogen synthase kinase (GSK-3β determines neutrophil apoptosis. As for this apoptotic process, an overdose of propofol (2,6-Diisopropylphenol; 25 μg/ml or 140 μM also causes GSK-3β-mediated macrophage apoptosis; however, the early deactivation of GSK-3β with low-dose propofol has been shown. Therefore, we hypothesize that low-dose propofol may induce neutrophil survival via GSK-3β inactivation. Following in vitro culture, the therapeutic concentration of propofol (10 μg/ml or 56 μM treatment decreased constitutive apoptosis in isolated human primary neutrophils and in granulocyte-differentiated HL60 cells after all-trans retinoic acid (1 μM treatment. The inactivation of phosphatidylinositol 3-kinase (PI3-kinase/AKT and the activation of GSK-3β results in myeloid cell leukemia 1 (Mcl-1 down-regulation, the loss of the mitochondrial transmembrane potential, and caspase-3 activation in these cells, which is accompanied by apoptosis. Notably, propofol treatment attenuates these effects in a PI3-kinase-regulated manner. We found that propofol initiates PI3-kinase/AKT-mediated GSK-3β inactivation and Mcl-1 stabilization, rescuing the constitutive apoptosis in primary neutrophils and granulocyte-differentiated acute promyelocytic leukemia HL60 cells.

  2. c-Jun N-terminal kinase mediates constitutive human eosinophil apoptosis

    OpenAIRE

    Hasala, Hannele; Zhang, Xianzhi; Saarelainen, Seppo; Moilanen, Eeva; Kankaanranta, Hannu

    2007-01-01

    c-Jun N-terminal kinase mediates constitutive human eosinophil apoptosis correspondence: Corresponding author. Tel.: +358335517318; fax: +358335518082. (Kankaanranta, Hannu) (Kankaanranta, Hannu) The Immunopharmacology Research Group--> , Medical School--> , University of Tampere--> , Tampere--> - FINLAND (Hasala, Hannele) The Immunopharmacology Research Group--> , Medical School--...

  3. Hydra constitutively expresses transcripts involved in vertebrate neural differentiation

    Indian Academy of Sciences (India)

    Sandipan Chatterjee; Shweta Lahudkar; N N Godbole; Surendra Ghaskadbi

    2001-06-01

    The diploblastic Hydra is among the most primitive multicellular organisms. Using cross-hybridization with Xenopus probes, noggin-like transcripts were detected in the hypostome and basal disc of adult Hydra (Pelmatohydra oligactis), regions with properties similar to that of the amphibian organizer. This points to the possibility of a close molecular similarity between the Xenopus and Hydra organizers. The constitutive expression of a noggin-like gene in Hydra may be responsible for its regenerative capacity.

  4. Constitutive NF-κB activity influences basal apoptosis and radiosensitivity of head-and-neck carcinoma cell lines

    International Nuclear Information System (INIS)

    Purpose: Nuclear factor-κB (NF-κB) has been implicated in anti-apoptotic gene transactivation, according to its transcriptional activity. The present study was designed to investigate whether constitutive NF-κB activity could modulate basal apoptosis and intrinsic radiosensitivity of KB head-and-neck carcinoma cell line and KB3 subline. The KB3 subline was more radiosensitive (SF2=0.48, α=0.064) than the radioresistant KB parental cell line (SF2=0.80, α=0.114). Methods and Materials: Constitutive NF-κB DNA-binding activity was determined using electrophoretic mobility shift assay. Modulation of NF-κB activity was performed by exposing both cell lines to tumor necrosis factor α or dexamethasone. Apoptotic cell population was analyzed using flow cytometry (annexin V/propidium iodide). Radiosensitivity was assessed from determination of the surviving fraction at 2 Gy (SF2), and α and β parameters were determined using the linear-quadratic model. Results: Constitutive NF-κB activity was found to be significantly lower in KB3 than in KB. KB cell line exposure to dexamethasone significantly decreased NF-κB DNA-binding activity and, consequently, enhanced baseline apoptosis and radiosensitivity (α values: 0.114 vs. 0.052). Conversely, exposure of KB3 cells to tumor necrosis factor α increased NF-κB DNA-binding activity and resulted in a significant decrease (50%) in rate of apoptosis and in radiosensitivity (SF2 values: 0.48 vs. 0.63). Conclusions: Modulation of NF-κB DNA-binding activity influences baseline apoptosis and intrinsic radiosensitivity

  5. Involvement of FKHR-Dependent TRADD Expression in Chemotherapeutic Drug-Induced Apoptosis

    OpenAIRE

    Rokudai, Susumu; Fujita, Naoya; Kitahara, Osamu; NAKAMURA, Yusuke; Tsuruo, Takashi

    2002-01-01

    Chemotherapeutic drugs exhibit their cytotoxic effect by inducing apoptosis in tumor cells. Because the serine/threonine kinase Akt is involved in apoptosis suppression, we investigated the relationship between Akt activity and drug sensitivity. We discovered that certain chemotherapeutic drugs induced apoptosis with caspase activation only when Akt was inactivated after drug treatment, while inactivation of Akt was not observed when tumor cells showed resistance to the drug-induced caspase a...

  6. 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.

  7. Involvement of FAN in TNF-induced apoptosis

    OpenAIRE

    Ségui, Bruno; Cuvillier, Olivier; Adam-Klages, Sabine; Garcia, Virginie; Malagarie-Cazenave, Sophie; Lévêque, Sophie; Caspar-Bauguil, Sylvie; Coudert, Jérôme,; Salvayre, Robert; Krönke, Martin; Levade, Thierry

    2001-01-01

    TNF-α is a pleiotropic cytokine activating several signaling pathways initiated at distinct intracellular domains of the TNF receptors. Although the C-terminal region is believed to be responsible for apoptosis induction, the functions of more membrane-proximal domains, including the domain that couples to neutral sphingomyelinase activation, are not yet fully elucidated. The roles of this region and of the associated adapter protein FAN (factor associated with neutral SMase activation) in th...

  8. Involvement of FAN in TNF-induced apoptosis.

    Science.gov (United States)

    Ségui, B; Cuvillier, O; Adam-Klages, S; Garcia, V; Malagarie-Cazenave, S; Lévêque, S; Caspar-Bauguil, S; Coudert, J; Salvayre, R; Krönke, M; Levade, T

    2001-07-01

    TNF-alpha is a pleiotropic cytokine activating several signaling pathways initiated at distinct intracellular domains of the TNF receptors. Although the C-terminal region is believed to be responsible for apoptosis induction, the functions of more membrane-proximal domains, including the domain that couples to neutral sphingomyelinase activation, are not yet fully elucidated. The roles of this region and of the associated adapter protein FAN (factor associated with neutral SMase activation) in the cytotoxic response to TNF have been investigated. We have now shown that stable expression in human fibroblasts of a dominant negative form of FAN abrogates TNF-induced ceramide generation from sphingomyelin hydrolysis and reduces caspase processing, thus markedly inhibiting TNF-triggered apoptosis. However, the cytotoxic responses to daunorubicin and exogenous ceramide remain unaltered, as do the TNF-induced p42/p44 MAPK activation and CD54 expression. Fibroblasts from FAN-knockout mice also proved to be resistant to TNF toxicity. These findings highlight the previously unrecognized role of the adapter protein FAN in signaling cell death induction by TNF. PMID:11435466

  9. Mitochondria-involved apoptosis induced by MPPa mediated photodynamic therapy

    International Nuclear Information System (INIS)

    Numerous new photosensitizers are now in various stages of trials demonstrating the broad applicability of Photodynamic therapy (PDT). However, only a handful of photosensitizers have received regulatory approval. Lack of effective photosensitizers has become a major limit for extensive application of PDT. Our previous study showed MPPa to be a good photosensitizer candidature, MPPa-PDT can lead PC-3M cell line to death mainly via apoptotic way both in vitro and in vivo, and part of the mechanism was investigated. Mitochondria may play a key role in the process, in order to further elucidate the mechanism, we investigated the level of ROS, GSH, NO, Ca2+, mitochondrial membrane potential, as well as cytochrome C. All in all, ROS production, depletion of GSH, and the activation of ROS downstream, such as mitochondria depolarization, cytochrome C release, were detected in our study. The results provide a mechanism by which oxidative stress provokes apoptosis of PC-3M cells

  10. Computer simulation of the mathematical modeling involved in constitutive equation development: Via symbolic computations

    Science.gov (United States)

    Arnold, S. M.; Tan, H. Q.; Dong, X.

    1989-01-01

    Development of new material models for describing the high temperature constitutive behavior of real materials represents an important area of research in engineering disciplines. Derivation of mathematical expressions (constitutive equations) which describe this high temperature material behavior can be quite time consuming, involved and error prone; thus intelligent application of symbolic systems to facilitate this tedious process can be of significant benefit. A computerized procedure (SDICE) capable of efficiently deriving potential based constitutive models, in analytical form is presented. This package, running under MACSYMA, has the following features: partial differentiation, tensor computations, automatic grouping and labeling of common factors, expression substitution and simplification, back substitution of invariant and tensorial relations and a relational data base. Also limited aspects of invariant theory were incorporated into SDICE due to the utilization of potentials as a starting point and the desire for these potentials to be frame invariant (objective). Finally not only calculation of flow and/or evolutionary laws were accomplished but also the determination of history independent nonphysical coefficients in terms of physically measurable parameters, e.g., Young's modulus, was achieved. The uniqueness of SDICE resides in its ability to manipulate expressions in a general yet predefined order and simplify expressions so as to limit expression growth. Results are displayed when applicable utilizing index notation.

  11. MEK inhibition induces apoptosis in osteosarcoma cells with constitutive ERK1/2 phosphorylation.

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    Baranski, Zuzanna; Booij, Tijmen H; Kuijjer, Marieke L; de Jong, Yvonne; Cleton-Jansen, Anne-Marie; Price, Leo S; van de Water, Bob; Bovée, Judith V M G; Hogendoorn, Pancras C W; Danen, Erik H J

    2015-11-01

    Conventional high-grade osteosarcoma is the most common primary bone cancer with relatively high incidence in young people. Recurrent and metastatic tumors are difficult to treat. We performed a kinase inhibitor screen in two osteosarcoma cell lines, which identified MEK1/2 inhibitors. These inhibitors were further validated in a panel of six osteosarcoma cell lines. Western blot analysis was performed to assess ERK activity and efficacy of MEK inhibition. A 3D culture system was used to validate results from 2D monolayer cultures. Gene expression analysis was performed to identify differentially expressed gene signatures in sensitive and resistant cell lines. Activation of the AKT signaling network was explored using Western blot and pharmacological inhibition. In the screen, Trametinib, AZD8330 and TAK-733 decreased cell viability by more than 50%. Validation in six osteosarcoma cell lines identified three cell lines as resistant and three as sensitive to the inhibitors. Western blot analysis of ERK activity revealed that sensitive lines had high constitutive ERK activity. Treatment with the three MEK inhibitors in a 3D culture system validated efficacy in inhibition of osteosarcoma viability. MEK1/2 inhibition represents a candidate treatment strategy for osteosarcomas displaying high MEK activity as determined by ERK phosphorylation status. PMID:26807203

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

    International Nuclear Information System (INIS)

    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

  13. Ginkgetin Blocks Constitutive STAT3 Activation and Induces Apoptosis through Induction of SHP-1 and PTEN Tyrosine Phosphatases.

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    Baek, Seung Ho; Lee, Jae Hwi; Ko, Jeong-Hyeon; Lee, Hanwool; Nam, Dongwoo; Lee, Seok Geun; Yang, Woong Mo; Um, Jae-Young; Lee, Junhee; Kim, Sung-Hoon; Shim, Bum Sang; Ahn, Kwang Seok

    2016-04-01

    Ginkgetin, a biflavone from Ginkgo biloba leaves, is known to exhibit antiinflammatory, antifungal, neuroprotective, and antitumor activities, but its precise mechanism of action has not been fully elucidated. Because the aberrant activation of STAT3 has been linked with regulation of inflammation, proliferation, invasion, and metastasis of tumors, we hypothesized that ginkgetin modulates the activation of STAT3 in tumor cells. We found that ginkgetin clearly suppressed constitutive phosphorylation of STAT3 through inhibition of the activation of upstream JAK1 and c-Src kinases and nuclear translocation of STAT3 on both A549 and FaDu cells. Treatment with sodium pervanadate reversed the ginkgetin-induced down-modulation of STAT3, thereby indicating a critical role for a PTP. We also found that ginkgetin strongly induced the expression of the SHP-1 and PTEN proteins and its mRNAs. Further, deletion of SHP-1 and PTEN genes by siRNA suppressed the induction of SHP-1 and PTEN, and reversed the inhibition of STAT3 activation. Ginkgetin induced apoptosis as characterized by an increased accumulation of cells in subG1 phase, positive Annexin V binding, loss of mitochondrial membrane potential, down-regulation of STAT3-regulated gene products, and cleavage of PARP. Overall, ginkgetin abrogates STAT3 signaling pathway through induction of SHP-1 and PTEN proteins, thus attenuating STAT3 phosphorylation and tumorigenesis. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27059688

  14. Involvement of Endoplasmic Reticulum Stress in Capsaicin-Induced Apoptosis of Human Pancreatic Cancer Cells

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    Shengzhang Lin

    2013-01-01

    Full Text Available Capsaicin, main pungent ingredient of hot chilli peppers, has been shown to have anticarcinogenic effect on various cancer cells through multiple mechanisms. In this study, we investigated the apoptotic effect of capsaicin on human pancreatic cancer cells in both in vitro and in vivo systems, as well as the possible mechanisms involved. In vitro, treatment of both the pancreatic cancer cells (PANC-1 and SW1990 with capsaicin resulted in cells growth inhibition, G0/G1 phase arrest, and apoptosis in a dose-dependent manner. Knockdown of growth arrest- and DNA damage-inducible gene 153 (GADD153, a marker of the endoplasmic-reticulum-stress- (ERS- mediated apoptosis pathway, by specific siRNA attenuated capsaicin-induced apoptosis both in PANC-1 and SW1990 cells. Moreover, in vivo studies capsaicin effectively inhibited the growth and metabolism of pancreatic cancer and prolonged the survival time of pancreatic cancer xenograft tumor-induced mice. Furthermore, capsaicin increased the expression of some key ERS markers, including glucose-regulated protein 78 (GRP78, phosphoprotein kinase-like endoplasmic reticulum kinase (phosphoPERK, and phosphoeukaryotic initiation factor-2α (phospho-eIF2α, activating transcription factor 4 (ATF4 and GADD153 in tumor tissues. In conclusion, we for the first time provide important evidence to support the involvement of ERS in the induction of apoptosis in pancreatic cancer cells by capsaicin.

  15. Electronegative low density lipoprotein induces renal apoptosis and fibrosis: STRA6 signaling involved.

    Science.gov (United States)

    Chen, Chao-Hung; Ke, Liang-Yin; Chan, Hua-Chen; Lee, An-Sheng; Lin, Kun-Der; Chu, Chih-Sheng; Lee, Mei-Yueh; Hsiao, Pi-Jung; Hsu, Chin; Chen, Chu-Huang; Shin, Shyi-Jang

    2016-08-01

    Dyslipidemia has been proven to capably develop and aggravate chronic kidney disease. We also report that electronegative LDL (L5) is the most atherogenic LDL. On the other hand, retinoic acid (RA) and RA receptor (RAR) agonist are reported to be beneficial in some kidney diseases. "Stimulated by retinoic acid 6" (STRA6), one retinol-binding protein 4 receptor, was recently identified to regulate retinoid homeostasis. Here, we observed that L5 suppressed STRA6 cascades [STRA6, cellular retinol-binding protein 1 (CRBP1), RARs, retinoid X receptor α, and retinol, RA], but L5 simultaneously induced apoptosis and fibrosis (TGFβ1, Smad2, collagen 1, hydroxyproline, and trichrome) in kidneys of L5-injected mice and L5-treated renal tubular cells. These L5-induced changes of STRA6 cascades, renal apoptosis, and fibrosis were reversed in kidneys of LOX1(-/-) mice. LOX1 RNA silencing and inhibitor of c-Jun N-terminal kinase and p38MAPK rescued the suppression of STRA6 cascades and apoptosis and fibrosis in L5-treated renal tubular cells. Furthermore, crbp1 gene transfection reversed downregulation of STRA6 cascades, apoptosis, and fibrosis in L5-treated renal tubular cells. For mimicking STRA6 deficiency, efficient silencing of STRA6 RNA was performed and was found to repress STRA6 cascades and caused apoptosis and fibrosis in L1-treated renal tubular cells. In summary, this study reveals that electronegative L5 can cause kidney apoptosis and fibrosis via the suppression of STRA6 cascades, and implicates that STRA6 signaling may be involved in dyslipidemia-mediated kidney disease. PMID:27256691

  16. A MODIFIED THERMAL VISCOPLASTIC CONSTITUTIVE LAW INVOLVING THE EFFECT OF TEMPERATURE RISE RATE

    Institute of Scientific and Technical Information of China (English)

    Huang Chenguang; Duan Zhuping

    2000-01-01

    At high temperature rise rate, the mechanical properties of 10 # steel were determined ex perimentally in a very wide range of temperature and strain rates. A new constitutive relationship was put for ward, which can fit with the experimental results and describe various phenomena observed in our experim ents. Meanwhile, some interesting characteristics about the temperature rise rate, strain and strain rate hard ening and thermal softening are also shown in this paper. Finally, the reliability of the constitutive law and the correctness of the constitutive parameters were verified by comparing the calculation results with the ex perimental data.

  17. Apoptosis Induced by Zinc Deficiency in Rat Osteoblast: Possible Involvement of Protein Kinase C

    Institute of Scientific and Technical Information of China (English)

    CEN XIAO-BO; WANG RUI-SHU; AND WANG HANG

    1999-01-01

    Rat osteoblasts were isolated from the 21-day fetal rat calvarias. The cells were grown in DMEM plus 10% FBS, and were treated for 24 h. With 10 μmol/L TPEN or 10 μmol/L TPEN supplemented with 10 μmol/L Zn2+ . Apoptosis of osteoblasts were measured by flow cytometry, electron microscopy and DNA fragmentation analyzed by gel electrophoresis. In addition, IP3 production and PKC activity were measured in order to show whether they are involved in apoptosis in osteoblast induced by zinc deficiency. The results showed that 10 μmol/L TPEN could induce apoptosis in osteoblast in 24 h. But cells treated with 10 μmol/L TPEN supplemented with 10 μmol/L Zn2+showed no apoptotic changes in 24 h. TPEN significantly reduced the formation of IP3 and PKC activity after 24 h incubation. No differences were observed between the cells treated with TPEN supplemented with Zn2 + simultaneously and the untreated cells. It can be inferred that apoptosis induced by zinc deficiency may be due to the decreased activity of PKC which is impaired by reduced formation of IP3.

  18. BimL involvement in Bax activation during UV irradiation-induced apoptosis

    International Nuclear Information System (INIS)

    Bax, a proapoptotic member of the Bcl-2 family, localizes largely in the cytoplasm but translocates to mitochondria and undergoes oligomerization to induce the release of apoptogenic factors in response to apoptotic stimuli. However, the molecular mechanism of Bax activation is not fully understood. We show here the role of BimL in Bax activation during UV irradiation-induced apoptosis. In this study, GFP-BimL plasmid was constructed. The dynamic interaction between BimL and Bax during UV irradiation-induced apoptosis was observed using fluorescence resonance energy transfer (FRET) technique. Our experimental results showed that BimL translocation to mitochondria occurred before Bax translocation, and that BimL activated Bax indirectly. Moreover, inhibition of c-Jun N-terminal protein kinase (JNK) activation blocked BimL translocation, delayed and attenuated Bax translocation and subsequent apoptosis. These results demonstrate that BimL is involved in UV irradiation-induced apoptosis by indirectly activating Bax

  19. Grape seed extract inhibits EGF-induced and constitutively active mitogenic signaling but activates JNK in human prostate carcinoma DU145 cells: possible role in antiproliferation and apoptosis.

    Science.gov (United States)

    Tyagi, Alpana; Agarwal, Rajesh; Agarwal, Chapla

    2003-03-01

    apoptosis independent of its affect on an increase in phospho-ERK1/2, we hypothesized that apoptotic effect of GSE could be by other mechanism(s) including its effect on stress-associated MAPK, the JNK. Indeed, GSE-treated cells showed a strong and sustained increase in phospho-JNK1/JNK2 levels, JNK activity and phospho-cJun levels. An inhibition of GSE-induced JNK activation by a novel JNK inhibitor SP600125 resulted in a significant reversal of GSE-induced apoptotic death suggesting the involvement of JNK activation by GSE in its apoptosis response. Together, these results suggest that anticancer effects of GSE in PCA be mediated via impairment of EGFR-ERK1/2-Elk1-AP1-mediated mitogenic signaling and activation of JNK causing growth inhibition and apoptosis, respectively. PMID:12618755

  20. 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 BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS: 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.

  1. NIK is involved in constitutive activation of the alternative NF-κB pathway and proliferation of pancreatic cancer cells

    International Nuclear Information System (INIS)

    Pancreatic cancer has one of the poorest prognoses among human neoplasms. Constitutive activation of NF-κB is frequently observed in pancreatic cancer cells and is involved in their malignancy. However, little is known about the molecular mechanism of this constitutive NF-κB activation. Here, we show that the alternative pathway is constitutively activated and NF-κB-inducing kinase (NIK), a mediator of the alternative pathway, is significantly expressed in pancreatic cancer cells. siRNA-mediated silencing of NIK expression followed by subcellular fractionation revealed that NIK is constitutively involved in the processing of p100 and nuclear transport of p52 and RelB in pancreatic cancer cells. In addition, NIK silencing significantly suppressed proliferation of pancreatic cancer cells. These results clearly indicate that NIK is involved in the constitutive activation of the alternative pathway and controls cell proliferation in pancreatic cancer cells. Therefore, NIK might be a novel target for the treatment of pancreatic cancer.

  2. Exosomes Secreted by Apoptosis-Resistant Acute Myeloid Leukemia (AML) Blasts Harbor Regulatory Network Proteins Potentially Involved in Antagonism of Apoptosis.

    Science.gov (United States)

    Wojtuszkiewicz, Anna; Schuurhuis, Gerrit J; Kessler, Floortje L; Piersma, Sander R; Knol, Jaco C; Pham, Thang V; Jansen, Gerrit; Musters, René J P; van Meerloo, Johan; Assaraf, Yehuda G; Kaspers, Gertjan J L; Zweegman, Sonja; Cloos, Jacqueline; Jimenez, Connie R

    2016-04-01

    Expression of apoptosis-regulating proteins (B-cell CLL/lymphoma 2 - BCL-2, Myeloid Cell Leukemia 1 - MCL-1, BCL-2 like 1 - BCL-X and BCL-2-associated X protein - BAX) in acute myeloid leukemia (AML) blasts at diagnosis is associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. Herein, we further explored this aspect of dynamic apoptosis regulation in AML. First, we showed that the intraindividualex vivoapoptosis-related profiles of normal lymphocytes and AML blasts within the bone marrow of AML patients were highly correlated. The expression values of apoptosis-regulating proteins were far beyond healthy control lymphocytes, which implicates the influence of microenvironmental factors. Second, we demonstrated that apoptosis-resistant primary AML blasts, as opposed to apoptosis-sensitive cells, were able to up-regulate BCL-2 expression in sensitive AML blasts in contact cultures (p= 0.0067 andp= 1.0, respectively). Using secretome proteomics, we identified novel proteins possibly engaged in apoptosis regulation. Intriguingly, this analysis revealed that major functional protein clusters engaged in global gene regulation, including mRNA splicing, protein translation, and chromatin remodeling, were more abundant (p= 4.01E-06) in secretomes of apoptosis-resistant AML. These findings were confirmed by subsequent extracellular vesicle proteomics. Finally, confocal-microscopy-based colocalization studies show that splicing factors-containing vesicles secreted by high AAI cells are taken up by low AAI cells. The current results constitute the first comprehensive analysis of proteins released by apoptosis-resistant and sensitive primary AML cells. Together, the data point to vesicle-mediated release of global gene regulatory protein clusters as a plausible novel mechanism of induction of apoptosis resistance. Deciphering the modes of communication

  3. Azadirachtin-induced apoptosis involves lysosomal membrane permeabilization and cathepsin L release in Spodoptera frugiperda Sf9 cells.

    Science.gov (United States)

    Wang, Zheng; Cheng, Xingan; Meng, Qianqian; Wang, Peidan; Shu, Benshui; Hu, Qiongbo; Hu, Meiying; Zhong, Guohua

    2015-07-01

    Azadirachtin as a kind of botanical insecticide has been widely used in pest control. We previously reported that azadirachtin could induce apoptosis of Spodoptera litura cultured cell line Sl-1, which involves in the up-regulation of P53 protein. However, the detailed mechanism of azadirachtin-induced apoptosis is not clearly understood in insect cultured cells. The aim of the present study was to address the involvement of lysosome and lysosomal protease in azadirachtin-induced apoptosis in Sf9 cells. The result confirmed that azadirachtin indeed inhibited proliferation and induced apoptosis. The lysosomes were divided into different types as time-dependent manner, which suggested that changes of lysosomes were necessarily physiological processes in azadirachtin-induced apoptosis in Sf9 cells. Interestingly, we noticed that azadirachtin could trigger lysosomal membrane permeabilization and cathepsin L releasing to cytosol. Z-FF-FMK (a cathepsin L inhibitor), but not CA-074me (a cathepsin B inhibitor), could effectively hinder the apoptosis induced by azadirachtin in Sf9 cells. Meanwhile, the activity of caspase-3 could also be inactivated by the inhibition of cathepsin L enzymatic activity induced by Z-FF-FMK. Taken together, our findings suggest that azadirachtin could induce apoptosis in Sf9 cells in a lysosomal pathway, and cathepsin L plays a pro-apoptosis role in this process through releasing to cytosol and activating caspase-3. PMID:25849458

  4. Involvement of caspase-2 and caspase-9 in endoplasmic reticulum stress-induced apoptosis: A role for the IAPs

    International Nuclear Information System (INIS)

    Dysregulation of apoptosis is involved in a wide spectrum of disease ranging from proliferative to degenerative disorders. An emerging area of study in apoptosis is the critical contribution of the endoplasmic reticulum (ER) in both mitochondrial and ER specific apoptosis pathways. Here we show that brefeldin A and tunicamycin-mediated ER stress lead to caspase-dependent apoptosis involving caspase-2. Confocal microscopy and subcellular fractionation indicate that caspase-2 is localized to the ER, and following ER stress, the processing of caspase-2 and -9 is an early event preceding the activation of caspase-3 and -7 and the cleavage of the caspase substrate poly(ADP-ribose) polymerase (PARP). Inhibition and silencing of either caspase-2 or caspase-9 suppress ER stress-induced apoptosis, as demonstrated by annexin V binding. Similarly, transduction with an adenovirus encoding either Inhibitors of Apoptosis (IAP) protein HIAP1/c-IAP2 or HIAP2/c-IAP1 also suppresses ER stress-induced apoptosis. However, among HIAP1, HIAP2 and XIAP, only HIAP2 binds and inhibits caspase-2. Our results thus indicate a novel mechanism by which HIAP2 can regulate ER-initiated apoptosis by modulating the activity of caspase-2

  5. Possible involvement of IL-18 in SLE-dysregulated apoptosis and cytopenia

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    Mona Hilmy Alrayes* and Mona Mohamed Moursy

    2001-12-01

    Full Text Available Background and objectives: Tissue homeostasis is maintained through a balance between cell proliferation and apoptotic cell death. Dysregulated apoptosis leads to development of autoimmunity like systemic lupus erythematosus (SLE. One of the key biological responses induced by IL-18 is that in combination with IL-12 it stimulates Th1 cell differentiation and involvement in immune responses. Up regulation of Fas ligand in Th1 cells by IL-18 may increase apoptosis of Fas receptor expressing cells that interact with activated Th1 cells. This induction of apoptosis may allow IL-18 to play a role in chronic inflammatory and autoimmune conditions. The aim of this study is to quantify the percentage of apoptotic peripheral blood neutrophils in SLE and to determine the relation with cytopenia. Also the serum level of the proinflammatory cytokine IL-18 is measured in SLE to be correlated with apoptotic neutrophils and other studied parameters. Methods: Neutrophil apoptosis in 30 SLE patients and 15 healthy controls was assessed by flow cytometry using annexin V and 7AAD binding. Serum IL-18 was measured by ELISA and CBC was done by automated cell counter. Results: The percentage of total, early and late apoptotic neutrophils, determined by annexin V and 7AAD binding, was increased in peripheral blood of SLE patients without corticosteroid therapy (group I, n=15 (54.2 ± 16.3 %, 36.35 ± 13.9 % and 17.8 ± 6.4 % respectively and also SLE patients with corticosteroid therapy (group II, n=15 (47.3 ± 28.1 %, 37.1 ± 25.6 % and 10.1 ± 6.6 % respectively compared with normal controls (group III, n=15 (7.24 ± 3.7 %, 2.5 ± 1.5 % and 4.7 ± 2.9 % respectively. SLE neutrophil apoptosis correlated negatively with WBC (p=0.01 in group I. Serum IL-18 was significantly elevated in SLE patients with renal complication within group I when compared with SLE patients without renal complication within the same group (p=0.01 and correlated positively with SLE disease

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

    Science.gov (United States)

    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. PMID:26971278

  7. MicroRNA-122 Down-Regulation Is Involved in Phenobarbital-Mediated Activation of the Constitutive Androstane Receptor

    OpenAIRE

    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 hepati...

  8. Perfluorononanoic acid-induced apoptosis in rat spleen involves oxidative stress and the activation of caspase-independent death pathway

    International Nuclear Information System (INIS)

    Perfluoroalkyl acid (PFAA)-induced apoptosis has been reported in many cell types. However, minimal information on its mode of action is available. This study explored the possible involvement of apoptotic signaling pathways in a nine-carbon-chain length PFAA-perfluorononanoic acid (PFNA)-induced splenocyte apoptosis. After a 14-day exposure to PFNA, rat spleens showed dose-dependent levels of apoptosis. The production of pro-inflammatory and anti-inflammatory cytokines was significantly increased and decreased, respectively. However, protein levels of tumor necrosis factor receptor 1 (TNFR1), fas-associated protein with death domain (FADD), caspase 8 and caspase 3, which are involved in inflammation-related and caspase-dependent apoptosis, were discordant. Peroxisome proliferator-activated receptors alpha (PPARα) and PPARγ genes expression was up-regulated in rats treated with 3 or 5 mg/kg/day of PFNA, and the level of hydrogen peroxide (H2O2) increased concurrently in rats treated with the highest dose. Moreover, superoxide dismutase (SOD) activity and Bcl-2 protein levels were dramatically decreased in spleens after treatment with 3 and 5 mg/kg/day of PFNA. However, protein levels of Bax were unchanged. Apoptosis-inducing factor (AIF), an initiator of caspase-independent apoptosis, was significantly increased in all PFNA-dosed rats. Thus, oxidative stress and the activation of a caspase-independent apoptotic signaling pathway contributed to PFNA-induced apoptosis in rat splenocytes.

  9. NF-kappa B modulation is involved in celastrol induced human multiple myeloma cell apoptosis.

    Directory of Open Access Journals (Sweden)

    Haiwen Ni

    Full Text Available Celastrol is an active compound extracted from the root bark of the traditional Chinese medicine Tripterygium wilfordii Hook F. To investigate the effect of celastrol on human multiple myeloma cell cycle arrest and apoptosis and explore its molecular mechanism of action. The activity of celastrol on LP-1 cell proliferation was detected by WST-8 assay. The celastrol-induced cell cycle arrest was analyzed by flow cytometry after propidium iodide staining. Nuclear translocation of the nuclear factor kappa B (NF-κB was observed by fluorescence microscope. Celastrol inhibited cell proliferation of LP-1 myeloma cell in a dose-dependent manner with IC50 values of 0.8817 µM, which was mediated through G1 cell cycle arrest and p27 induction. Celastrol induced apoptosis in LP-1 and RPMI 8226 myeloma cells in a time and dose dependent manner, and it involved Caspase-3 activation and NF-κB pathway. Celastrol down-modulated antiapoptotic proteins including Bcl-2 and survivin expression. The expression of NF-κB and IKKa were decreased after celastrol treatment. Celastrol effectively blocked the nuclear translocation of the p65 subunit and induced human multiple myeloma cell cycle arrest and apoptosis by p27 upregulation and NF-kB modulation. It has been demonstrated that the effect of celastrol on NF-kB was HO-1-independent by using zinc protoporphyrin-9 (ZnPPIX, a selective heme oxygenase inhibitor. From the results, it could be inferred that celastrol may be used as a NF-kB inhibitor to inhibit myeloma cell proliferation.

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

    International Nuclear Information System (INIS)

    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/TNFR1 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, TNFR1, 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 TNFR1 was suppressed with its siRNA. The protein levels of TNFα, TNFR1 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, TNFR1 and caspase-12 increased after the chondrocytes were exposed to ofloxacin. The downregulated mRNA expressions of TNFR1, Caspase-8 and TRADD, and the decreased apoptosis rates of the ofloxacin-treated chondrocytes occurred after TNFR1–siRNA interference. Conclusions and implications: Ofloxacin-induced chondrocyte apoptosis in a time- and concentration-dependent fashion. TNF/TNFR1 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. • TNF/TNFR1

  11. JNK signaling pathway is involved in piperlongumine-mediated apoptosis in human colorectal cancer HCT116 cells

    OpenAIRE

    Li, Wen; WEN, CHUANGYU; BAI, HAIYAN; Wang, Xiaoyan; Zhang, Xiaoli; HUANG, LANLAN; Yang, Xiangling; Iwamoto, Aikichi; Liu, Huanliang

    2015-01-01

    Piperlongumine (PPLGM), an alkaloid isolated from the long pepper (Piper longum L.), can selectively trigger cancer cell death in colorectal cancer cells. The present study investigated whether the c-Jun NH2-terminal kinase (JNK) signaling pathway is involved in PPLGM-induced apoptosis in the human colorectal cancer HCT116 cell line. The results demonstrated that PPLGM reduced the cell viability and induced cell apoptosis in a time- and concentration-dependent manner, without a significant ef...

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

    OpenAIRE

    Chen Quan; Wang Shengqi; Bai Jinfeng; Quan Lanping; Yang Shangbin; Zhang Wei; Yin Yanbing; Zhu Hongxia; Sun Daochun; Wang Yihua; Huang Moli; Li Songgang; Xu Ningzhi

    2006-01-01

    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 an...

  13. Constitutional Hardball

    OpenAIRE

    Tushnet, Mark V.

    2004-01-01

    This Essay develops the idea that there is a practice called constitutional hardball. The practice has three characteristics: it involves arguments and behavior by political actors (including judges, although their role is less interesting than that of other political actors) that are defensible - though sometimes only barely so - by standard constitutional doctrine; it is inconsistent with settled pre-constitutional understandings; and it involves extremely high stakes (control over the nati...

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

    Science.gov (United States)

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

    2015-12-30

    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. PMID:26223015

  15. Evidence for a direct involvement of hMSH5 in promoting ionizing radiation induced apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Tompkins, Joshua D.; Wu, Xiling; Chu, Yen-Lin [School of Molecular Biosciences and Center for Reproductive Biology, PO Box 644660, Washington State University, Pullman, WA 99164-4660 (United States); Her, Chengtao, E-mail: cher@wsu.edu [School of Molecular Biosciences and Center for Reproductive Biology, PO Box 644660, Washington State University, Pullman, WA 99164-4660 (United States)

    2009-08-15

    Although increasing evidence has suggested that the hMSH5 protein plays an important role in meiotic and mitotic DNA recombinational repair, its precise functions in recombination and DNA damage response are presently elusive. Here we show that the interaction between hMSH5 and c-Abl confers ionizing radiation (IR)-induced apoptotic response by promoting c-Abl activation and p73 accumulation, and these effects are greatly enhanced in cells expressing hMSH5{sup P29S} (i.e. the hMSH5 variant possessing a proline to serine change within the N-terminal (Px){sub 5} dipeptide repeat). Our current study provides the first evidence that the (Px){sub 5} dipeptide repeat plays an important role in modulating the interaction between hMSH5 and c-Abl and alteration of this dipeptide repeat in hMSH5{sup P29S} leads to increased IR sensitivity owing to enhanced caspase-3-mediated apoptosis. In addition, RNAi-mediated hMSH5 silencing leads to the reduction of apoptosis in IR-treated cells. In short, this study implicates a role for hMSH5 in DNA damage response involving c-Abl and p73, and suggests that mutations impairing this process could significantly affect normal cellular responses to anti-cancer treatments.

  16. Endoplasmic Reticulum Stress-Mediated Hippocampal Neuron Apoptosis Involved in Diabetic Cognitive Impairment

    Directory of Open Access Journals (Sweden)

    Xiaoming Zhang

    2013-01-01

    Full Text Available Poor management of DM causes cognitive impairment while the mechanism is still unconfirmed. The aim of the present study was to investigate the activation of C/EBP Homology Protein (CHOP, the prominent mediator of the endoplasmic reticulum (ER stress-induced apoptosis under hyperglycemia. We employed streptozotocin- (STZ- induced diabetic rats to explore the ability of learning and memory by the Morris water maze test. The ultrastructure of hippocampus in diabetic rats and cultured neurons in high glucose medium were observed by transmission electron microscopy and scanning electron microscopy. TUNEL staining was also performed to assess apoptotic cells while the expression of CHOP was assayed by immunohistochemistry and Western blot assay in these hippocampal neurons. Six weeks after diabetes induction, the escape latency increased and the average frequency in finding the platform decreased in diabetic rats (P<0.05. The morphology of neuron and synaptic structure was impaired; the number of TUNEL-positive cells and the expression of CHOP in hippocampus of diabetic rats and high glucose medium cultured neurons were markedly altered (P<0.05. The present results suggested that the CHOP-dependent endoplasmic reticulum (ER stress-mediated apoptosis may be involved in hyperglycemia-induced hippocampal synapses and neurons impairment and promote the diabetic cognitive impairment.

  17. Signaling pathways involved in apoptosis induced by novel angucycline antibiotic landomycin E in Jurkat T leukemia cells

    Directory of Open Access Journals (Sweden)

    Panchuk R. R.

    2011-04-01

    Full Text Available Aim. To study the molecular mechanisms of action of novel anticancer antibiotic landomycin E (LE. Methods. Annexin V/propidium iodide, DAPI (4',6-diamidino-2-phenylindole staining, Western-blot analysis. Results. LE applied in 2 µg/ml dose (IC50, induced reactive oxygen species (ROS-dependent splitting of poly [ADP-ribose] polymerase 1 (PARP-1 and DNA Fragmentation Factor 45 (DFF45 proteins involved in DNA reparation. This effect was observed 6 h after the start of treatment and it positively correlated with phosphatidyl serine externalization (early morphological marker of apoptosis. We suggest that cleavage of PARP-1 and DFF45 was mediated by active caspase-7 which is a key effector caspase in the LE-induced apoptosis in leukemia cells. We found that activation of initiator procaspase-10 (involved in receptor- mediated apoptosis was the earliest detected event in LE-induced apoptotic signaling pathways; however, this activation was shown to be ROS-independent. We also demonstrated that the induction of apoptosis by LE is accompanied by activation of apoptosis-inducing factor (AIF in mitochondria. Conclusions. Our data suggest that LE-induced cascade of apoptotic events is started by the initiator caspase-10 which leads to activation of the effector caspase-7 and AIF that is known to induce caspase-independent apoptosis involving ROS generation.

  18. Involvement of Mouse Constitutive Androstane Receptor in Acifluorfen-Induced Liver Injury and Subsequent Tumor Development.

    Science.gov (United States)

    Kuwata, Kazunori; Inoue, Kaoru; Ichimura, Ryohei; Takahashi, Miwa; Kodama, Yukio; Shibutani, Makoto; Yoshida, Midori

    2016-06-01

    Acifluorfen (ACI), a protoporphyrinogen oxidase (PROTOX) inhibitor herbicide, promotes the accumulation of protoporphyrin IX (PPIX), and induces tumors in the rodent liver. Porphyria is a risk factor for liver tumors in humans; however, the specific mechanisms through which ACI induces hepatocarcinogenesis in rodents are unclear. Here, we investigated the mode of action of ACI-induced hepatocarcinogenesis, focusing on constitutive androstane receptor (CAR, NR1I3), which is essential for the development of rodent liver tumors in response to certain cytochrome P450 (CYP) 2B inducers. Dietary treatment with 2500 ppm ACI for up to 13 weeks increased Cyp2b10 expression in the livers of wild-type (WT) mice, but not in CAR-knockout (CARKO) mice. Microscopically, ACI treatment-induced cytotoxic changes, including hepatocellular necrosis and inflammation, and caused regenerative changes accompanied by prolonged increases in the numbers of proliferating cell nuclear antigen-positive hepatocytes in WT mice. In contrast, these cytotoxic and regenerative changes in hepatocytes were significantly attenuated, but still observed, in CARKO mice. ACI treatment also increased liver PPIX levels similarly in both genotypes; however, no morphological evidence of porphyrin deposition was found in hepatocytes from either genotype. Treatment with 2500 ppm ACI for 26 weeks after initiation with diethylnitrosamine increased the incidence and multiplicities of altered foci and adenomas in hepatocytes from WT mice; these effects were significantly reduced in CARKO mice. These results indicated that prolonged cytotoxicity in the liver was a key factor for ACI-induced hepatocarcinogenesis, and that CAR played an important role in ACI-induced liver injury and tumor development in mice. PMID:26928356

  19. Musashi2 modulates K562 leukemic cell proliferation and apoptosis involving the MAPK pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Huijuan; Tan, Shi; Wang, Juan; Chen, Shana; Quan, Jing; Xian, Jingrong; Zhang, Shuai shuai; He, Jingang; Zhang, Ling, E-mail: lingzhang@cqmu.edu.cn

    2014-01-01

    The RNA-binding protein Musashi2 (Msi2) has been identified as a master regulator within a variety of stem cell populations via the regulation of translational gene expression. A recent study has suggested that Msi2 is strongly expressed in leukemic cells of acute myeloid leukemia patients, and elevated Msi2 is associated with poor prognosis. However, the potential role of Msi2 in leukemogenesis is still not well understood. Here, we investigated the effect of Msi2 knockdown on the biological properties of leukemic cells. High expression of Msi2 was found in K562 and KG-1a leukemic cell lines, and low expression was observed in the U937 cell line. We transduced K562 cells with two independent adenoviral shRNA vectors targeting Msi2 and confirmed knockdown of Msi2 at the mRNA and protein levels. Msi2 silencing inhibited cell growth and caused cell cycle arrest by increasing the expression of p21 and decreasing the expression of cyclin D1 and cdk2. In addition, knockdown of Msi2 promoted cellular apoptosis via the upregulation of Bax and downregulation of Bcl-2 expression. Furthermore, Msi2 knockdown resulted in the inactivation of the ERK/MAPK and p38/MAPK pathways, but no remarkable change in p-AKT was observed. These data provide evidence that Msi2 plays an important role in leukemogenesis involving the MAPK signaling pathway, which indicates that Msi2 may be a novel target for leukemia treatment. - Highlights: • Knockdown of Msi2 inhibited K562 cell growth and arrested cell cycle progression. • Knockdown of Msi2 induced K562 cell apoptosis via the regulation of Bax and Bcl-2. • The MAPK pathway was involved in the process of Msi2-mediated leukemogenesis. • Our data indicate that Msi2 is a potential new target for leukemia treatment.

  20. Possible involvement of DNA methylation in 5-azacytidine-induced neuronal cell apoptosis

    OpenAIRE

    Nakayama, Hiroyuki; Kajikawa, S.; Shinozuka, J.; Su, W. P.; Doi, K

    1999-01-01

    Eight chemicals that are cytidine analogues or nucleosides (5-azacytidine (SAzC), 5-azadeoxycytidine, 6-azacytidine, 5-azacytosin, cytidine, 3-deazaadenine, 3-deazauridine and 6-azauridine) were examined for the ability to induce neuronal apoptosis. 5AzC and 5-azadeoxycytidine induced apoptosis in the brain and spinal cord of the fetuses at 24 hr after the injection to dams, while the other chemicals tested failed to induce apoptosis. In the system of PC12 cell...

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

    International Nuclear Information System (INIS)

    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. 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. 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. 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

  2. Involvement of ASK1 activation in apoptosis induced by NPe6-PDT

    Science.gov (United States)

    Liu, Lei; Zhang, Zhen-zhen; Zhang, Zhigang

    2010-02-01

    Photodynamic therapy (PDT) employing photosensiter N-aspartyl chlorin e6 (NPe6) can induce lysosome disruption and initiate apoptotic pathway. Apoptosis signal-regulating kinase (ASK1) is an important regulator of apoptosis in response to various stresses, such as reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, lipopolysaccharide (LPS) and calcium influx. In this study, we investigated the molecular mechanisms of apoptosis induced by NPe6-PDT in ASTC-a-1 cells. The results showed that the activities of ASK1 increased in response to NPe6-PDT. Over-expression of wild-type or activated mutant of ASK1 could obviously decrease cell viability and increase cell death; while inhibition of ASK1 significantly decreased cell apoptosis. These results suggested that ASK1 plays an important role in apoptosis induced by NPe6-PDT.

  3. Up-regulation of podoplanin involves in neuronal apoptosis in LPS-induced neuroinflammation.

    Science.gov (United States)

    Song, Yan; Shen, Jianhong; Lin, Yuchang; Shen, Jiabing; Wu, Xinming; Yan, Yaohua; Zhou, Li; Zhang, Haiyan; Zhou, Ying; Cao, Maohong; Liu, Yonghua

    2014-08-01

    Podoplanin (PDPN) is a mucin-type transmembrane sialoglycoprotein expressed in multiple tissues in adult animals, including the brain, lungs, kidney, and lymphoid organs. Studies of this molecule have demonstrated its great importance in tumor metastasis, platelet aggregation, and lymphatic vessel formation. However, information regarding its regulation and possible function in the central nervous system is still limited. In this study, we performed a neuroinflammatory model by lipopolysaccharide (LPS) lateral ventral injection in adult rats and detected increased expression of PDPN in the brain cortex. Immunofluorescence indicated that PDPN was located in the neurons, but not astrocytes. Moreover, there was a concomitant up-regulation of active caspase-3, cyclin D1, and CDK4 in vivo and vitro studies. In addition, the expression of these three proteins in cortical primary neurons was decreased after knocking down PDPN by siRNA. Collectively, all these results suggested that the up-regulation of PDPN might be involved in neuronal apoptosis in neuroinflammation after LPS injection. PMID:24821010

  4. Singlet oxygen mediated apoptosis by anthrone involving lysosomes and mitochondria at ambient UV exposure

    International Nuclear Information System (INIS)

    Highlights: ► Photomodification of anthrone at ambient environmental intensities of UV-radiation. ► Phototoxicity of anthrone through type-II photodynamic reaction by generating 1O2. ► Role of DNA damage and lipid peroxidation in anthrone phototoxicity. ► Apototic cell death and involvement of lysosomes and mitochondria. ► Up-regulation of p21 and bax concomitantly down regulation of bcl2 genes expression. -- Abstract: Anthrone a tricyclic aromatic hydrocarbon which is toxic environmental pollutant comes in the environment through photooxidation of anthracene. We have studied the photomodification of anthrone under environmental conditions. Anthrone generates reactive oxygen species (ROS) like 1O2 through Type-II photodynamic reaction. Significant intracellular ROS generation was measured through dichlorohydrofluorescein fluorescence intensity. The generation of 1O2 was further substantiated by using specific quencher like sodium azide. UV induced photodegradation of 2-deoxyguanosine and photoperoxidation of linoleic acid accorded the involvement of 1O2 in the manifestation of anthrone phototoxicity. Phototoxicity of anthrone was done on human keratinocytes (HaCaT) through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and neutral red uptake assays. Anthrone induced cell cycle arrest (G2/M-phase) and DNA damage in a concentration dependent manner. We found apoptosis as a pattern of cell death which was confirmed through sub-G1 fraction, morphological changes, caspase-3 activation, acridine orange/ethidium bromide staining and phosphatidylserine translocation. Mitochondrial depolarization and lysosomal destabilization was parallel to apoptotic process. Our RT-PCR results strongly supports our view point of apoptotic cell death through up-regulation of pro-apoptotic genes p21 and Bax, and down regulation of anti-apoptotic gene Bcl2. Therefore, much attention should be paid to concomitant exposure of anthrone and UV-R for its total

  5. Singlet oxygen mediated apoptosis by anthrone involving lysosomes and mitochondria at ambient UV exposure

    Energy Technology Data Exchange (ETDEWEB)

    Mujtaba, Syed Faiz [Photobiology Division, (CSIR)-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow 226001, Uttar Pradesh (India); College of Pharmacy, Faculty of Pharmaceutical Sciences, Pt. B.D.S University of Health Sciences, Rohtak, Haryana (India); Dwivedi, Ashish; Yadav, Neera [Photobiology Division, (CSIR)-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow 226001, Uttar Pradesh (India); Ray, R.S., 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); Singh, Gajendra [College of Pharmacy, Faculty of Pharmaceutical Sciences, Pt. B.D.S University of Health Sciences, Rohtak, Haryana (India)

    2013-05-15

    Highlights: ► Photomodification of anthrone at ambient environmental intensities of UV-radiation. ► Phototoxicity of anthrone through type-II photodynamic reaction by generating {sup 1}O{sub 2}. ► Role of DNA damage and lipid peroxidation in anthrone phototoxicity. ► Apototic cell death and involvement of lysosomes and mitochondria. ► Up-regulation of p21 and bax concomitantly down regulation of bcl2 genes expression. -- Abstract: Anthrone a tricyclic aromatic hydrocarbon which is toxic environmental pollutant comes in the environment through photooxidation of anthracene. We have studied the photomodification of anthrone under environmental conditions. Anthrone generates reactive oxygen species (ROS) like {sup 1}O{sub 2} through Type-II photodynamic reaction. Significant intracellular ROS generation was measured through dichlorohydrofluorescein fluorescence intensity. The generation of {sup 1}O{sub 2} was further substantiated by using specific quencher like sodium azide. UV induced photodegradation of 2-deoxyguanosine and photoperoxidation of linoleic acid accorded the involvement of {sup 1}O{sub 2} in the manifestation of anthrone phototoxicity. Phototoxicity of anthrone was done on human keratinocytes (HaCaT) through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and neutral red uptake assays. Anthrone induced cell cycle arrest (G2/M-phase) and DNA damage in a concentration dependent manner. We found apoptosis as a pattern of cell death which was confirmed through sub-G1 fraction, morphological changes, caspase-3 activation, acridine orange/ethidium bromide staining and phosphatidylserine translocation. Mitochondrial depolarization and lysosomal destabilization was parallel to apoptotic process. Our RT-PCR results strongly supports our view point of apoptotic cell death through up-regulation of pro-apoptotic genes p21 and Bax, and down regulation of anti-apoptotic gene Bcl{sub 2}. Therefore, much attention should be paid to concomitant

  6. Protein Kinase C-δ mediates down-regulation of heterogeneous nuclear ribonucleoprotein K protein: involvement in apoptosis induction

    International Nuclear Information System (INIS)

    We reported previously that NSC606985, a camptothecin analogue, induces apoptosis of acute myeloid leukemia (AML) cells through proteolytic activation of protein kinase C delta (ΔPKC-δ). By subcellular proteome analysis, heterogeneous nuclear ribonucleoprotein K (hnRNP K) was identified as being significantly down-regulated in NSC606985-treated leukemic NB4 cells. HnRNP K, a docking protein for DNA, RNA, and transcriptional or translational molecules, is implicated in a host of processes involving the regulation of gene expression. However, the molecular mechanisms of hnRNP K reduction and its roles during apoptosis are still not understood. In the present study, we found that, following the appearance of the ΔPKC-δ, hnRNP K protein was significantly down-regulated in NSC606985, doxorubicin, arsenic trioxide and ultraviolet-induced apoptosis. We further provided evidence that ΔPKC-δ mediated the down-regulation of hnRNP K protein during apoptosis: PKC-δ inhibitor could rescue the reduction of hnRNP K; hnRNP K failed to be decreased in PKC-δ-deficient apoptotic KG1a cells; conditional induction of ΔPKC-δ in U937T cells directly down-regulated hnRNP K protein. Moreover, the proteasome inhibitor also inhibited the down-regulation of hnRNP K protein by apoptosis inducer and the conditional expression of ΔPKC-δ. More intriguingly, the suppression of hnRNP K with siRNA transfection significantly induced apoptosis. To our knowledge, this is the first demonstration that proteolytically activated PKC-δ down-regulates hnRNP K protein in a proteasome-dependent manner, which plays an important role in apoptosis induction.

  7. Canine parvovirus NS1 induced apoptosis involves mitochondria, accumulation of reactive oxygen species and activation of caspases.

    Science.gov (United States)

    Gupta, Shishir Kumar; Sahoo, Aditya Prasad; Rosh, Nighil; Gandham, Ravi Kumar; Saxena, Lovleen; Singh, Arvind Kumar; Harish, D R; Tiwari, Ashok Kumar

    2016-02-01

    The non-structural protein (NS1) of parvoviruses plays an important role in viral replication and is thought to be responsible for inducing cell death. However, the detailed mechanism and the pathways involved in canine parvovirus type 2 NS1 (CPV2.NS1) induced apoptosis are not yet known. In the present study, we report that expression of CPV2.NS1 in HeLa cells arrests cells in G1 phase of the cell cycle and the apoptosis is mitochondria mediated as indicated by mitochondrial depolarization, release of cytochrome-c and activation of caspase 9. Treatment of cells with caspase 9 inhibitor Z-LEHD-FMK reduced the induction of apoptosis significantly. We also report that expression of CPV2.NS1 causes accumulation of reactive oxygen species (ROS) and treatment with an antioxidant reduces the ROS levels and the extent of apoptosis. Our results provide an insight into the mechanism of CPV2.NS1 induced apoptosis, which might prove valuable in developing NS1 protein as an oncolytic agent. PMID:26555166

  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. HCA520, A NOVEL TUMOR ASSOCIATED ANTIGEN, INVOLVED IN CELL PROLIFERATION AND APOPTOSIS

    Institute of Scientific and Technical Information of China (English)

    杨美香; 曲迅; 刘福利; 郑广娟

    2003-01-01

    Objective: Tumor associated antigen encoding gene HCA520 (AF146019) was identified by screening a human hepatocellular carcinoma expressing cDNA library using SEREX technique. In this experiment we studied the effect of HCA520 on cell proliferation and apoptosis. Methods: Gene HCA520 was gained by PCR and transfected into 293 cells. The stable expression cells were obtained by G418 selection. The cell proliferation was measured by [3H]-TdR uptake and apoptosis assay was measured by FACS. Results: Eukaryotic expression plasmid pcDNA3-HCA520 was constructed and its stable transfectants were obtained. Overexpression of HCA520 inhibited the cell proliferation and enhanced cell apoptosis after serum deprivation. Conclusion: HCA520 is a novel tumor associated antigen that can affect cell proliferation and apoptosis.

  10. Calcium-Mediated Mitochondrial Permeability Transition Involved in Hydrogen Peroxide-Induced Apoptosis in Tobacco Protoplasts

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In the present study, we focused on whether intracellular free Ca2+ ([Ca2+]i) regulates the formation of mitochondrial permeability transition pore (MPTP) in H2O2-induced apoptosis in tobacco protoplasts. It was shown that the decrease in mitochondrial membrane potential (△Ψm) preceded the appearance of H2O2-induced apoptosis;pretreatment with the specific MPTP inhibitor cyclosporine A, which also inhibits Ca2+ cycling by the mitochondria,effectively retarded apoptosis and the decrease in △Ψm. Apoptosis and decreased △Ψm were exacerbated by CaCl2, whereas the plasma membrane voltage-dependent Ca2+ channel blocker lanthanum chloride (LaCl3)attentuated these responses. Chelation of extracellular Ca2+ with EGTA almost totally inhibited apoptosis and the decrease in △Ψm induced by H2O2. The time-course of changes in [Ca2+]i in apoptosis was detected using the Ca2+ probe Fluo-3 AM. These studies showed that [Ca2+]i was increased at the very early stage of H2O2-induced apoptosis. The EGTA evidently inhibited the increase in [Ca2+]i induced by H2O2, whereas it was only partially inhibited by LaCl3. The results suggest that H2O2 may elevate cytoplasmic free Ca2+ concentrations in tobacco protoplasts, which mainly results from the entry of extracellular Ca2+, to regulate mitochondrial permeability transition. The signaling pathway of [Ca2+]i-mediated mitochondrial permeability transition was associated with H2O2-induced apoptosis in tobacco protoplasts.

  11. 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

    2015-06-01

    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 contribute

  12. Involvement of seven in absentia homolog-1 in ethanol-induced apoptosis in neural crest cells

    Science.gov (United States)

    Sun, Haijing; Chen, Xiaopan; Yuan, Fuqiang; Liu, Jie; Zhao, Yingming; Chen, Shao-yu

    2014-01-01

    Ethanol-induced apoptosis in selected cell populations is a major component of pathogenesis underlying ethanol-induced teratogenesis. However, there is a fundamental gap in understanding how ethanol leads to apoptosis in embryos. In this study, we investigate the role of seven in absentia homolog-1 (Siah1) protein, an E3 ubiquitin ligase, in ethanol-induced apoptosis. Using an in vitro model of neural crest cell (NCC), JoMa1.3 cells, we found that exposure to 100 mM ethanol resulted in a significant increase in Siah1 mRNA expression in NCCs, an ethanol-sensitive cell population implicated in Fetal Alcohol Spectrum Disorders (FASD). Treatment with 100 mM ethanol for 24 hours also significantly increased the protein expression of Siah1 in JoMa1.3 cells. The nuclear translocation and accumulation of Siah1 was evidenced in the cells exposed to ethanol. In addition, we have found that the inhibition of Siah1 function with siRNA prevents ethanol-induced increase in Siah1 protein expression and nuclear translocation in NCCs. Down-regulation of Siah1 by siRNA also greatly diminished ethanol-induced cell death and caspase-3 activation, indicating that inhibition of Siah1 can attenuate ethanol-induced apoptosis. These results strongly suggest that Siah1 plays an important role in ethanol-induced apoptosis in NCCs. PMID:25193017

  13. BRCA1 involved in regulation of Bcl-2 expression and apoptosis susceptibility to ionizing radiation

    Science.gov (United States)

    Wang, YanLing; Wang, Bing; Zhang, Hong; Li, Ning; Tanaka, Kaoru; Zhou, Xin; Chen, RuPing; Zhang, Xin

    2011-05-01

    BRCA1 has been proposed to be tightly linked to the resistance of tumor cells to ionizing radiation. The pathway leading to this phenomenon is not yet clear. In this work, we investigated the role of BRCA1 in the apoptosis regulation in response to carbon ion irradiation. We utilized three different cancer cell lines with various states for BRCA1 and p53 to identify the relationship between endogenous BRCA1 and the apoptosis-related genes, and determine whether p53 function would affect the role of BRCA1 in apoptosis regulation. By Western blot analysis, we found that Bax expressions were not significantly changed after irradiation in all of three cell lines. However, Bcl-2 expression showed an up-regulation by endogenous BRCA1 regardless of p53 status. Moreover, the changes in Bcl-2 protein were due to the increase in the transcriptional levels of Bcl-2 mRNA, based on real-time PCR assay. At the same time, BRCA1-deficient cells showed a greater apoptosis susceptibility to irradiation when compared with BRCA1-proficient cells. The results suggest that BRCA1 might exert p53-independent regulative activities for Bcl-2, which seems account for the low apoptosis susceptibility in BRCA1-proficient carcinomas.

  14. Up-Regulation of KPNB1 Involves in Neuronal Apoptosis Following Intracerebral Hemorrhage in Adult Rats.

    Science.gov (United States)

    Dai, Aihua; Liu, Xiaorong; Zhang, Yu; Han, Lijian; Zhu, Liang; Ni, Haidan; Chen, Rongrong; Cao, Maohong

    2015-11-01

    Kpnb1, also known as Importin β1, is a member of the Karyopherin protein family which plays a important role in nuclear import and export pathways. Its expression has been shown to be responsive to stress, such as heat shock, ethanol and oxidative stress. Previous studies demonstrated that Kpnb1 had anti-apoptotic in cervical cancer. These together prompted us to explore whether Kpnb1 has some association with neuron apoptosis in the pathophysiology of intracerebral hemorrhage (ICH). In our study, an ICH model was established by injecting into the right basal ganglia of adult rats with their autologous whole blood and assessed by behavioral tests. We found Kpnb1 were significantly up-regulated adjacent to the hematoma following ICH by Western blot and immunohistochemistry. Double immunofluorenscence manifested Kpnb1 was strikingly increased in neurons, not astrocytes or microglia. Furthermore, we also found that kpnb1 had co-localizations with active-caspase-3 which is a neuronal apoptosis marker suggesting its role in neuronal apoptosis. What's more, our in vitro study, using Kpnb1 RNA interference in PC12 cells, further indicated that Kpnb1 might exert its pro-apoptotic function on neuronal apoptosis. Therefore, Kpnb1 may play a role in the neuronal apoptosis following ICH. PMID:26303509

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

    Directory of Open Access Journals (Sweden)

    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.

  16. Bax is not involved in the resveratrol-induced apoptosis in human lung adenocarcinoma cells

    Science.gov (United States)

    Zhang, Wei-wei; Wang, Zhi-ping; Chen, Tong-sheng

    2010-02-01

    Resveratrol (RV) is a natural plant polyphenol widely present in foods such as grapes, wine, and peanuts. Previous studies indicate that RV has an ability to inhibit various stages of carcinogenesis and eliminate preneoplastic cells in vitro and in vivo. However, little is known about the molecular mechanism of RV-induced apoptosis in human lung adenocarcinoma (ASTC-a-1) cell. In this report, we analyzed whether Bax translocation from cytoplasm to mitochondria during RV-induced apoptosis in single living cell using onfocal microscopey. Cells were transfected with GFP-Bax plasmid. Cell counting kit (CCK-8) assay was used to assess the inhibition of RV on the cells viability. Apoptotic activity of RV was detected by Hoechst 33258 and propidium iodide (PI) staining. Our results showed that RV induced a dose-dependent apoptosis in which Bax did not translocate to mitochondrias.

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

    International Nuclear Information System (INIS)

    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

  18. 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.

  19. 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)

    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 (Ca2+) 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 Ca2+ homeostasis on arsenic-induced HKM apoptosis. We suggest that arsenic-induced alteration in intracellular Ca2+ 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 Ca2+ 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.

  20. Involvement of sulfhydryl oxidase QSOX1 in the protection of cells against oxidative stress-induced apoptosis

    International Nuclear Information System (INIS)

    The QSOX1 protein, belonging to a new class of FAD-linked Quiescin/Sulfhydryl oxidase, catalyzes disulfide bond formation. To give new insight into the biological function of QSOX1, we studied its involvement in oxidative stress-induced apoptosis and cell recovery of PC12 cells. By real time RT-PCR and flow cytometric analysis, we show that the QSOX1 mRNA and protein levels increased late after the beginning of oxidative treatment and were sustained for 72 h. These levels were still high when the PC12 cells were not dying but had resumed proliferation. The kinetics of QSOX1 expression suggest a more protective effect of QSOX1 rather than an involvement of this protein in apoptosis. Human breast cancer MCF-7 cell lines overexpressing the guinea pig QSOX1 protein submitted to the same treatments appeared less sensitive to cell death than the MCF-7 control cells. The protective effect is partly due to a preservation of the mitochondrial polarization generally lost after an oxidative stress. These results strengthen our hypothesis of a protective role of QSOX1 against apoptosis

  1. 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.

  2. 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. PMID:22815988

  3. OPA1 downregulation is involved in sorafenib-induced apoptosis in hepatocellular carcinoma

    OpenAIRE

    Zhao, Xiangxuan; Tian, Changhai; Puszyk, William M; Ogunwobi, Olorunseun O.; Cao, Mengde; Wang, Ton; Cabrera, Roniel; Nelson, David R.; Liu, Chen

    2012-01-01

    Sorafenib has been used to treat advanced hepatocellular carcinoma (HCC), but the underlying molecular mechanisms remain controversial and why some patients do not respond to this therapy is poorly understood. In this study, we show that sorafenib triggers cell growth inhibition and apoptosis in HCC cells by directly targeting the mitochondria. Treatment with sorafenib induces rapid mitochondrial fragmentation, which is associated with the deregulation of mitochondria fusion-related protein o...

  4. Muscle to meat conversion in common carp (cyprinus carpio): new insights involving apoptosis

    OpenAIRE

    Boudida, Yasmine; Becila, Samira; GAGAOUA, Mohammed; Boudjellal, Abdelghani; Sentandreu, Miguel; Ouali, Ahmed

    2015-01-01

    Tenderization of fish muscle results in its deterioration. Different proteolytic systems exist within the muscular cell. In this decade we have integrated a new process capable to better explain the meat tenderization process namely apoptosis. This process is orchestrated by the family of cysteine aspartate-specific proteases named caspases, which are probably the first proteolytic system to be implicated in postmortem proteolysis and meat tenderization. Our study contribute to understanding ...

  5. JNK3 involvement in nerve cell apoptosis and neurofunctional recovery after traumatic brain injury☆

    Institute of Scientific and Technical Information of China (English)

    Jiang Long; Li Cai; Jintao Li; Lei Zhang; Haiyang Yang; Tinghua Wang

    2013-01-01

    Increasing evidence has revealed that the activation of the JNK pathway participates in apoptosis of nerve cells and neurological function recovery after traumatic brain injury. However, which genes in the JNK family are activated and their role in traumatic brain injury remain unclear. Therefore, in this study, in situ end labeling, reverse transcription-PCR and neurological function assessment were adopted to investigate the alteration of JNK1, JNK2 and JNK3 gene expression in cerebral injured rats, and their role in cell apoptosis and neurological function restoration. Results showed that JNK3 expression significantly decreased at 1 and 6 hours and 1 and 7 days post injury, but that JNK1 and JNK2 expression remained unchanged. In addition, the number of apoptotic nerve cells surrounding the injured cerebral cortex gradually reduced over time post injury. The Neurological Severity Scores gradually decreased over 1, 3, 5, 14 and 28 days post injury. These findings suggested that JNK3 expression was downregulated at early stages of brain injury, which may be associated with apoptosis of nerve cells. Downregulation of JNK3 expression may promote the recovery of neurological function following traumatic brain injury.

  6. MDA-7/IL-24 induces Bcl-2 denitrosylation and ubiquitin-degradation involved in cancer cell apoptosis.

    Directory of Open Access Journals (Sweden)

    Hui Tian

    Full Text Available MDA-7/IL-24 was involved in the specific cancer apoptosis through suppression of Bcl-2 expression, which is a key apoptosis regulatory protein of the mitochondrial death pathway. However, the underlying mechanisms of this regulation are unclear. We report here that tumor-selective replicating adenovirus ZD55-IL-24 leads to Bcl-2 S-denitrosylation and concomitant ubiquitination, which take part in the 26S proteasome degradation. IL-24-siRNA completely blocks Bcl-2 ubiquitination via reversion of Bcl-2 S-denitrosylation and protects it from proteasomal degradation which confirmed the significant role of MDA-7/IL-24 in regulating posttranslational modification of Bcl-2 in cancer cells. Nitric oxide (NO is a key regulator of protein S-nitrosylation and denitrosylation. The NO donor, sodium nitroprusside (SNP, down-regulates Bcl-2 S-denitrosylation, attenuates Bcl-2 ubiquitination and subsequently counteracts MDA-7/IL-24 induced cancer cell apoptosis, whereas NO inhibitor 2-(4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide (PTIO shows the opposite effect. At the same time, these NO modulators fail to affect Bcl-2 phosphorylation, suggesting that NO regulates Bcl-2 stability in a phosphorylation-independent manner. In addition, Bcl-2 S-nitrosylation reduction induced by ZD55-IL-24 was attributed to both iNOS decrease and TrxR1 increase. iNOS-siRNA facilitates Bcl-2 S-denitrosylation and ubiquitin-degradation, whereas the TrxR1 inhibitor auranofin prevents Bcl-2 from denitrosylation and ubiquitination, thus restrains the caspase signal pathway activation and subsequent cancer cell apoptosis. Taken together, our studies reveal that MDA-7/IL-24 induces Bcl-2 S-denitrosylation via regulation of iNOS and TrxR1. Moreover, denitrosylation of Bcl-2 results in its ubiquitination and subsequent caspase protease family activation, as a consequence, apoptosis susceptibility. These findings provide a novel insight into MDA-7/IL-24 induced growth

  7. Potential mechanisms involved in resistant phenotype of MCF-7 breast carcinoma cells to ionizing radiation induced apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Wang Yanling [Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou 730000 (China); Graduate School of Chinese Academy of Sciences, Beijing 100039 (China); Zhang Hong [Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou 730000 (China)], E-mail: zhangh@impcas.ac.cn; Li Ning [Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou 730000 (China); Graduate School of Chinese Academy of Sciences, Beijing 100039 (China); Wang Xiaohu [Department of Radiotherapy, Gansu Tumor Hospital, Lanzhou 730050 (China); Hao Jifang [Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou 730000 (China); Zhao Weiping [Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou 730000 (China); Graduate School of Chinese Academy of Sciences, Beijing 100039 (China)

    2009-03-15

    In the present study, we investigated the mechanisms of apoptosis resistance and the roles of the phosphorylation of BRCA1, p21, the Bax/Bcl-2 protein ratio and cell cycle arrest in IR-induced apoptosis in MCF-7 cells. X-irradiation, in particular at low dose (1 Gy), but not carbon ion irradiation, had a significant antiproliferative effect on the growth of MCF-7 cells. 1 Gy X-irradiation resulted in G1 and G2 phase arrest, but 4 Gy induced a significant G1 block. In contrast, carbon ion irradiation resulted in a significant accumulation in the G2 phase. Concomitant with the phosphorylation of H2AX induced by DNA damage, carbon ion irradiation resulted in an approximately 1.9-2.8-fold increase in the phosphorylation of BRCA1 on serine residue 1524, significantly greater than that detected for X-irradiation. Carbon ion irradiation caused a dramatic increase in p21 expression and drastic decrease in Bax expression compared with X-irradiation. The data implicated that phosphorylation of BRCA1 on serine residue 1524 might, at least partially, induce p21 expression but repress Bax expression. Together, our results suggested that the phosphorylation of BRCA1 at Ser-1524 might contribute to the G2 phase arrest and might be an upstream signal involved in preventing apoptosis signal via upregulation of p21 and downregulation of the Bax/Bcl-2 ratio.

  8. Potential mechanisms involved in resistant phenotype of MCF-7 breast carcinoma cells to ionizing radiation induced apoptosis

    Science.gov (United States)

    Wang, Yan-ling; Zhang, Hong; Li, Ning; Wang, Xiao-hu; Hao, Ji-fang; Zhao, Wei-ping

    2009-03-01

    In the present study, we investigated the mechanisms of apoptosis resistance and the roles of the phosphorylation of BRCA1, p21, the Bax/Bcl-2 protein ratio and cell cycle arrest in IR-induced apoptosis in MCF-7 cells. X-irradiation, in particular at low dose (1 Gy), but not carbon ion irradiation, had a significant antiproliferative effect on the growth of MCF-7 cells. 1 Gy X-irradiation resulted in G1 and G2 phase arrest, but 4 Gy induced a significant G1 block. In contrast, carbon ion irradiation resulted in a significant accumulation in the G2 phase. Concomitant with the phosphorylation of H2AX induced by DNA damage, carbon ion irradiation resulted in an approximately 1.9-2.8-fold increase in the phosphorylation of BRCA1 on serine residue 1524, significantly greater than that detected for X-irradiation. Carbon ion irradiation caused a dramatic increase in p21 expression and drastic decrease in Bax expression compared with X-irradiation. The data implicated that phosphorylation of BRCA1 on serine residue 1524 might, at least partially, induce p21 expression but repress Bax expression. Together, our results suggested that the phosphorylation of BRCA1 at Ser-1524 might contribute to the G2 phase arrest and might be an upstream signal involved in preventing apoptosis signal via upregulation of p21 and downregulation of the Bax/Bcl-2 ratio.

  9. 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.

  10. The involvement of the mitochondrial pathway in manganese-induced apoptosis of chicken splenic lymphocytes.

    Science.gov (United States)

    Zhu, Yihao; Li, Shu; Teng, Xiaohua

    2016-06-01

    The purpose of this study was to investigate the effect of excess manganese (Mn)-induced cytotoxicity on apoptosis in chicken splenic lymphocytes. Chicken splenic lymphocytes were cultured in medium in the absence and presence of manganese (II) chloride (MnCl2) (2 × 10(-4), 4 × 10(-4), 6 × 10(-4), 8 × 10(-4), 10 × 10(-4), and 12 × 10(-4) mM), in N-acetyl-l-cysteine (NAC) (1 mM), and the combination of MnCl2 and NAC for 12, 24, 36, and 48 h. Tests were performed on morphologic observation, reactive oxygen species (ROS) and malondialdehyde (MDA) content, manganese superoxide dismutase (Mn-SOD) and glutathione peroxidase (GSH-Px) activities, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), p53, and calmodulin (CaM) messenger RNA (mRNA) expression, Caspase-3 mRNA and protein expression, intracellular free Ca(2+) ([Ca(2+)]i), and mitochondrial transmembrane potential (ΔΨm). Our research indicated that excess Mn induced ROS and MDA content, inhibited Mn-SOD and GSH-Px activities, induced Bax and p53 mRNA expression, inhibited Bcl-2 and CaM mRNA expression, induced Caspase-3 mRNA and protein expression, upregulated [Ca(2+)]i, inhibited ΔΨm, and induced apoptosis in a dose effect. NAC relieved excess Mn-caused the changes of all above factors. Mn-induced oxidative injuries were alleviated by treatment with NAC, an ROS scavenger. The above results demonstrated that excess Mn caused oxidative stress and apoptosis via mitochondrial pathway in chicken splenic lymphocytes. PMID:27035383

  11. Acute ammonia neurotoxicity in vivo involves increase in cytoplasmic protein P53 without alterations in other markers of apoptosis.

    Science.gov (United States)

    Kosenko, Elena; Kaminsky, Yuri; Solomadin, Ilia; Marov, Nikolay; Venediktova, Natalia; Felipo, Vicente; Montoliu, Carmina

    2007-08-15

    Acute intoxication with large ammonia doses leads to activation of NMDA receptors in the brain, resulting in oxidative stress and disturbance of mitochondrial function. Altered mitochondrial function is a crucial step in some mechanisms of cellular apoptosis. This study assesses whether ammonia intoxication in vivo leads to induction of apoptotic markers such as permeability transition pore (PTP) formation, caspase-3, and caspase-9 activation, changes in p53 protein, or cytochrome c release. Acute ammonia intoxication did not affect caspase-9 or caspase-3 activities. The mitochondrial membrane potential also remained unaltered in non-synaptic brain mitochondria after injection of ammonia, indicating that ammonia did not induce PTP formation in brain in vivo. The nuclear level of p53 did not change, whereas its cytoplasmic level increased approximately two-fold. In agreement with the theory that translocation of the p53 from cytosol to nuclei is an essential step for induction of apoptosis we did not find apoptotic nuclei in brain of rats injected with ammonia. This supports the idea that ammonia neurotoxicity does not involve apoptosis and points to impaired p53 transfer from cytoplasm to nuclei as a possible preventer of apoptosis. We did not find any release of cytochrome c from mitochondria to cytosol after ammonia injection. Cytochrome c content was significantly reduced (30%) in brain mitochondria from rats injected with ammonia. This decrease may contribute to the reduced state 3 respiration, decreased respiratory control index, and disturbances in the mitochondrial electron transport chain in brain mitochondria from rats injected with ammonia. PMID:17551980

  12. A Hypothesis Concerning a Potential Involvement of Ceramide in Apoptosis and Acantholysis Induced by Pemphigus Autoantibodies

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    Wendy B. Bollag

    2010-01-01

    Full Text Available Autoimmune diseases affect more than 50 million Americans, resulting in significant healthcare costs. Most autoimmune diseases occur sporadically; however, endemic pemphigus foliaceus (EPF is an autoimmune skin disease localized to specific geographic loci. EPF, and the related diseases pemphigus vulgaris (PV and pemphigus foliaceus (PF, are characterized by skin lesions and autoantibodies to molecules found on epidermal keratinocytes. A variant of EPF in patients from El Bagre, Colombia, South America, has recently been reported to be distinct from previously described loci in Brazil and Tunisia epidemiologically and immunologically. As in PF and EPF, El Bagre EPF patients exhibit autoantibodies towards desmoglein-1, a cell adhesion molecule critical for maintaining epidermal integrity. An association of El Bagre EPF with sun exposure has been detected, and ultraviolet irradiation also exacerbates symptoms in PV, PF and EPF. Our hypothesis is that: (1 the autoantibodies generate pathology through an alteration in ceramide metabolism in targeted keratinocytes, resulting in apoptosis and/or cell death and acantholysis, but only when the cell's ability to metabolize ceramide is exceeded, and (2 apoptosis in response to this altered ceramide metabolism is initiated and/or exacerbated by other agents that increase ceramide levels, such as cytokines, ultraviolet irradiation, and senescence.

  13. 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.

  14. Bad is not involved in DHA-induced apoptosis in human lung adenocarcinoma ASTC-a-1 cells

    Science.gov (United States)

    Yu, Huai-na; Lu, Ying-ying; Chen, Tong-sheng

    2011-03-01

    Dihydroartemisinin (DHA), a first-line anti-malarial drug with low toxicity, has been shown to possess promising anticancer activities and induce cancer cell death through apoptotic pathway, but the molecular mechanisms are not well understood. In this paper, we focus on whether Bad, a BH3-only pro-apoptotic protein, is involved in apoptotic cell death in DHA-treated human lung adenocarcinoma (ASTC-a-1) cells. Confocal fluorescence microscope imaging was used to monitor the temporal and spatial distribution of Bad in single living cells. Our results indicate that Bad is still located in cytoplasm and does not translocate to mitochondria after treatment with DHA for 24 h, while only a small proportion of Bad located in cytoplasm in the STS-treated cells for 6 h. These results show for the first time that Bad is not involved in DHA-induced apoptosis in ASTC-a-1 cells, which could give more evidence for the molecular mechanisms of apoptosis induced by DHA.

  15. Calcium-dependent trichosanthin-induced generation of reactive oxygen species involved in apoptosis of human choriocarcinoma cells

    Science.gov (United States)

    Zhang, Chunyang; Ma, Hui; Chen, Die Yan

    2001-04-01

    The type-I ribosome-inactivating protein trichosanthin (TCS) has a broad spectrum of biological and pharmacological activities, including abortifacient, anti-tumor and anti-HIV. We found for the first time that TCS induced production of reactive oxygen species (ROS) in JAR cells by using fluorescent probe 2',7'-dichlorofluorescin diacetate with confocal laser scanning microscopy. TCS-induced ROS showed dependence on the increase in intracellular calcium and on the presence of extracellular calcium. The production of ROS increased rapidly after the application of TCS, which paralleled TCS-indued increase in intracellular calcium monitored using fluo 3-AM, suggesting that TCS-induced ROS might mediate by the increase in intracellular Ca2PLU concentration. Simultaneous observation of the nuclear morphological changes and production of ROS in JAR cells with two-photon laser scanning microscopy and confocal laser scanning microscopy revealed that ROS involved in the apoptosis of JAR cells, which was confirmed by that antioxidant (alpha) -tocopherol prevented TCS-induced ROS formation and cell death. The finding that calcium-dependent TCS-induced ROS involved in the apoptosis of JAR cells might provide new insight into the anti-tumor and anti-HIV mechanism of TCS.

  16. 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

  17. Constitutive activation of the ATM/BRCA1 pathway prevents DNA damage-induced apoptosis in 5-azacytidine-resistant cell lines.

    Science.gov (United States)

    Imanishi, Satoshi; Umezu, Tomohiro; Ohtsuki, Kazushige; Kobayashi, Chiaki; Ohyashiki, Kazuma; Ohyashiki, Junko H

    2014-06-01

    5-Azacytidine (AZA) exerts its anti-tumor effects by exerting cytotoxicity via its incorporation into RNA and DNA, which causes the reactivation of aberrantly silenced growth-regulatory genes by promoter demethylation, as well as DNA damage. AZA is used for patients with myelodysplastic syndrome and acute myeloid leukemia. However, some patients demonstrate resistance to AZA, the mechanisms of which are not fully elucidated. We therefore sought to better characterize the molecular mechanism of AZA resistance using an in vitro model of AZA resistance. We established AZA-resistant cell lines by exposing the human leukemia cell lines U937 and HL-60 to clinical concentrations of AZA, and characterized these cells. AZA-resistant cells showed a down-regulation of the DNMT3A protein, in correlation with their marked genome-wide DNA hypomethylation. Furthermore, genes involved in pyrimidine metabolism were down-regulated in both AZA-resistant cell lines; AZA sensitivity was restored by inhibition of CTP synthase. Of note is that the DNA damage response pathway is constitutively activated in the AZA-resistant cell lines, but not in the parental cell lines. Inhibition of the DNA damage response pathway canceled the AZA resistance, in association with an increase in apoptotic cells. We found that the molecular mechanism underlying AZA resistance involves pyrimidine metabolism and the DNA damage response through ATM kinase. This study therefore sheds light on the mechanisms underlying AZA resistance, and will enable better understanding of AZA resistance in patients undergoing AZA treatment. PMID:24680865

  18. 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

  19. Involvement of Hydrogen Peroxide in Safingol-Induced Endonuclease G-Mediated Apoptosis of Squamous Cell Carcinoma Cells

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    Masakazu Hamada

    2014-02-01

    Full Text Available Safingol, a L-threo-dihydrosphingosine, induced the nuclear translocation of a mitochondrial apoptogenic mediator—endonuclease G (endo G—and apoptosis of human oral squamous cell carcinoma (SCC cells. Upstream mediators remain largely unknown. The levels of hydrogen peroxide (H2O2 in cultured oral SCC cells were measured. Treatment with safingol increased intracellular H2O2 levels but not extracellular H2O2 levels, indicating the production of H2O2. The cell killing effect of safingol and H2O2 was diminished in the presence of reactive oxygen species (ROS scavenger N-acetyl-L-cysteine (NAC. Dual staining of cells with annexin V and propidium iodide (PI revealed that apoptotic cell death occurred by treatment with H2O2 and safingol. The number of apoptotic cells was reduced in the presence of NAC. In untreated cells, endo G distributed in the cytoplasm and an association of endo G with mitochondria was observed. After treatment with H2O2 and safingol, endo G was distributed to the nucleus and cytoplasm, indicating the nuclear translocation of the mitochondrial factor. NAC prevented the increase of apoptotic cells and the translocation of endo G. Knock down of endo G diminished the cell killing effect of H2O2 and safingol. These results suggest that H2O2 is involved in the endo G-mediated apoptosis of oral SCC cells by safingol.

  20. Upregulated Expression of Karyopherin α2 is Involved in Neuronal Apoptosis Following Intracerebral Hemorrhage in Adult Rats.

    Science.gov (United States)

    Xu, Zhiwei; Chen, Jianping; Shi, Jiansheng; Zhao, Jianmei; Wang, Jun; Ji, Yuhong; Han, Lijian; Zhu, Liang; Li, Xiaohong; Zhang, Dongmei

    2016-07-01

    Karyopherin α2 (KPNA2) plays a central role in nucleocytoplasmic transport. It is involved in controlling the flow of genetic information and the modulation of diverse cellular activities. Here we explored the KPNA2's roles during the pathophysiological processes of intracerebral hemorrhage (ICH). An ICH rat model was built and evaluated according to behavioral testing. Using Western blot, immunohistochemistry, and immunofluorescence, significant upregulation of KPNA2 was found in neurons in brain areas surrounding the hematoma following ICH. Increasing KPNA2 level was found to be accompanied by the upregulation of active caspase-3, Bax, and decreased expression of Bcl-2. Besides, KPNA2 co-localized well with active caspase-3 in neurons, indicating its potential role in neuronal apoptosis. What's more, knocking down KPNA2 by RNA-interference in PC12 cells reduced active caspase-3 expression. Thus, KPNA2 may play a role in promoting the brain secondary damage following ICH. PMID:26340948

  1. Colistin-Induced Apoptosis of Neuroblastoma-2a Cells Involves the Generation of Reactive Oxygen Species, Mitochondrial Dysfunction, and Autophagy.

    Science.gov (United States)

    Dai, Chongshan; Tang, Shusheng; Velkov, Tony; Xiao, Xilong

    2016-09-01

    Neurotoxicity remains a poorly characterized adverse effect associated with colistin therapy. The aim of the present study was to investigate the mechanism of colistin-induced neurotoxicity using the mouse neuroblastoma2a (N2a) cell line. Colistin treatment (0-200 μM) of N2a neuronal cells induced apoptotic cell death in a dose-dependent manner. Colistin-induced neurotoxicity was associated with a significant increase of reactive oxygen species (ROS) levels, with a concomitant decrease in the activities of superoxide dismutase (SOD), catalase (CAT), and the glutathione (GSH) levels. Mitochondrial dysfunction was evident from the dissipation of membrane potential and the increase of Bax/Bcl-2, followed by the release of cytochrome c (CytC). Caspase-3/7, -8, and -9 activations were also detected. Colistin-induced neurotoxicity significantly increased the gene expression of p53 (1.6-fold), Bax (3.3-fold), and caspase-8 (2.2-fold) (all p colistin treatment (50-200 μM). Furthermore, inhibition of autophagy by pretreatment with chloroquine diphosphate (CQ) enhanced colistin-induced apoptosis via caspase activation, which could be attenuated by co-treatment with the pan-caspase inhibitor Z-VAD-FMK. In summary, our study reveals that colistin-induced neuronal cell death involves ROS-mediated oxidative stress and mitochondrial dysfunction, followed by caspase-dependent apoptosis and autophagy. A knowledge base of the neuronal signaling pathways involved in colistin-induced neurotoxicity will greatly facilitate the discovery of neuroprotective agents for use in combination with colistin to prevent this undesirable side effect. PMID:26316077

  2. Inhibitor of apoptosis proteins and apoptosis

    Institute of Scientific and Technical Information of China (English)

    Yunbo Wei; Tingjun Fan; Miaomiao Yu

    2008-01-01

    Apoptosis is a physiological cell death process that plays a critical role in development, homeostasis, and immune defense of multicellular animals. Inhibitor of apoptosis proteins (IAPs) constitute a family of proteins that possess between one and three baculovirus IAP repeats. Some of them also have a really interesting new gene finger domain, and can prevent cell death by binding and inhibiting active caspases, but are regulated by IAP antagonists. Some evidence also indicates that IAP can modulate the cell cycle and signal transduction. The three main factors, IAPs, IAP antagonists, and caspases, are involved in regulating the progress of apoptosis in many species. Many studies and assumptions have been focused on the anfractuous interactions between these three main factors to explore their real functional model in order to develop potential anticancer drugs.In this review, we describe the classification, molecular structures, and properties of IAPs and discuss the mechanisms of apoptosis. We also discuss the promising significance of clinical applications of IAPs in the diagnosis and treatment of malignancy.

  3. A High-Resolution Comparative Chromosome Map of Cricetus cricetus and Peromyscus eremicus Reveals the Involvement of Constitutive Heterochromatin in Breakpoint Regions.

    Science.gov (United States)

    Vieira-da-Silva, Ana; Louzada, Sandra; Adega, Filomena; Chaves, Raquel

    2015-01-01

    Compared to humans and other mammals, rodent genomes, specifically Muroidea species, underwent intense chromosome reshuffling in which many complex structural rearrangements occurred. This fact makes them preferential animal models for studying the process of karyotype evolution. Here, we present the first combined chromosome comparative maps between 2 Cricetidae species, Cricetus cricetus and Peromyscus eremicus, and the index species Mus musculus and Rattus norvegicus. Comparative chromosome painting was done using mouse and rat paint probes together with in silico analysis from the Ensembl genome browser database. Hereby, evolutionary events (inter- and intrachromosomal rearrangements) that occurred in C. cricetus and P. eremicus since the putative ancestral Muroidea genome could be inferred, and evolutionary breakpoint regions could be detected. A colocalization of constitutive heterochromatin and evolutionary breakpoint regions in each genome was observed. Our results suggest the involvement of constitutive heterochromatin in karyotype restructuring of these species, despite the different levels of conservation of the C. cricetus (derivative) and P. eremicus (conserved) genomes. PMID:25999143

  4. DNA damage and apoptosis induction by the pesticide Mancozeb in rat cells: Involvement of the oxidative mechanism

    International Nuclear Information System (INIS)

    The DNA damaging and proapoptotic effects of Mancozeb, a widely used fungicide of the ethylene-bis-dithiocarbamate (EBDC) group, were studied in RAT-1 fibroblasts cultured in vitro and in peripheral blood mononucleated cells (PBMC) isolated from Wistar rats. After 1 h exposition to Mancozeb (up to 500 ng/ml), cells produced a dose-dependent induction in DNA single strand break (SSB) formation, measured by single cell gel electrophoresis (SCGE). Concomitantly, a concentration-dependent increase in the levels of the oxidative markers of DNA oxidation, the DNA adduct 8-hydroxy-2'-deoxyguanosine (8-OHdG) and of reactive oxygen species (ROS) were observed, suggesting a prooxidant action of Mancozeb. PBMC were less responsive than fibroblasts to the oxidative insult carried out by Mancozeb, as shown by the lower increase in the levels of ROS, 8-OHdG adducts and SSB measured in these cells after exposure to the pesticide. A 4-h treatment with Mancozeb induced also apoptosis in both PBMC and RAT-1 cells, even though leukocytes were less sensitive than fibroblasts to the proapoptotic action. This effect was dose-dependent and was inhibited by the action of the antioxidant α-tocopherol. The proapoptotic effect was accompanied by the altered expression of several proteins involved in the regulation of apoptosis, such as the prosurvival protein BCL-2 and the proapoptotic protein c-MYC. Exposition of cells to higher concentrations of Mancozeb or for longer periods (>4 h) caused post-apoptotic, necrotic alterations in cell membrane integrity. The data herein presented demonstrate the oxidative effect of Mancozeb and suggest that its prooxidant action may be involved in the proapoptotic effect exerted by this compound in rat cells. It appears possible that the observed oxidative and genotoxic damage may be involved in the pathogenesis of various pathologies associated with the chronic exposition to Mancozeb, including cancer. On the other hand, the proapoptotic effect of

  5. Increased cytotoxicity of ionizing radiation in combination with membrane-targeted apoptosis modulators involves downregulation of protein kinase B/Akt-mediated survival-signaling

    International Nuclear Information System (INIS)

    Background and purpose: The membrane-targeted apoptosis modulators erucylphosphocholine (ErPC) and erucylphosphohomocholine (ErPC3) induce apoptosis in highly apoptosis resistant malignant glioma cell lines and enhance radiation-induced cell death and eradication of clonogenic tumor cells in vitro. Aim of the present study was to elucidate molecular mechanisms of combined action. Materials and methods: Induction of apoptosis was evaluated by determination of nuclear morphology (fluorescence microscopy), alteration of mitochondrial function and caspase-activation (flow cytometry, Western blot). Activity of protein kinase B (PKB/Akt) and key downstream effectors involved in apoptosis regulation was verified by Western blot analysis using activation-specific antibodies. Results: Increased cytotoxicity of the combination was linked to a more efficient activation of the intrinsic apoptosis pathway with increased damage of the mitochondria and caspase-activation. Moreover, activity of the survival kinase PKB/Akt was downregulated upon treatment with ErPC/ErPC3 alone or in combination with ionizing radiation. Inhibition of PKB/Akt was associated with decreased phosphorylation and thus activation of the pro-apoptotic Bcl-2 protein Bad as well as dephosphorylation of the transcription factor FOXO3A (FKHRL1) that may be responsible for the observed increased expression of the pro-apoptotic Bcl-2 protein Bim. Conclusions: Our data suggest a role for inhibition of PKB/Akt-mediated anti-apoptotic signaling in increased efficacy of the combination

  6. Fas-mediated apoptosis regulates the composition of peripheral alphabeta T cell repertoire by constitutively purging out double negative T cells.

    Directory of Open Access Journals (Sweden)

    Abdiaziz S Mohamood

    Full Text Available BACKGROUND: The Fas pathway is a major regulator of T cell homeostasis, however, the T cell population that is controlled by the Fas pathway in vivo is poorly defined. Although CD4 and CD8 single positive (SP T cells are the two major T cell subsets in the periphery of wild type mice, the repertoire of mice bearing loss-of-function mutation in either Fas (lpr mice or Fas ligand (gld mice is predominated by CD4(-CD8(- double negative alphabeta T cells that also express B220 and generally referred to as B220+DN T cells. Despite extensive analysis, the basis of B220+DN T cell lymphoproliferation remains poorly understood. In this study we re-examined the issue of why T cell lymphoproliferation caused by gld mutation is predominated by B220+DN T cells. METHODOLOGY AND PRINCIPAL FINDINGS: We combined the following approaches to study this question: Gene transcript profiling, BrdU labeling, and apoptosis assays. Our results show that B220+DN T cells are proliferating and dying at exceptionally high rates than SP T cells in the steady state. The high proliferation rate is restricted to B220+DN T cells found in the gut epithelium whereas the high apoptosis rate occurred both in the gut epithelium and periphery. However, only in the periphery, apoptosis of B220+DN T cell is Fas-dependent. When the Fas pathway is genetically impaired, apoptosis of peripheral B220+DN T cells was reduced to a baseline level similar to that of SP T cells. Under these conditions of normalized apoptosis, B220+DN T cells progressively accumulate in the periphery, eventually resulting in B220+DN T cell lymphoproliferation. CONCLUSIONS/SIGNIFICANCE: The Fas pathway plays a critical role in regulating the tissue distribution of DN T cells through targeting and elimination of DN T cells from the periphery in the steady state. The results provide new insight into pathogenesis of DN T cell lymphoproliferation.

  7. Anti-immunoglobulin-induced apoptosis in WEHI 231 cells involves the slow formation of ceramide from sphingomyelin and is blocked by bcl-XL.

    Science.gov (United States)

    Wiesner, D A; Kilkus, J P; Gottschalk, A R; Quintáns, J; Dawson, G

    1997-04-11

    Prolonged (>24 h) exposure to anti-IgM (an antigen surrogate that induces membrane cross-linking and apoptosis) induced a 3-fold increase in the mass of endogenous ceramide measured by 32P labeling by diacylglycerol kinase and a 4-fold increase in ceramide as measured by metabolic labeling with [3H]palmitate in a B-lymphocyte cell line, WEHI 231. This correlated with the induction of apoptosis. Shorter exposure times to anti-IgM (up to 8 h) failed to elicit apoptosis and did not elicit increased ceramide formation. After 8 h, apoptosis occurs concomitantly with ceramide formation over the next 40 h. Further, we showed that exogenous ceramide mimicked anti-IgM-induced apoptosis and that apoptosis was potentiated in serum-free media. Treatment of cells with an inhibitor of ceramide catabolism, N-oleoylethanolamine, increased both ceramide formation and apoptosis and accelerated apoptosis induced by anti-IgM. To examine further how ceramide metabolism is involved in apoptosis, we derived cell lines from a small population of cells resistant to N-oleoylethanolamine. These cell lines were selected based on an altered ceramide metabolic pathway, were resistant to apoptosis induced by anti-IgM, and showed no significant increase in ceramide when challenged with anti-IgM. The basis of this resistance was shown to be the failure to activate neutral sphingomyelinase activity following 24-h treatment with anti-IgM, in contrast to the 2-fold increase in neutral sphingomyelinase activity observed in wild type cells. We have shown previously that transfection of WEHI cells with bcl-xL conferred resistance to anti-IgM-induced apoptosis, whereas transfection with bcl-2 did not (Gottschalk, A., Boise, L., Thompson, C., and Quintans, J. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 7350-7354). In this study, these bcl-xL transfectants also displayed increased resistance to exogenous N-acetylsphingosine (C2-ceramide) or N-hexanoylsphingosine (C6-ceramide). However, when challenged with

  8. Involvement of VDAC, Bax and ceramides in the efflux of AIF from mitochondria during curcumin-induced apoptosis.

    NARCIS (Netherlands)

    Scharstuhl, A.; Mutsaers, H.A.M.; Pennings, S.W.C.; Russel, F.G.M.; Wagener, F.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-inhibitor

  9. Apoptosis of Alveolar Wall Cells in Chronic Obstructive Pulmonary Disease Patients with Pulmonary Emphysema Is Involved in Emphysematous Changes

    Institute of Scientific and Technical Information of China (English)

    Hongmei LIU; Lijun MA; Jizhen WU; Kai WANG; Xianliang CHEN

    2009-01-01

    s of alveolar wall cells, espe-cially apoptosis of type-Ⅱ cells, may take part in the pathogenesis of emphysema. Up-regulation of Bax expression may be responsible for the apoptosis of alveolar wall cells in the COPD patients with pulmonary emphysema.

  10. Hsp90 is involved in apoptosis of Candida albicans by regulating the calcineurin-caspase apoptotic pathway.

    Science.gov (United States)

    Dai, BaoDi; Wang, Yan; Li, DeDong; Xu, Yi; Liang, RongMei; Zhao, LanXue; Cao, YongBing; Jia, JianHui; Jiang, YuanYing

    2012-01-01

    Candida albicans is the most common human fungal pathogen. Recent evidence has revealed the occurrence of apoptosis in C. albicans that is inducible by environmental stresses such as hydrogen peroxide, acetic acid, and amphotericin B. Apoptosis is regulated by the calcineurin-caspase pathway in C. albicans, and calcineurin is under the control of Hsp90 in echinocandin resistance. However, the role of Hsp90 in apoptosis of C. albicans remains unclear. In this study, we investigated the role of Hsp90 in apoptosis of C. albicans by using an Hsp90-compromised strain tetO-HSP90/hsp90 and found that upon apoptotic stimuli, including hydrogen peroxide, acetic acid or amphotericin B treatment, less apoptosis occurred, less ROS was produced, and more cells survived in the Hsp90-compromised strain compared with the Hsp90/Hsp90 wild-type strain. In addition, Hsp90-compromised cells were defective in up-regulating caspase-encoding gene CaMCA1 expression and activating caspase activity upon the apoptotic stimuli. Investigations on the relationship between Hsp90 and calcineurin revealed that activation of calcineurin could up-regulate apoptosis but could not further down-regulate apoptosis in Hsp90-compromised cells, indicating that calcineurin was downstream of Hsp90. Hsp90 inhibitor geldanamycin (GdA) could further decrease the apoptosis in calcineurin-pathway-defect strains, indicating that compromising Hsp90 function had a stronger effect than compromising calcineurin function on apoptosis. Collectively, this study demonstrated that compromised Hsp90 reduced apoptosis in C. albicans, partially through downregulating the calcineurin-caspase pathway. PMID:23028789

  11. Hsp90 is involved in apoptosis of Candida albicans by regulating the calcineurin-caspase apoptotic pathway.

    Directory of Open Access Journals (Sweden)

    BaoDi Dai

    Full Text Available Candida albicans is the most common human fungal pathogen. Recent evidence has revealed the occurrence of apoptosis in C. albicans that is inducible by environmental stresses such as hydrogen peroxide, acetic acid, and amphotericin B. Apoptosis is regulated by the calcineurin-caspase pathway in C. albicans, and calcineurin is under the control of Hsp90 in echinocandin resistance. However, the role of Hsp90 in apoptosis of C. albicans remains unclear. In this study, we investigated the role of Hsp90 in apoptosis of C. albicans by using an Hsp90-compromised strain tetO-HSP90/hsp90 and found that upon apoptotic stimuli, including hydrogen peroxide, acetic acid or amphotericin B treatment, less apoptosis occurred, less ROS was produced, and more cells survived in the Hsp90-compromised strain compared with the Hsp90/Hsp90 wild-type strain. In addition, Hsp90-compromised cells were defective in up-regulating caspase-encoding gene CaMCA1 expression and activating caspase activity upon the apoptotic stimuli. Investigations on the relationship between Hsp90 and calcineurin revealed that activation of calcineurin could up-regulate apoptosis but could not further down-regulate apoptosis in Hsp90-compromised cells, indicating that calcineurin was downstream of Hsp90. Hsp90 inhibitor geldanamycin (GdA could further decrease the apoptosis in calcineurin-pathway-defect strains, indicating that compromising Hsp90 function had a stronger effect than compromising calcineurin function on apoptosis. Collectively, this study demonstrated that compromised Hsp90 reduced apoptosis in C. albicans, partially through downregulating the calcineurin-caspase pathway.

  12. TAK1 inhibition-induced RIP1-dependent apoptosis in murine macrophages relies on constitutive TNF-α signaling and ROS production

    OpenAIRE

    Wang, Jang-Shiun; Wu, Dean; Huang, Duen-Yi; Lin, Wan-Wan

    2015-01-01

    Background Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a key regulator of signal cascades of TNF-α receptor and TLR4, and can induce NF-κB activation for preventing cell apoptosis and eliciting inflammation response. Results TAK1 inhibitor (TAKI) can decrease the cell viability of murine bone marrow-derived macrophages (BMDM), RAW264.7 and BV-2 cells, but not dermal microvascular endothelial cells, normal human epidermal keratinocytes, THP-1 monocytes, human retinal pigm...

  13. Green tea polyphenols-induced apoptosis in human osteosarcoma SAOS-2 cells involves a caspase-dependent mechanism with downregulation of nuclear factor-κB

    International Nuclear Information System (INIS)

    Development of chemotherapy resistance and evasion from apoptosis in osteosarcoma, a primary malignant bone tumor, is often correlated with constitutive nuclear factor-κB (NF-κB) activation. Here, we investigated the ability of a polyphenolic fraction of green tea (GTP) that has been shown to have antitumor effects on various malignant cell lines to inhibit growth and induce apoptosis in human osteosarcoma SAOS-2 cells. Treatment of SAOS-2 cells with GTP (20-60 μg/ml) resulted in reduced cell proliferation and induction of apoptosis, which correlated with decreased nuclear DNA binding of NF-κB/p65 and lowering of NF-κB/p65 and p50 levels in the cytoplasm and nucleus. GTP treatment of cells reduced IκB-α phosphorylation but had no effect on its protein expression. Furthermore, GTP treatment resulted in the inhibition of IKK-α and IKK-β, the upstream kinases that phosphorylate IκB-α. The increase in apoptosis in SAOS-2 cells was accompanied with decrease in the protein expression of Bcl-2 and concomitant increase in the levels of Bax. GTP treatment of SAOS-2 cells also resulted in significant activation of caspases as was evident by increased levels of cleaved caspase-3 and caspase-8 in these cells. Treatment of SAOS-2 cells with a specific caspase-3 inhibitor Ac-Asp-Glu-Val-Asp-CHO (Ac-DEVD-CHO) and general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone (Z-VAD-FMK) rescued SAOS-2 cells from GTP-induced apoptosis. Taken together, these results indicate that GTP is a candidate therapeutic for osteosarcoma that mediates its antiproliferative and apoptotic effects via activation of caspases and inhibition of NF-κB

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

    Science.gov (United States)

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

    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/PGE2 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. PMID:27262506

  15. PUMA and survivin are involved in the apoptosis of HepG2 cells induced by microcystin-LR via mitochondria-mediated pathway.

    Science.gov (United States)

    Ma, Junguo; Feng, Yiyi; Liu, Yang; Li, Xiaoyu

    2016-08-01

    The present study aimed to determine the cytotoxicity of microcystin-LR (MC-LR) on the human hepatocellular carcinoma (HepG2) cells in order to elucidate the mechanism of apoptosis induced by MC-LR. Morphological evaluation results showed that MC-LR induced time- and concentration-dependent apoptosis in HepG2 cells. The biochemical assays revealed that MC-LR-exposure caused overproduction of reactive oxygen species (ROS), cyclooxygenase-2 activity alteration, cytochrome c release, and remarkable activation of caspase-3 and caspase-9 in HepG2 cells, indicating that MC-LR-induced apoptosis is mediated by mitochondrial pathway. Moreover, we also found that p53 and Bax might play an important role in MC-LR-induced apoptosis in HepG2 cells in which PUMA and survivin were involved. However, further studies are necessary to elucidate the possible functions of PUMA and survivin in MC-LR-induced apoptosis in HepG2 cells. PMID:27235693

  16. The issue of constitutional law legitimacy on "human assisted reproduction" between reasonableness of the choices and effectiveness of the protection of all involved subjects.

    Science.gov (United States)

    Penasa, Simone

    2006-01-01

    This artiche analyzes the constitutionality petition to the constitutional Court against Law 40 of 2004 on "human assisted reproduction", where it prohibits the "preimplantatory genetical diagnosis", because it could be against the mother's right to health (art. 32 Italian Constitution) and the egalitarian protection clause (art. 3 Italian Constitution). In the constitutionally petition the ordinary judge proposes an interpretation in accordance with Constitution of the contested disposition (art. 13 of Law 40 of 2004) and this could be the possibility to teste the "living law" theory and its relation with the "adequate interpretation" of the law and the Constitution. PMID:17393800

  17. Inhibition of PKB/Akt activity involved in apigenin-induced apoptosis in human gastric carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    YUAN LinHong; XIA Wei; ZHAO XiuJuan; ZHANG XiaoHua; ZHANG Ling; WU Kun

    2007-01-01

    Apigenin is a flavonoid widely distributed in fruits and vegetables.It possesses growth inhibitory properties against numerous cancer cell lines.However, the molecular mechanism(s) by which apigenin elicits its effects have not been fully elucidated.Here we studied whether apigenin inhibits growth and induces apoptosis in human gastric carcinoma cells.We showed that the flavonoid inhibited growth of the cells and caused apoptosis, as evidenced by DNA Ladder, cleavage of pro-caspase-3 in a time-dependent manner.Induction of apoptosis was dependent on inhibition of the PKB/Akt activity.We found that while apigenin had no effect on the expression of Akt and Bad, it inhibited specific phosphorylation of the two proteins that are associated with pro-survival mechanisms.We propose that this important flavonoid induces apoptosis in gastric cancer cells by inhibiting Akt activity.Since Akt is often activated in cancers, our findings may have clinical implications.

  18. 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.

  19. Constitutional Constraints

    OpenAIRE

    Fallon, Richard Henry

    2009-01-01

    The main ambition of "Constitutional Constraints" is to open up the subject of constitutional constraints on government officials, including Presidents and Supreme Court Justices, as a topic for discussion within the field of Constitutional Theory. The subject has so far received little comprehensive discussion in the law reviews, in part because of a division between scholarly approaches that treat constitutional law as a system of norms and political scientific theories that portray judges ...

  20. 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 origin...... the adhesion GPCR ADGRG2 is critically involved in the adhesion and migration of certain breast cancer cells through mechanisms including a non-canonical NFkB pathway and that ADGRG2 could be a target for treatment of certain types of cancer.......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...

  1. Involvement of ROS-p38-H2AX axis in novel curcumin analogues-induced apoptosis in breast cancer cells.

    Science.gov (United States)

    Dong, Yinhui; Yin, Shutao; Song, Xinhua; Huo, Yazhen; Fan, Lihong; Ye, Min; Hu, Hongbo

    2016-04-01

    Curcumin-based structural modification for developing more effective curcumin analogues has been drawning increasing attention. As alternative approach, using LC/MS guided purification, we previously obtained a series of novel natural terpene-conjugated curcuminoids from turmeric, and some of them exhibited even more potent anti-cancer activity against multiple types of cancer cells than curcumin. The purpose of this follow-up study was designed to decipher the mechanisms involved in anti-cancer activity of these novel curcumin analogues. Apoptosis was evaluated using sub-G1 analysis by flow cytometry and Cell Death ELISA Kit. Changes of protein expression were analyzed by western blotting. RNA interference was employed to inhibit expression of specific protein. We found that bisabolocurcumin ether (T1) and demethoxybisabolocurcumin ether (T2) were able to trigger much stronger apoptosis induction in multiple types of cancer cells than curcumin, which was attributed to persistent and stronger ROS generation. ROS induction by T1 resulted in activation of p38/H2AX axis and p53. Inhibition of p38/H2AX led to a significant reduction of apoptosis, whereas inactivation of p53 caused a dramatically enhanced H2AX phosphorylation and apoptosis induction, suggesting activation of p38/H2AX contributed to apoptosis induction by T1, whereas p53 activation protected novel curcumins-induced apoptosis via suppression of H2AX activation. Our findings provide mechanistic support for the potential use of terpene-conjugated curcuminoids as a novel class of cancer chemopreventive agents. © 2015 Wiley Periodicals, Inc. PMID:25647442

  2. Capsaicin sensitizes TRAIL-induced apoptosis through Sp1-mediated DR5 up-regulation: Involvement of Ca2+ influx

    International Nuclear Information System (INIS)

    Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various malignant cells, several cancers including human hepatocellular carcinoma (HCC) exhibit potent resistance to TRAIL-induced cell death. The aim of this study is to evaluate the anti-cancer potential of capsaicin in TRAIL-induced cancer cell death. As indicated by assays that measure phosphatidylserine exposure, mitochondrial activity and activation of caspases, capsaicin potentiated TRAIL-resistant cells to lead to cell death. In addition, we found that capsaicin induces the cell surface expression of TRAIL receptor DR5, but not DR4 through the activation Sp1 on its promoter region. Furthermore, we investigated that capsaicin-induced DR5 expression and apoptosis are inhibited by calcium chelator or inhibitors for calmodulin-dependent protein kinase. Taken together, our data suggest that capsaicin sensitizes TRAIL-mediated HCC cell apoptosis by DR5 up-regulation via calcium influx-dependent Sp1 activation. Highlights: ► Capsaicin sensitizes TRAIL-induced apoptosis through activation of caspases. ► Capsaicin induces expression of DR5 through Sp1 activation. ► Capsaicin activates calcium signaling pathway.

  3. Mitochondrial and caspase pathways are involved in the induction of apoptosis by IB-MECA in ovarian cancer cell lines.

    Science.gov (United States)

    Abedi, Hamideh; Aghaei, Mahmoud; Panjehpour, Mojtaba; Hajiahmadi, Sima

    2014-11-01

    A3 adenosine receptor agonist (IB-MECA) has been shown to play important roles in cell proliferation and apoptosis in a variety of cancer cell lines. The present study was designed to understand the mechanism underlying IB-MECA-induced apoptosis in human ovarian cancer cell lines. The messenger RNA (mRNA) and protein expression levels of A3 adenosine receptor were detected in OVCAR-3 and Caov-4 ovarian cancer cells. IB-MECA was capable of decreasing intracellular cyclic adenosine monophosphate (cAMP) that was the reason for the presence of functional A3 adenosine receptor on the cell lines. IB-MECA significantly reduced cell viability in a dose-dependent manner. Cytotoxicity of IB-MECA was suppressed by MRS1220, an A3 adenosine receptor antagonist. The growth inhibition effect of IB-MECA was related to the induction of cell apoptosis, which was manifested by annexin V-FITC staining, activation of caspase-3 and caspase-9, and loss of mitochondrial membrane potentials (ΔΨm). In addition, downregulation of the regulatory protein Bcl-2 and upregulation of Bax protein by IB-MECA were also observed. These findings demonstrated that IB-MECA induces apoptosis via the mitochondrial signaling pathway. These suggest that A3 adenosine receptor agonists may be a potential agent for induction of apoptosis in human ovarian cancer cells. PMID:25095978

  4. INVOLVEMENT OF p38 MITOGEN-ACTIVATED PROTEIN KINASE IN E.Coli-INDUCED U937 APOPTOSIS

    Institute of Scientific and Technical Information of China (English)

    Jia-he Wang; Yi-jun Zhou; Ping He; Bai-yi Chen

    2007-01-01

    Objective To investigate whether the effect of E. coli on U937 cell lines apoptosis is mediated via p38 mitogen-activated protein kinase (MAPK) activation.Methods The U937 cell lines were treated with E. coli at different time or together with SB203580, an inhibitor for p38. Cell apoptosis was analyzed by flow cytometry. p38 activities were detected by Western blotting.Results E. coli induced apoptosis in cultured U937 cell lines in a time-dependent manner. The phosphorylation of p38 was induced after 10 minutes infection, reached the peak after 20 minutes, and started to decline after 30 minutes. In contrast, the level of total p38 protein was not changed in whole experimental period. Inhibition of p38 with SB203580 significantly inhibited E. coli induced apoptosis in U937 cells.Conclusion The activation of the p38 MAPK in U937 cell lines by E. coli is a major pathway to mediate the apoptosis.

  5. Reactive oxygen species involved in apoptosis induction of human respiratory epithelial (A549) cells by Streptococcus agalactiae.

    Science.gov (United States)

    da Costa, Andréia Ferreira Eduardo; Moraes, João Alfredo; de Oliveira, Jessica Silva Santos; dos Santos, Michelle Hanthequeste Bittencourt; Santos, Gabriela da Silva; Barja-Fidalgo, Christina; Mattos-Guaraldi, Ana Luiza; Nagao, Prescilla Emy

    2016-01-01

    Streptococcus agalactiae (Group B Streptococcus; GBS) is an important pathogen and is associated with pneumonia, sepsis and meningitis in neonates and adults. GBS infections induce cytotoxicity of respiratory epithelial cells (A549) with generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential (ψm). The apoptosis of A549 cells by GBS was dependent on the activation of caspase-3 and caspase-9 with increased pro-apoptotic Bim and Bax molecules and decreased Bcl-2 pro-survival protein. Treatment of infected A549 cells with ROS inhibitors (diphenyleniodonium chloride or apocynin) prevented intracellular ROS production and apoptosis. Consequently, oxidative stress is included among the cellular events leading to apoptosis during GBS human invasive infections. PMID:26490153

  6. Enzymes involved in apoptosis of medical protozoan%原虫凋亡中相关酶类研究进展

    Institute of Scientific and Technical Information of China (English)

    杨秋林(综述); 许丽芳(审校)

    2015-01-01

    近年鉴定到Metacaspase、组织蛋白酶B、组织蛋白酶D、核酸酶( Endo G、Tatd 、Fen-1)等分子参与了原虫的凋亡,但不清楚这些分子在凋亡信号途径中的位置及相互关系。实验结果显示,Metacaspase可能具有调节原虫凋亡与细胞周期等功能,但是Metacaspase与Caspase的活化方式及作用底物不同,提示原虫存在与多细胞动物不同的凋亡途径;在疟原虫及利什曼原虫中发现其线粒体及溶酶体参与了其凋亡,提示原虫可能具有类似哺乳动物的溶酶体-线粒体凋亡途径;在利什曼原虫和锥虫中发现存在通过核酸酶而不依赖Caspase的凋亡途径。阐明原虫的凋亡机制有助于通过设计新药物诱导原虫凋亡来达到治疗疾病的目的。%Recently, a number of molecules which are involved in the apoptosis in protozoa have been discovered, for ex-ample:metacaspase, cathepsin B and D, nuclease( Endo G, Tatd, Fen-1 et al) .So far the locations of these molecules in the signal pathway of protozoan apoptosis and the relationship associated to these molecules in the signal pathway have not been identified.The results of experiments showed that the activation mode is different between metacaspase and caspase. The substrates are also different for metacaspase and caspase.The results suggested that the apoptosis mechanism is different between protozoan and metazoan.Metacaspase has multifunction, for example: control of apoptosis, cell cycle and clear-ance of insoluble protein aggregates.The results of experiment showed that mitochondrial and lysosomal body are involved in the apoptosis in protozoan, possibly, there are mitochondrial-lysosomal body pathway and caspase-independent pathway which control the apoptosis in protozoan.Uncovering clearly the mechanism of apoptosis in protozoan is benefit for design of new drugs in prevention and treatment of diseases caused by the protozoa.

  7. Constitutive active/androstane receptor, peroxisome proliferator-activated receptor α, and cytotoxicity are involved in oxadiazon-induced liver tumor development in mice.

    Science.gov (United States)

    Kuwata, Kazunori; Inoue, Kaoru; Ichimura, Ryohei; Takahashi, Miwa; Kodama, Yukio; Yoshida, Midori

    2016-02-01

    Oxadiazon (OX) is a protoporphyrinogen oxidase-inhibiting herbicide that induces porphyria and liver tumors in rodents. Although porphyria is generally considered to be a risk factor for liver tumor development, the mechanisms through which OX mediates tumor development are unclear. Therefore, in this study, we investigated the mechanisms of tumor development by focusing on constitutive active/androstane receptor (CAR), which is essential for the development of tumors in response to several chemicals. After 1, 4, or 13 weeks of dietary treatment with 1000 ppm OX, hepatic Cyp2b10 expression was induced in wild-type (WT) mice. However, this effect was blocked in CAR-knockout (CARKO) mice. Hepatic Cyp4a10 expression, indicative of peroxisome proliferator-activated receptor α (PPARα) activation, and cytotoxic changes in hepatocytes were also observed in both groups of mice. After initiation by diethylnitrosamine, 26-week treatment with OX resulted in an increase in proliferative lesions, including foci and adenomas, in both genotypes, and the incidence and multiplicity of proliferative lesions in CARKO mice were higher than those in control mice but lower than those in WT mice. These results suggested that CAR, PPARα activation, and cytotoxicity were involved in the development of liver tumors. Moreover, porphyrin was not apparently involved in OX-induced tumor development. PMID:26710982

  8. Ketamine-induced ulcerative cystitis and bladder apoptosis involve oxidative stress mediated by mitochondria and the endoplasmic reticulum.

    Science.gov (United States)

    Liu, Keh-Min; Chuang, Shu-Mien; Long, Cheng-Yu; Lee, Yi-Lun; Wang, Chao-Chuan; Lu, Mei-Chin; Lin, Rong-Jyh; Lu, Jian-He; Jang, Mei-Yu; Wu, Wen-Jeng; Ho, Wan-Ting; Juan, Yung-Shun

    2015-08-15

    Ketamine abusers develop severe lower urinary tract symptoms. The major aims of the present study were to elucidate ketamine-induced ulcerative cystitis and bladder apoptosis in association with oxidative stress mediated by mitochondria and the endoplasmic reticulum (ER). Sprague-Dawley rats were distributed into three different groups, which received normal saline or ketamine for a period of 14 or 28 days, respectively. Double-labeled immunofluorescence experiments were performed to investigate tight junction proteins for urothelial barrier functions. A TUNEL assay was performed to evaluate the distribution of apoptotic cells. Western blot analysis was carried out to examine the expressions of urothelial tight junction proteins, ER stress markers, and apoptosis-associated proteins. Antioxidant enzymes, including SOD and catalase, were investigated by real-time PCR and immunofluorescence experiments. Ketamine-treated rats were found to display bladder hyperactivity. This bladder dysfunction was accompanied by disruptions of epithelial cadherin- and tight junction-associated proteins as well as increases in the expressions of apoptosis-associated proteins, which displayed features of mitochondria-dependent apoptotic signals and ER stress markers. Meanwhile, expressions of mitochondria respiratory subunit enzymes were significantly increased in ketamine-treated bladders. Conversely, mRNA expressions of the antioxidant enzymes Mn-SOD (SOD2), Cu/Zn-SOD (SOD1), and catalase were decreased after 28 days of ketamine treatment. These results demonstrate that ketamine enhanced the generation of oxidative stress mediated by mitochondria- and ER-dependent pathways and consequently contributed to bladder apoptosis and urothelial lining defects. Such oxidative stress-enhanced bladder cell apoptosis and urothelial barrier defects are potential factors that may play a crucial role in bladder overactivity and ulceration. PMID:26109091

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

    International Nuclear Information System (INIS)

    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.

  10. 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.

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

    Science.gov (United States)

    Yang, Jing-Iong; Tang, Jen-Yang; Liu, Ya-Sin; Wang, Hui-Ru; Lee, Sheng-Yang; Yen, Ching-Yu

    2016-01-01

    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. PMID:27195297

  12. INTRACELLULAR MECHANISMS OF A-TRICHOTHECENES INVOLVED IN THE REGULATION OF CELL SURVIVAL AND APOPTOSIS: A REVIEW

    Directory of Open Access Journals (Sweden)

    Marcela Capcarová

    2012-02-01

    Full Text Available Mycotoxins are secondary metabolites produced by filamentous fungi. Mycotoxins are worldwide contaminats of animal feed, food and food products. T-2 toxin and its metabolit HT-2 toxin are one of the most toxic mycotoxins of type A trichothecenes, which are produced mainly by Fusarium species. T-2 and HT-2 toxin cause a different toxic effects in both animal and human. They are inhibitors of DNA and RNA synthesis and synthesis of proteins in several cellular systems, immunosuppressive agents, induce lesions in hematopoetic, lymphoid and digestive tract, impact reproduction functions and cause oxidative stress. T-2 toxin is a strong cytotoxic mycotoxin, which can induce apoptosis of various cells. This review examine the T-2 toxin induce cytotoxicity up to apoptosis on various cells, for instance cells of imunite system, on ovarian granulosa cells as well as induction of maternal and fetal toxicity.

  13. 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.

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

    International Nuclear Information System (INIS)

    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

  15. Apaf-1-deficient fog mouse cell apoptosis involves hypopolarization of the mitochondrial inner membrane,ATP depletion and citrate accumulation

    Institute of Scientific and Technical Information of China (English)

    Iyoko Katoh; Shingo Sato; Nahoko Fukunishi; Hiroki Yoshida; Takasuke Imai; Shun-ichi Kurata

    2008-01-01

    To explore how the intrinsic apoptosis pathway is controlled in the spontaneous fog (forebrain overgrowth) mutant mice with an Apaf1 splicing deficiency,we examined spleen and bone marrow cells from Apaf1+/+(+/+) and Apaf1fog/fog (fog/fog) mice for initiator caspase-9 activation by cellular stresses.When the mitochondrial inner membrane potential (△Ψm) was disrupted by staurosporine,+/+ cells but not fog/fog cells activated caspase-9 to cause apoptosis,indicating the lack of apoptosomc (apoptosis protease activating factor 1 (Apaf-1)/cytochrome c/(d)ATP/procaspase-9) function in fog/fog cells.However,when a marginal (~20%) decrease in △Ψm was caused by hydrogen peroxide (0.1 mM),peroxynitrite donor 3-morpholinosydnonimine (0.1 mM) and UV-C irradiation (20 J/m2),both +/+ and fog/fog cells triggeredprocaspase-9 auto-processing and its downstream cascade activation.Supporting our previous results,procaspase-9 pre-existing in the mitochondria induced its auto-processing before the cytosolic caspase activation regardless of the geuotypes.Cellular ATP concentration significantly decreased under the hypoactive AΨm condition.Furthermore,we detected accumulation of citrate,a kosmotrope known to facilitate procaspase-9 dimerization,probably due to a feedback control of the Krebs cycle by the electron transfer system.Thus,mitochondrial in situ caspase-9 activation may be caused by the major metabolic reactions in response to physiological stresses,which may represent a mode of Apaf-1-independent apoptosis hypothesized from recent genetic studies.

  16. Involvement of P53 and Bax/Bad triggering apoptosis in thioacetamide-induced hepatic epithelial cells

    Institute of Scientific and Technical Information of China (English)

    Li-Hsuen Chen; Chia-Yu Hsu; Ching-Feng Weng

    2006-01-01

    AIM: Thioacetamide (TAA) has been used in studying liver fibrosis and cirrhosis, however, the mechanisms of TAA-induced apoptosis in liver are still unclear. The hepatic epithelial cell line clone 9 was cultured and treated with TAA to investigate the causes of cell death. METHODS: The cell viability of TAA-induced clone 9 cells was determined using MTT assay. Total cellular GSH in TAA-induced clone 9 cells was measured using a slight modification of the Tietze assay. The activity of caspase 3 in TAA-induced clone 9 cells was monitored by the cleavage of DEVD-p-nitroanaline. TUNEL assay and flow cytometry were applied for the determination of DNA fragmentation and the proportion of apoptosis in TAAinduced clone 9 cells, respectively. The alterations of caspase 3, Bad, Bax and Phospho-P53 contents in TAAinduced clone 9 cells were measured by Western blot. RESULTS: The experimental data indicated that TAA caused rat hepatic epithelial cell line clone 9 cell death in a dose-and time-dependent manner; 60% of the cells died (MTT assay) within 24 h after 100 mg/L TAA was applied. Apoptotic cell percentage (TUNEL assay) and caspase 3 activities were highest after 100 mg/L TAA was added for 8 h. The release of GSH and the elevation in caspase content after TAA treatment resulted in clone 9 cell apoptosis via oxidative stress and a caspasedependent mechanism. The phospho-p53, Bax and Bad protein expressions in clone 9 cells were increased after TAA treatment.CONCLUSION: These results reveal that TAA activates p53, increases caspase 3, Bax and Bad protein contents,perhaps causing the release of cytochrome c from mitochondria and the disintegration of membranes, leading to apoptosis of cells.

  17. Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury Roles of cytochrome c, Bax, Bid, and caspases

    International Nuclear Information System (INIS)

    The role of apoptosis in acetaminophen (AAP)-induced hepatic injury was investigated. Six hours after AAP administration to BALB/c mice, a significant loss of hepatic mitochondrial cytochrome c was observed that was similar in extent to the loss observed after in vivo activation of CD95 by antibody treatment. AAP-induced loss of mitochondrial cytochrome c coincided with the appearance in the cytosol of a fragment corresponding to truncated Bid (tBid). At the same time, tBid became detectable in the mitochondrial fraction, and concomitantly, Bax was found translocated to mitochondria. However, AAP failed to activate the execution caspases 3 and 7 as evidenced by a lack of procaspase processing and the absence of an increase in caspase-3-like activity. In contrast, the administration of the pan-inhibitor of caspases, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (but not its analogue benzyloxycarbonyl-Phe-Ala-fluoromethylketone) prevented the development of liver injury by AAP and the appearance of apoptotic parenchymal cells. This correlated with the inhibition of the processing of Bid to tBid. The caspase inhibitor failed to prevent both the redistribution of Bax to the mitochondria and the loss of cytochrome c. In conclusion, apoptosis is an important causal event in the initiation of the hepatic injury inflicted by AAP. However, as suggested by the lack of activation of the main execution caspases, apoptosis is not properly executed and degenerates into necrosis

  18. Constitutional economics

    OpenAIRE

    Ludwig Van den Hauwe

    2005-01-01

    This article summarizes the main points discussed at the seminar ?Constitutional Economics: Cinderella in the Czech Economic Community? held by the Czech Economic Association in February 2000. The main speaker at the seminar was Prof. Karel Kouba (Faculty of Social Sciences, Charles University, Prague), who characterized constitutional economics as a still relatively new and promising research program. The ensuing discussion concerned several topics, including the relationship between public ...

  19. Hypericum perforatum Attenuates Spinal Cord Injury-Induced Oxidative Stress and Apoptosis in the Dorsal Root Ganglion of Rats: Involvement of TRPM2 and TRPV1 Channels.

    Science.gov (United States)

    Özdemir, Ümit Sinan; Nazıroğlu, Mustafa; Şenol, Nilgün; Ghazizadeh, Vahid

    2016-08-01

    Oxidative stress and cytosolic Ca(2+) overload have important roles on apoptosis in dorsal root ganglion (DRG) neurons after spinal cord injury (SCI). Hypericum perforatum (HP) has an antioxidant property in the DRGs due to its ability to modulate NADPH oxidase and protein kinase C pathways. We aimed to investigate the protective property of HP on oxidative stress, apoptosis, and Ca(2+) entry through transient receptor potential melastatin 2 (TRPM2) and transient receptor potential vanilloid 1 (TRPV1) channels in SCI-induced DRG neurons of rats. Rats were divided into four groups as control, HP, SCI, and SCI + HP. The HP groups received 30 mg/kg HP for three concessive days after SCI induction. The SCI-induced TRPM2 and TRPV1 currents and cytosolic free Ca(2+) concentration were reduced by HP. The SCI-induced decrease in glutathione peroxidase and cell viability values were ameliorated by HP treatment, and the SCI-induced increase in apoptosis, caspase 3, caspase 9, cytosolic reactive oxygen species (ROS) production, and mitochondrial membrane depolarization values in DRG of SCI group were overcome by HP treatment. In conclusion, we observed a protective role of HP on SCI-induced oxidative stress, apoptosis, and Ca(2+) entry through TRPM2 and TRPV1 in the DRG neurons. Our findings may be relevant to the etiology and treatment of SCI by HP. Graphical Abstract Possible molecular pathways of involvement of Hypericum perforatum (HP) on apoptosis, oxidative stress, and calcium accumulation through TRPM2 and TRPV1 channels in DRG neurons of SCI-induced rats. The TRPM2 channel is activated by ADP-ribose and oxidative stress through activation of ADP-ribose pyrophosphate although it was inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and 2-aminoethyl diphenylborinate (2APB). The TRPV1 channel is activated by oxidative stress and capsaicin and it is blocked by capsazepine. Injury in the DRG can result in augmented ROS release, leading to Ca(2+) uptake through

  20. Butanol-Partitioned Extraction from Aqueous Extract of Gracilaria tenuistipitata Inhibits Cell Proliferation of Oral Cancer Cells Involving Apoptosis and Oxidative Stress.

    Science.gov (United States)

    Yeh, Chi-Chen; Li, Kun-Tzu; Tang, Jen-Yang; Wang, Hui-Ru; Liu, Jing-Ru; Huang, Hurng-Wern; Chang, Fang-Rong; Tsai, Cheng-En; Lo, I-Wen; Huang, Ming-Yii; Chang, Hsueh-Wei

    2016-05-01

    We have previously found that the aqueous extract of Gracilaria tenuistipitata (AEGT) and its partitioned fractions had antioxidant properties in biochemical assays. Although the butanol-partitioned fraction of AEGT (AEGT-pBuOH) had a stronger antioxidant performance than AEGT, its biological effects are still unknown. In this study, the cellular responses of oral cancer cells to AEGT-pBuOH were monitored in terms of cell viability, cell cycle progression, apoptosis, and oxidative stress responses. In an ATP content assay, the cell viability of oral cancer cells treated with AEGT-pBuOH was dose responsively inhibited (p < 0.005). For flow cytometry, AEGT-pBuOH was also found to dose responsively induce cell cycle disturbance by propidium iodide (PI) staining and to induce apoptosis by annexin V/PI and pan-caspase staining (p < 0.005). In AEGT-pBuOH-treated oral cancer cells, the reactive oxygen species (ROS) was increased and mitochondrial membrane potential was decreased in a dose-response manner (p < 0.005). These results suggest that AEGT-pBuOH inhibited the proliferation and induced apoptosis of oral cancer cells involving the ROS generation and mitochondrial depolarization. PMID:27138906

  1. PI3K/Akt signaling pathway involved in regulation of T lymphocyte activation and apoptosis mediated by CD3e

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    To study the expression and kinase activity of phosphatidylinositol 3′-kinase (PI3K) and protein kinase B (PKB or Akt) during activation and apoptosis of human Jurkat T lymphocytes (TJK) with stable expression of CD8e chimera fused human CD8a extracellular and transmembra-ne domains to intracellular domain of mouse CD3e, Western blot, kinase activities detection and immunoprecipitation were carried out. It was shown that Jurkat cells with expres-sion of wild type chimera CD8e died by apoptosis after con-tinuous stimulation of anti-CD8 monoclonal antibody. The expressions of PI3K and Akt, and the kinase activity of Akt remarkably increased during the process. However, this phenomenon did not occur in the Jurkat cells (T1JK) with expression of the mutant of CD8e chimera (Y170F), sug-gesting that PI3K/Akt signaling pathway is involved in acti-vation and apoptosis of T lymphocyte mediated by CD3e.

  2. Paroxetine-induced apoptosis in human osteosarcoma cells: Activation of p38 MAP kinase and caspase-3 pathways without involvement of [Ca2+]i elevation

    International Nuclear Information System (INIS)

    Selective serotonin reuptake inhibitors (SSRIs), a group of antidepressants, are generally used for treatment of various mood and anxiety disorders. There has been much research showing the anti-tumor and cytotoxic activities of some antidepressants; but the detailed mechanisms were unclear. In cultured human osteosarcoma cells (MG63), paroxetine reduced cell viability in a concentration- and time-dependent manner. Paroxetine caused apoptosis as assessed by propidium iodide-stained cells and increased caspase-3 activation. Although immunoblotting data revealed that paroxetine could activate the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), only SB203580 (a p38 MAPK inhibitor) partially prevented cells from apoptosis. Paroxetine also induced [Ca2+]i increases which involved the mobilization of intracellular Ca2+ stored in the endoplasmic reticulum and Ca2+ influx from extracellular medium. However, pretreatment with BAPTA/AM, a Ca2+ chelator, to prevent paroxetine-induced [Ca2+]i increases did not protect cells from death. The results suggest that in MG63 cells, paroxetine caused Ca2+-independent apoptosis via inducing p38 MAPK-associated caspase-3 activation

  3. Adiponectin Inhibits Nutrient Transporters and Promotes Apoptosis in Human Villous Cytotrophoblasts: Involvement in the Control of Fetal Growth.

    Science.gov (United States)

    Duval, Fabien; Santos, Esther Dos; Poidatz, Dorothée; Sérazin, Valérie; Gronier, Héloïse; Vialard, François; Dieudonné, Marie-Noëlle

    2016-05-01

    The placenta exchanges nutrients between the mother and the fetus and requires a constant abundant energy supply. Adiponectin (a cytokine produced primarily by adipose tissue) controls glucose and lipid homeostasis. It is well-known that maternal serum adiponectin levels are inversely related to birth weight, suggesting that adiponectin has a negative effect on fetal growth. This effect appears to be related to the control of nutrient transporters in human placenta. However, the underlying molecular mechanisms have not yet been characterized. In the present work, we studied adiponectin's direct effect on human primary cytotrophoblasts from first-trimester placenta. Our result showed that in placental cells, adiponectin 1) inhibits the expression of the major glucose transporters (GLUT1 and GLUT12) and sodium-coupled neutral amino acid transporters (SNAT1, SNAT2, and SNAT4), 2) enhances total ATP production but decreases lactate production, 3) inhibits mitochondrial biogenesis and function, and 4) stimulates cell death by enhancing the expression of the pro-apoptotic B-cell lymphoma-2 (BCL-2)-associated X protein (BAX) and tumor protein P53 (TP53) gene expression and inducing the caspase activity. Small-interfering RNA mediating the down-regulation of adiponectin receptors (ADIPOR1 and ADIPOR2) was used to demonstrate that adiponectin effects on placental nutrient transport and apoptosis seemed to be essentially mediated by these specific receptors. Taken as a whole, these results strongly suggest that adiponectin regulates human placental function by limiting nutrient transporter expression and inducing apoptosis. These findings may help us to better understand adiponectin's role in placental pathologies such as intrauterine growth restriction, which is characterized by fetal weight loss and drastic apoptosis of placental cells. PMID:27030046

  4. Regulation of HSP27 on NF-κB pathway activation may be involved in metastatic hepatocellular carcinoma cells apoptosis

    Directory of Open Access Journals (Sweden)

    Sun Lu

    2009-03-01

    Full Text Available Abstract Background During the process of metastasis, cells are subjected to various apoptotic stimuli. Aberrant expression of apoptotic regulators often contribute to cell metastasis. Heat shock protein 27(HSP27 is confirmed as an apoptosis regulator, but its antiapoptotic mechanism in metastatic hepatocellular carcinoma (HCC cells remains unclear. Methods Levels of HSP27 protein and its phosphorylation in Hep3B, MHCC97L to MHCC97H cells with different metastatic potentials were determined by western blot analysis. MHCC97H cells were transfected with specific small interference RNA (siRNA against HSP27. The in vitro migration and invasion potentials of cells were evaluated by Transwell assay. The apoptosis ratio of MHCC97H cells was analyzed by TUNEL staining and Flow Cytometry. Alteration of signal transduction pathway after HSP27 knockdown in MHCC97H cells was evaluated through a Human Q Series Signal Transduction in Cancer Gene Array analysis. Nuclear NF-κB contentration and endogenous IKK activity were demonstrated by ELISA assay. The association of IKKα, IKKβ, IκBα with HSP27 and the association between IKKβ and IKKα in MHCC97H cells were determined by co-immunoprecipitation assay followed by western blot analysis. Results HSP27 protein and its phosphorylation increased in parallel with enhanced metastatic potentials of HCC cells. siRNA-mediated HSP27 knockdown in MHCC97H significantly suppressed cells migration and invasion in vitro and induced cell apoptosis; the prominently altered signal transduction pathway was NF-κB pathway after HSP27 knockdown in MHCC97H cells. Furthermore, inhibition of HSP27 expression led to a significant decrease of nuclear NF-κB contentration and endogenous IKK activity. In addition, HSP27 was associated with IKKα, IKKβ, IκBα in three HCC cells above. ELISA assay and western blot analysis also showed a decrease of the association between IKKβ and IKKα, the association between phosphor-HSP27 and

  5. Regulation of HSP27 on NF-κB pathway activation may be involved in metastatic hepatocellular carcinoma cells apoptosis

    International Nuclear Information System (INIS)

    During the process of metastasis, cells are subjected to various apoptotic stimuli. Aberrant expression of apoptotic regulators often contribute to cell metastasis. Heat shock protein 27(HSP27) is confirmed as an apoptosis regulator, but its antiapoptotic mechanism in metastatic hepatocellular carcinoma (HCC) cells remains unclear. Levels of HSP27 protein and its phosphorylation in Hep3B, MHCC97L to MHCC97H cells with different metastatic potentials were determined by western blot analysis. MHCC97H cells were transfected with specific small interference RNA (siRNA) against HSP27. The in vitro migration and invasion potentials of cells were evaluated by Transwell assay. The apoptosis ratio of MHCC97H cells was analyzed by TUNEL staining and Flow Cytometry. Alteration of signal transduction pathway after HSP27 knockdown in MHCC97H cells was evaluated through a Human Q Series Signal Transduction in Cancer Gene Array analysis. Nuclear NF-κB contentration and endogenous IKK activity were demonstrated by ELISA assay. The association of IKKα, IKKβ, IκBα with HSP27 and the association between IKKβ and IKKα in MHCC97H cells were determined by co-immunoprecipitation assay followed by western blot analysis. HSP27 protein and its phosphorylation increased in parallel with enhanced metastatic potentials of HCC cells. siRNA-mediated HSP27 knockdown in MHCC97H significantly suppressed cells migration and invasion in vitro and induced cell apoptosis; the prominently altered signal transduction pathway was NF-κB pathway after HSP27 knockdown in MHCC97H cells. Furthermore, inhibition of HSP27 expression led to a significant decrease of nuclear NF-κB contentration and endogenous IKK activity. In addition, HSP27 was associated with IKKα, IKKβ, IκBα in three HCC cells above. ELISA assay and western blot analysis also showed a decrease of the association between IKKβ and IKKα, the association between phosphor-HSP27 and IKK complex, and an increase of total IκBα but

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

    International Nuclear Information System (INIS)

    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

  7. Constitutional Conservatism

    Science.gov (United States)

    Berkowitz, Peter

    2009-01-01

    After their dismal performance in election 2008, conservatives are taking stock. As they examine the causes that have driven them into the political wilderness and as they explore paths out, they should also take heart. After all, election 2008 shows that America's constitutional order is working as designed. Indeed, while sorting out their errors…

  8. 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.

  9. Apoptosis-Related Factors in the Luteal Phase of the Domestic Cat and Their Involvement in the Persistence of Corpora Lutea in Lynx.

    Directory of Open Access Journals (Sweden)

    Olga Amelkina

    Full Text Available The corpus luteum (CL is a transient gland formed in the ovary after ovulation and is the major source of progesterone. In the Iberian and Eurasian lynx, CL physiologically persist after parturition and retain their capacity to produce progesterone, thus suppressing the ovarian activity. This unique reproductive characteristic has a big impact on the success of assisted reproduction techniques in the endangered Iberian lynx. The mechanisms behind CL persistence are not yet understood and require extensive studies on potential luteotropic and luteolytic factors in felids. Because the apoptosis system has been shown to be involved in structural regression of CL in many species, we aimed to investigate the capacity of perCL to undergo apoptosis. In addition, we performed initial studies on the apoptosis system in the luteal phase of the domestic cat. No previous research on this system has been made in this species. Our factors of interest included agents of the intrinsic apoptosis pathway, i.e., pro-survival B-cell CLL/lymphoma 2 (BCL2 and pro-apoptotic BCL2-associated X protein (BAX, the executioner caspase-3 (CASP3, as well as of the extrinsic pathway, i.e., pro-apoptotic receptor FAS, and tumor necrosis factor (TNF and its receptors (pro-apoptotic TNFRSF1A and pro-survival TNFRSF1B. We analyzed the relative mRNA levels of these factors, as well as protein localization of CASP3 and TNF during stages of pregnancy and the non-pregnant luteal phase in CL of domestic cats. The same factors were investigated in freshly ovulated CL (frCL and perCL of Iberian and Eurasian lynx, which were histologically analyzed. All factors were present in the CL tissue of both domestic cat and lynx throughout all analyzed stages. The presence of pro-apoptotic factors BAX, CASP3, FAS and TNFRSF1A in perCL of the Eurasian and Iberian lynx might indicate the potential sensitivity of perCL to apoptotic signals. The expression of pro-survival factors BCL2 and TNFRSF1B was

  10. 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...... covered, illustrating several models such as the Wilson equation and NRTL equation, along with their solution strategies. A section shows how to use experimental data to regress the property model parameters using a least squares approach. A full model analysis is applied in each example that discusses...

  11. Sphingosine in apoptosis signaling.

    Science.gov (United States)

    Cuvillier, Olivier

    2002-12-30

    The sphingolipid metabolites ceramide, sphingosine, and sphingosine 1-phosphate contribute to controlling cell proliferation and apoptosis. Ceramide and its catabolite sphingosine act as negative regulators of cell proliferation and promote apoptosis. Conversely, sphingosine 1-phosphate, formed by phosphorylation of sphingosine by a sphingosine kinase, has been involved in stimulating cell growth and inhibiting apoptosis. As the phosphorylation of sphingosine diminishes apoptosis, while dephosphorylation of sphingosine 1-phosphate potentiates it, the role of sphingosine as a messenger of apoptosis is of importance. Herein, the effects of sphingosine on diverse signaling pathways implicated in the apoptotic process are reviewed. PMID:12531549

  12. 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)

    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

  13. 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.

  14. Apoptosis and p53 are not involved in the anti-tumor efficacy of 125I-labeled monoclonal antibodies targeting the cell membrane

    International Nuclear Information System (INIS)

    Introduction: 125I-labeled monoclonal antibodies (125I-mAbs) can efficiently treat small solid tumors. Here, we investigated the role of apoptosis, autophagy and mitotic catastrophe in 125I-mAb toxicity in p53−/− and p53+/+ cancer cells. Methods: We exposed p53−/− and p53+/+ HCT116 cells to increasing activities of internalizing (cytoplasmic location) anti-HER1 125I-mAbs, or non-internalizing (cell surface location) anti-CEA 125I-mAbs. For each targeting model we established the relationship between survival and mean nucleus absorbed dose using the MIRD formalism. Results: In both p53−/− and p53+/+ HCT116 cells, anti-CEA 125I-mAbs were more cytotoxic per Gy than anti-HER1 125I-mAbs. Sensitivity to anti-CEA 125I-mAbs was p53-independent, while sensitivity to anti-HER1 125I-mAbs was higher in p53−/− HCT 116 cells, suggesting that they act through different signaling pathways. Apoptosis was only induced in p53+/+ HCT116 cells and could not explain cell membrane radiation sensitivity. Inhibition of autophagy did not modify the cell response to 125I-mAbs. By contrast, mitotic death was similarly induced in both p53−/− and p53+/+ HCT116 cells by the two types of 125I-mAbs. We also showed using medium transfer experiments that γ-H2AX foci were produced in bystander cells. Conclusion: Cell membrane sensitivity to 125I-mAbs is not mediated by apoptosis and is p53-independent. Bystander effects-mediated mitotic death could be involved in the efficacy of 125I-mAbs binding cell surface receptors

  15. 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

  16. Inhibition of Myeloid Cell Leukemia 1 and Activation of Caspases Are Critically Involved in Gallotannin-induced Apoptosis in Prostate Cancer Cells.

    Science.gov (United States)

    Park, Eunkyung; Kwon, Hee Young; Jung, Ji Hoon; Jung, Deok-Beom; Jeong, Arong; Cheon, Jinhong; Kim, Bonglee; Kim, Sung-Hoon

    2015-08-01

    Although gallotannin contained in several medicinal plants was known to have multi-biological activities, such as antioxidant, antiinflammatory, antimicrobial, immunomodulatory, and antitumor effects, the underlying apoptotic mechanism of gallotannin is not fully understood so far. Thus, in the present study, the apoptotic mechanism of gallotannin was elucidated in DU145, PC-3, and M2182 prostate cancer cells in association with myeloid cell leukemia 1 (Mcl-1) signaling. Gallotannin exerted dose-dependent cytotoxicity in DU145, PC-3, and M2182 prostate cancer cells. Also, gallotannin showed apoptotic morphological features and increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells and sub-G1 accumulation in three prostate cancer cell lines. Consistently, gallotannin cleaved poly (ADP-ribose) polymerase (PARP) and attenuated the expression of procaspases 9 and 3 in three prostate cancer cell lines. Furthermore, gallotannin attenuated the expression of survival genes such as Mcl-1, B-cell lymphoma 2, and B-cell lymphoma 2 extra large in three prostate cancer cell lines. Interestingly, overexpression of Mcl-1 reversed the ability of gallotannin to cleave PARP and increase sub-G1 population in three prostate cancer cell lines. Conversely, silencing of Mcl-1 enhanced apoptosis by gallotannin in three prostate cancer cell lines by FACSCalibur (Becton Dickinson, Franklin Lakes, NJ, USA). Taken together, our findings demonstrate that inhibition of Mcl-1 and activation of caspases are critically involved in gallotannin-induced apoptosis in prostate cancer cells. PMID:26014377

  17. Antiangiogenesis, Loss of Cell Adhesion and Apoptosis Are Involved in the Antitumoral Activity of Proteases from V. cundinamarcensis (C. candamarcensis in Murine Melanoma B16F1

    Directory of Open Access Journals (Sweden)

    Dalton Dittz

    2015-03-01

    Full Text Available The proteolytic enzymes from V. cundinamarcensis latex, (P1G10, display healing activity in animal models following various types of lesions. P1G10 or the purified isoforms act as mitogens on fibroblast and epithelial cells by stimulating angiogenesis and wound healing in gastric and cutaneous ulcers models. Based on evidence that plant proteinases act as antitumorals, we verified this effect on a murine melanoma model. The antitumoral effect analyzed mice survival and tumor development after subcutaneous administration of P1G10 into C57BL/6J mice bearing B16F1 low metastatic melanoma. Possible factors involved in the antitumoral action were assessed, i.e., cytotoxicity, cell adhesion and apoptosis in vitro, haemoglobin (Hb, vascular endothelial growth factor (VEGF, tumor growth factor-β (TGF-β, tumor necrosis factor-α (TNF-α content and N-acetyl-glucosaminidase (NAG activity. We observed that P1G10 inhibited angiogenesis measured by the decline of Hb and VEGF within the tumor, and TGF-β displayed a non-significant increase and TNF-α showed a minor non-significant reduction. On the other hand, there was an increase in NAG activity. In treated B16F1 cells, apoptosis was induced along with decreased cell binding to extracellular matrix components (ECM and anchorage, without impairing viability.

  18. Involvement of endoplasmic reticulum stress and p53 in lncRNA MEG3-induced human hepatoma HepG2 cell apoptosis.

    Science.gov (United States)

    Chen, Rui-Pei; Huang, Zhen-Lun; Liu, Li-Xuan; Xiang, Meng-Qi; Li, Guo-Ping; Feng, Jia-Lin; Liu, Bin; Wu, Ling-Fei

    2016-09-01

    Long non-coding RNAs (lncRNAs) play important roles in diverse biological processes. Although downregulation of lncRNA maternally expressed gene 3 (MEG3) has been identified in several types of cancers, little is known concerning its biological role and regulatory mechanism in hepatoma. Our previous studies demonstrated that MEG3 induces apoptosis in a p53-dependent manner. The aim of the present study was to determine whether endoplasmic reticulum (ER) stress is involved in MEG3‑induced apoptosis. Recombinant lentiviral vectors containing MEG3 (Lv‑MEG3) were constructed and transfected into HepG2 cells. A 3‑(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, RT‑PCR, flow cytometry, western blot analysis, immunofluorescence and immunohistochemistry were applied. Transfected HepG2 cells were also transplanted into nude mice, and the tumor growth curves were determined. The results showed that the recombinant lentivirus of MEG3 was transfected successfully into the HepG2 cells and the expression level of MEG3 was significantly increased. Ectopic expression of MEG3 inhibited HepG2 cell proliferation in vitro and in vivo, and also induced apoptosis. Ectopic expression of MEG3 increased ER stress‑related proteins 78‑kDa glucose‑regulated protein (GRP78), inositol‑requiring enzyme 1 (IRE1), RNA‑dependent protein kinase‑like ER kinase (PERK), activating transcription factor 6 (ATF6), C/EBP homologous protein (CHOP), caspase‑3, as well as p53 and NF‑κB expression accompanied by NF‑κB translocation from the cytoplasm to the nucleus. Furthermore, inhibition of NF‑κB with Bay11‑7082 decreased p53 expression in the MEG3‑transfected cells. These results indicate that MEG3 inhibits cell proliferation and induces apoptosis, partially via the activation of the ER stress and p53 pathway, in which NF‑κB signaling is required for p53 activation in ER stress. PMID:27432655

  19. Oxidative stress pathways involved in cytotoxicity and genotoxicity of titanium dioxide (TiO2) nanoparticles on cells constitutive of alveolo-capillary barrier in vitro.

    Science.gov (United States)

    Hanot-Roy, Maïté; Tubeuf, Emilie; Guilbert, Ariane; Bado-Nilles, Anne; Vigneron, Pascale; Trouiller, Bénédicte; Braun, Anne; Lacroix, Ghislaine

    2016-06-01

    The health risks of nanoparticles remain a serious concern given their prevalence from industrial and domestic use. The primary route of titanium dioxide nanoparticle exposure is inhalation. The extent to which nanoparticles contribute to cellular toxicity is known to associate induction of oxidative stress. To investigate this problem further, the effect of titanium dioxide nanoparticles was examined on cell lines representative of alveolo-capillary barrier. The present study showed that all nanoparticle-exposed cell lines displayed ROS generation. Macrophage-like THP-1 and HPMEC-ST1.6R microvascular cells were sensitive to endogenous redox changes and underwent apoptosis, but not alveolar epithelial A549 cells. Genotoxic potential of titanium dioxide nanoparticles was investigated using the activation of γH2AX, activation of DNA repair proteins and cell cycle arrest. In the sensitive cell lines, DNA damage was persistent and activation of DNA repair pathways was observed. Moreover, western blot analysis showed that specific pathways associated with cellular stress response were activated concomitantly with DNA repair or apoptosis. Nanoparticles-induced oxidative stress is finally signal transducer for further physiological effects including genotoxicity and cytotoxicity. Within activated pathways, HSP27 and SAPK/JNK proteins appeared as potential biomarkers of intracellular stress and of sensitivity to endogenous redox changes, respectively, enabling to predict cell behavior. PMID:26928046

  20. 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

  1. Glutathione, N-acetylcysteine and lipoic acid down-regulate starvation-induced apoptosis, RANKL/OPG ratio and sclerostin in osteocytes: involvement of JNK and ERK1/2 signalling.

    Science.gov (United States)

    Fontani, Filippo; Marcucci, Gemma; Iantomasi, Teresa; Brandi, Maria Luisa; Vincenzini, Maria Teresa

    2015-04-01

    Osteocyte apoptosis due to microdamage and/or oxidative stress is related to increased local bone turnover and resorption observed in various bone diseases. Previous data on osteoblasts and osteoclasts have linked reactive oxygen species and antioxidants to bone remodelling. This study performs a comprehensive analysis on the effect of antioxidants such as glutathione (GSH), N-acetylcysteine and lipoic acid (LA) on starvation-induced osteocyte apoptosis and on cytokines involved in bone remodelling such as the receptor activator kB ligand (RANKL), osteoprotegerin (OPG) and sclerostin. For this study, apoptosis was induced by serum starvation in a murine osteocyte-like cell line MLO-Y4; this condition mimics in part osteocyte apoptosis due to microdamage. The results show that starvation-induced apoptosis and expression of RANKL, OPG and sclerostin are redox regulated processes. All antioxidants are able to inhibit the apoptosis due to starvation. They down-regulate the expression and the release of RANKL, the expression of sclerostin and RANKL/OPG ratio, whereas they only in part up-regulate OPG expression. Antioxidants mediate their effect on starvation-induced apoptosis by JNK signalling and on cytokine expression by both JNK and ERK1/2 activities. This study shows the possible involvement of biological antioxidants such as GSH and LA on redox regulated mechanisms related to apoptosis and expression of cytokines involved in bone remodelling. Moreover, it suggests that both JNK and ERK1/2 may be useful biological targets for drugs affecting bone diseases associated with increased oxidative stress. PMID:25660312

  2. MicroRNA-205 directly targets Krüppel-like factor 12 and is involved in invasion and apoptosis in basal-like breast carcinoma.

    Science.gov (United States)

    Guan, Bing; Li, Qing; Shen, Li; Rao, Qiu; Wang, Yan; Zhu, Yun; Zhou, Xiao-Jun; Li, Xiao-Hong

    2016-08-01

    We investigated microRNAs (miRs) specific to its target gene and exerting distinct biological functions for basal-like breast carcinoma (BLBC). Total RNA was extracted and subjected to miR microarray and bioinformatics analysis. Based on the comprehensive analysis, expression of miRs including its target was analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blot analysis and immunohistochemistry (IHC). Further functional analyses were conducted including proliferation, invasion and apoptosis. miR-205 was identified as downregulated (less than 0.5-fold) in BLBC relatively to normal control (NC). Gene ontology (GO) analysis suggested miR-205 may directly targeted Krüppel-like factor 12 (KLF12; degree=4). Luciferase assay revealed miR-205 directly targeted KLF12 through binding its 3'-untranslated region (3'-UTR; p=0.0016). qRT-PCR and western blot analysis showed miR-205 expression was low in cells (p=0.007) and tumor tissues (n=6; p=0.0074), and KLF12 RNA/protein was observed at high levels in cells (p=0.0026; p=0.0079) and tumor tissues (n=9; p=0.0083); knock-up of miR-205 increased its expression (p=0.0021) but reduced KLF12 RNA/protein levels (p=0.0038; p=0.009) in cells. Modulation of miR-205 expression by transfecting its mimics in cells, was involved in invasion (p=0.00175) and apoptosis (p=0.006). In conclusion, our results supported that miR-205 was a miR specific to BLBC which functioned as tumor suppressor gene through directly targeting and negatively regulating proto-oncogene KLF12. miR-205 dysregulation was involved in invasion and apoptosis. miR-205 and KLF12 provided a potential diagnosis biomarker and therapeutic approach for BLBC. PMID:27278159

  3. ER stress and autophagy are involved in the apoptosis induced by cisplatin in human lung cancer cells

    OpenAIRE

    Shi, Shaomin; Tan, Ping; Yan, Bingdi; Gao, Rong; Zhao, Jianjun; Jing WANG; Guo, Jia; Li, Ning; Ma, Zhongsen

    2016-01-01

    Cisplatin [cis-diamminedichloroplatinum II (CDDP)] is one of the most classical and effective chemotherapeutic drugs for the treatment of cancers including lung cancer. However, the presence of cisplatin resistance in cancer lowers its curative effect and limits its usage in the clinic. The aim of the present study was to investigate the underlying mechanisms of cisplatin resistance in lung cancer involving endoplasmic reticulum (ER) stress and autophagy. In the present study, we detected the...

  4. Constitutional Law--Elective.

    Science.gov (United States)

    Gallagher, Joan; Wood, Robert J.

    The elective unit on Constitutional Law is intended for 11th and 12th grade students. The unit is designed around major course goals which are to develop those concepts whereby students recognize and understand the following three topic areas: 1) Role of the Federal Judicial Branch of Government, 2) Supreme Court Cases Involving the Three Branches…

  5. 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)

    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 α1-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 α1-adrenoceptors in this cellular response is suggested. Labedipinedilol-A-induced growth inhibition was associated with G0/G1 arrest, and G2/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 α1-adrenoceptor blockade, and the apoptotic effects of labedipinedilol-A primarily through caspases and

  6. Down-regulation of Sonic hedgehog signaling pathway activity is involved in 5-fluorouracil-induced apoptosis and motility inhibition in Hep3B cells

    Institute of Scientific and Technical Information of China (English)

    Qiyu Wang; Shuhong Huang; Ling Yang; Ling Zhao; Yuxia Yin; Zhongzhen Liu; Zheyu Chen; Hongwei Zhang

    2008-01-01

    The Sonic hedgehog (SHh) pathway plays a critical role in normal embryogenesis and carcinogenesis, but its function in cancer cells treated with 5-fluorouracil (5-FU) remains unknown. We examined the expression of a subset of SHh signaling pathway genes, including SHh, SMO, PTC1, Su(Fu) and HIP in human hepatocellular carcinoma (HCC) cell lines,Hep3B and HepG2, treated with 5-FU by reverse transcriptionpolymerase chain reaction. Using trypan blue analysis,3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling assay, we also detected the apoptosis of Hep3B cells resulting from the transfection of pCS2-Gli1 expression vector combined with 5-FU treatment.The motility of the cells was detected by scratch wound closure assay. The expression and subcellular location of PTC1 protein in Hep3B cells treated by 5-FU were also investigated by Western blot analysis and immunofluorescent microscopy. The results indicated that the expression of SHh pathway target molecules at both messenger RNA and protein levels are evidently down-regulated in Hep3B cells treated with 5-FU. The overexpression of Gli1 restores cell viability and, to some extent, the migration abilities inhibited by 5-FU.Furthermore, 5-FU treatment affects the subcellular localization of PTC1 protein, a key member in SHh signaling pathway. Our data showed that the down-regulation of SHh signaling pathway activity was involved in 5-FU-induced apoptosis and the inhibition of motility in hedgehog-activated HCC cell lines. This implies that the combination of SHh signaling pathway inhibitor and 5-FU-based chemotherapy might represent a more promising strategy against HCC.

  7. Extensive macrophage accumulation in young and old Niemann-Pick C1 model mice involves the alternative, M2, activation pathway and inhibition of macrophage apoptosis.

    Science.gov (United States)

    Deutsch, Gail; Muralidhar, Akshay; Le, Ellen; Borbon, Ivan A; Erickson, Robert P

    2016-03-10

    We have studied the pathophysiology of lung disease which occurs in two mouse models of Niemann-Pick C1 disease. We utilized Npc1(-/-) mice transgenic for normal gene expression in glia or neurons and glia at ages several fold the usual and a mouse model of the juvenile form of NPC1, a point mutation, at one age to confirm some findings. Lung weights, as per cent of body weight, increase much more than liver and spleen weights. Although pulmonary function parameters only vary for hysteresis between young and older Npc1(-/-) mice, they are markedly different than those found in normal control mice. Cholesterol accumulation continued in the older mice but sphingosine-1-phosphate was not increased. Bronchoalveolar lavage (BAL) showed a massive increase (26×) in the number of macrophages. Histologic examination from the older, transgenic Npc1(-/-) mice showed small foci of alveolar proteinosis and evidence of hemorrhage, as well as dense macrophage accumulation. A large subset of macrophages was immunopositive for Fizz1 or arginase-1, markers of the alternative activation pathway, while no Fizz1 or arginase-1 positive macrophages were found in wild-type mice. The percentage of marker positive macrophages was relatively stable at 5-10% at various ages and within the 2 transgenic models. Phosphohistone H3 and Ki67 showed low levels of proliferation of these macrophages. Apoptosis was prominent within lung capillary endothelial cells, but limited within macrophages. Thus, activation of the alternative pathway is involved in Niemann-Pick C1 associated pulmonary macrophage accumulation, with low proliferation of these cells balanced by low levels of apoptosis. PMID:26707209

  8. Involvement of sphingosine in mitochondria-dependent Fas-induced apoptosis of type II Jurkat T cells.

    Science.gov (United States)

    Cuvillier, O; Edsall, L; Spiegel, S

    2000-05-26

    Exposure to anti-Fas antibody in Jurkat cells (type II cells), which are characterized by a weak caspase-8 activation at the death-inducing signaling complex (DISC), induced a biphasic increase in ceramide levels. The early generation of ceramide preceded transient activation of acidic ceramidase and subsequent production of sphingosine, followed by cytochrome c release, activation of caspases-2, -3, -6, -7, -8, and -9, Bid cleavage, and a later sustained ceramide accumulation. The caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone inhibited early increases of ceramide and sphingosine, whereas overexpression of Bcl-x(L) had no effect, and both prevented the later sustained ceramide accumulation. Exogenous sphingosine, as well as cell-permeable C(2)-ceramide, induced cytochrome c release from mitochondria in a caspase-independent fashion leading to activation of caspase-9 and executioner caspases and, surprisingly, activation of the initiator caspase-8 and processing of its substrate Bid. These effects were also completely abolished by Bcl-x(L) overexpression. Our results suggest that sphingosine might also be involved in the mitochondria-mediated pathway of Fas-induced cell death in type II cells. PMID:10747891

  9. 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.

  10. What Is a Constitution?

    Science.gov (United States)

    OAH Magazine of History, 1988

    1988-01-01

    Provides a lesson plan designed to help students better understand the concept of a constitution, distinguish constitutional law from statutory law, and recognize examples of constitutional government. (BSR)

  11. 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)

    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

  12. 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.

  13. Involvement of stress-activated protein kinase and p38 mitogen-activated protein kinase in mIgM-induced apoptosis of human B lymphocytes

    OpenAIRE

    Graves, J. D.; Draves, K. E.; Craxton, A.; Saklatvala, J; Krebs, E. G.; Clark, E. A.

    1996-01-01

    Despite intensive efforts, the intracellular signaling pathways that mediate apoptosis remain unclear. The human B lymphoma cell line, B104, possesses characteristics that make it an attractive model for analysis of receptor-mediated apoptosis. Although these cells express both membrane IgM (mIgM) and membrane IgD (mIgD) crosslinking mIgM results in significant apoptosis while crosslinking mIgD does not. Our results show that crosslinking mIgM but not mIgD induced ...

  14. Gene network revealed involvements of Birc2, Birc3 and Tnfrsf1a in anti-apoptosis of injured peripheral nerves.

    Directory of Open Access Journals (Sweden)

    Yongjun Wang

    Full Text Available Crush injury or axotomy of peripheral nerves results in the rapid production of the inflammatory cytokines, which were confirmed in various models, to some extent, to be noxious to the myelin sheath or Schwann cells (SCs. TNF-α is one of the primary initiators of the inflammatory cascade and exerts pleiotropic functions in the physiological conditions by binding to its receptors, type I (TNFRI and type II (TNFRII. The pathway molecules TNFRI, Birc2 and Birc3 play key roles during the activation of the signaling. Injured peripheral nerves, preventing them from TNF-α-mediated destruction and proceeding to successful regeneration, might initiate an anti-apoptotic mechanism. To identity the exact functions of TNFRI, Birc2 and Birc3, as well as its involved pathways in the cellular events, we inferred a dynamic gene regulatory network from short time-series measurements of the proximal nerve segment cDNA microarray following rat sciatic nerve transection. TNFRI family member Tnfrsf1a, Birc2 and Birc3 were mined out integrating as master regulators to mediate inflammatory responses. Experiments revealed that Tnfrsf1a, Birc2 and Birc3 proteins colocalized with S100 in the rat peripheral nerve tissues, and the expression levels increased with the time extension. Knockdown of the proteins induced the apoptotic formation of primary cultured SCs by upregulation of caspase 3 and caspase 6. Our systematic analysis indicated that Tnfrsf1a, Birc2 and Birc3 of SCs, not originally regarded as XIAP, were mainly responsible for the inflammation-mediated anti-apoptosis of peripheral nerves. Birc2 and Birc3 might be the most potential targets for anti-apoptotic protection mediated by inflammatory cytokines.

  15. Capsaicin sensitizes TRAIL-induced apoptosis through Sp1-mediated DR5 up-regulation: Involvement of Ca{sup 2+} influx

    Energy Technology Data Exchange (ETDEWEB)

    Moon, Dong-Oh [Department of Biology Education, Daegu University, Gyungsan, Gyeongbuk 712–714 (Korea, Republic of); Kang, Chang-Hee; Kang, Sang-Hyuck [Department of Marine Life Sciences, Jeju National University, Jeju 690–756 (Korea, Republic of); Choi, Yung-Hyun [Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan 614–054 (Korea, Republic of); Hyun, Jin-Won; Chang, Weon-Young; Kang, Hee-Kyoung; Koh, Young-Sang; Maeng, Young-Hee; Kim, Young-Ree [School of Medicine, Jeju National University, Jeju-si 690–756 (Korea, Republic of); Kim, Gi-Young, E-mail: immunkim@jejunu.ac.kr [Department of Marine Life Sciences, Jeju National University, Jeju 690–756 (Korea, Republic of)

    2012-02-15

    Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various malignant cells, several cancers including human hepatocellular carcinoma (HCC) exhibit potent resistance to TRAIL-induced cell death. The aim of this study is to evaluate the anti-cancer potential of capsaicin in TRAIL-induced cancer cell death. As indicated by assays that measure phosphatidylserine exposure, mitochondrial activity and activation of caspases, capsaicin potentiated TRAIL-resistant cells to lead to cell death. In addition, we found that capsaicin induces the cell surface expression of TRAIL receptor DR5, but not DR4 through the activation Sp1 on its promoter region. Furthermore, we investigated that capsaicin-induced DR5 expression and apoptosis are inhibited by calcium chelator or inhibitors for calmodulin-dependent protein kinase. Taken together, our data suggest that capsaicin sensitizes TRAIL-mediated HCC cell apoptosis by DR5 up-regulation via calcium influx-dependent Sp1 activation. Highlights: ► Capsaicin sensitizes TRAIL-induced apoptosis through activation of caspases. ► Capsaicin induces expression of DR5 through Sp1 activation. ► Capsaicin activates calcium signaling pathway.

  16. The involvement of Smac/DIABLO, p53, NF-kB and MAPK pathways in apoptosis of keratinocytes from perilesional vitiligo skin: protective effects of curcumin and capsaicin

    OpenAIRE

    Becatti, M; F. Prignano; Fiorillo, C>; L. Pescitelli; P. Nassi; T Lotti; N. TADDEI

    2010-01-01

    Oxidative stress has been suggested as the initial pathogenetic event in melanocyte degeneration in vitiligo. Our previous results indicate that keratinocytes from perilesional skin show the features of damaged cells. In the present study, biopsies were taken from the perilesional skin of 12 patients suffering from nonsegmental vitiligo. The intracellular pathways involved in keratinocyte damage and apoptosis and the antioxidant protection of curcumin and capsaicin in these cells were investi...

  17. 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.

  18. Apoptosis of human melanoma cells induced by inhibition of B-RAFV600E involves preferential splicing of bimS

    OpenAIRE

    Jiang, C C; Lai, F; Tay, K H; Croft, A; Rizos, H; Becker, T M; Yang, F.; Liu, H; Thorne, R F; Hersey, P; Zhang, X. D.

    2010-01-01

    Bim is known to be critical in killing of melanoma cells by inhibition of the RAF/MEK/ERK pathway. However, the potential role of the most potent apoptosis-inducing isoform of Bim, BimS, remains largely unappreciated. Here, we show that inhibition of the mutant B-RAFV600E triggers preferential splicing to produce BimS, which is particularly important in induction of apoptosis in B-RAFV600E melanoma cells. Although the specific B-RAFV600E inhibitor PLX4720 upregulates all three major isoforms ...

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

    International Nuclear Information System (INIS)

    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

  20. 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.

  1. Inhibition of fibroblast growth factor 2-induced apoptosis involves survivin expression, protein kinase Cα activation and subcellular translocation of Smac in human small cell lung cancer cells

    Institute of Scientific and Technical Information of China (English)

    Desheng Xiao; Kuansong Wang; Jianhua Zhou; Huiqiu Cao; Zhenghao Deng; Yongbin Hu; Xiahui Qu; Jifang Wen

    2008-01-01

    To investigate the mechanism by which fibroblast growth factor 2 (FGF-2) inhibits apoptosis in the human small cell lung cancer cell line H446 subjected to serum starvation,apoptosis was evaluated by flow cytometry, Hoechst 33258 staining, caspase-3 activity, and DNA fragmentation.Survivin expression induced by FGF-2 and protein kinase Cα (PKCα) translocation was detected by subcellular fractionation and Western blot analysis. In addition, FGF-2-induced release of Smac from mitochondria to the cytoplasm was analyzed by Western blotting and immunofluorescence.FGF-2 reduced apoptosis induced by serum starvation and up-regulated survivin expression in H446 cells in a dosedependent and time-dependent manner, and inhibited caspase-3 activity. FGF-2 also inhibited the release of Smac from mitochondria to the cytoplasm induced by serum starvation and increased PKCα translocation from the cytoplasm to the cell membrane. In addition, PKC inhibitor inhibited the expression of survivin. FGF-2 up-regulates the expression of survivin protein in H446 cells and blocks the release of Smac from mitochondria to the cytoplasm. PKCα regulated FGF-2-induced survivin expression. Thus, survivin, Smac,and PKCα might play important roles in the inhibition of apoptosis by FGF-2 in human small cell lung cancer cells.

  2. 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 ostatní: 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

  3. Protein tyrosine kinase, JNK, and ERK involvement in p seudolaric acid B-induced apoptosis of human breast cancer MCF-7 cells

    Institute of Scientific and Technical Information of China (English)

    Jing-hua YU; Hong-jun WANG; Xiang-ru LI; Shin-ichi TASHIRO; Satoshi ONODERA; Takashi IKEJIMA

    2008-01-01

    Aim:To investigate the apoptotic mechanism ofpseudolaric acid B (PAB) in hu-man breast cancer MCF-7 cells. Methods: 3-(4,5-Dimethylthiazol-2-yl)-2, 5-di-phenyltetrazolium bromide analysis and morphological changes were applied to detect apoptosis. The percentage of apoptotic and necrotic cells were calculated by the lactate dehydrogenase activity-based cytotoxicity assay, and the protein expression was examined by Western blot analysis. Results: PAB and/or the mitogen-activated protein kinases, including p38, c-Jun-N-terrninal kinase (JNK) and extracellular signal-regulated kinase (ERK), did not participate in necrosis. P38 had no obvious function on apoptosis after 4 μmol/L PAB treatment for 36 h, but PAB induced JNK phosphorylation and inhibited ERK phosphorylation in the apoptotic process. In this study the inhibitor of protein tyrosine kinase (PTK) genistein inverted the inhibitory effect of PAB, instead promoting the survival of MCF-7 cells. Like genistein, another PTK inhibitor AG1024 had a similar ef-fect on PAB-treated MCF-7 cells, indicating that PAB activated PTK to induce apoptosis. Together with PAB, genistein increased the expression of p-ERK, and decreased the expressions of JNK and p-JNK in PAB-treated MCF-7 cells at 36 h. And it is considered that the p-ERK and p-JNK were active patterns of ERK and JNK, respectively. Conclusion: PTK were upstream of ERK and JNK, and PTK induced apoptosis through activating JNK and inactivating ERK in PAB-treated MCF-7 cells.

  4. Inhibition of caspases and intracellular free Ca2+ concentrations are involved in resveratrol protection against apoptosis in rat primary neuron cultures

    Institute of Scientific and Technical Information of China (English)

    Qi-hai GONG; Qian WANG; Jing-shan SHI; Xie-nan HUANG; Qiong LIU; Hu MA

    2007-01-01

    Aim:To investigate the influence of resveratrol (Res),a nutritional antioxidant,on the inhibition of apoptosis in rat primary neuron cultures. Methods:The cultured cortical neurons of neonatal Sprague-Dawley rats were pretreated with Res (0. 1,1.0,and 10.0μmol/L) and oxygen-glucose deprivation/reperfusion (OGD/RP) with oxygen and glucose were initiated at d 10 in vitro. Neuronal apoptosis was determined by flow cytometry,and morphological changes of neurons were observed by an electron microscope. For the mechanism studies,the intracellular free calcium concentration ([Ca2+]i) and the transcription of caspases-3 and -12 in neurons were detected by Fura 2/AM loading and real-time RT-PCR,respectively.Results:OGD/RP insult could induce an increase in the apoptotic rate of neurons (from 11.1% to 49.0%),and elicit an obvious morphological change in neurons;pretreatments with Res (0.1,1.0,and 10.0 μmol/L,respectively) significantly reduced the elevated rate of apoptosis to 41.7%,40.8%,and 37.4%,respectively,and ameliorated the neuronal morphological injury. Similarly,the OGD/RP insult obviously elicited the elevated levels of the [Ca2+]i and the expressions of caspases-3 and-12 mRNA in neurons. Res pretreatments markedly depressed the neuronal abnormal elevation of [Ca2+]i and the overexpression of caspases-3 and -12 mRNA in a concentration-dependent manner. Conclusion:Res can attenuate the rat cortical neuronal apoptosis induced by OGD/RP. The mechanisms are,at least partly,due to the inhibition of the calcium overload and the overexpression of caspases-3 and - 12 mRNA.

  5. 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

    2015-01-01

    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. PMID:26436384

  6. Nucleolin down-regulation is involved in ADP-induced cell cycle arrest in S phase and cell apoptosis in vascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Wenmeng Wang

    Full Text Available High concentration of extracellular ADP has been reported to induce cell apoptosis, but the molecular mechanisms remain not fully elucidated. In this study, we found by serendipity that ADP treatment of human umbilical vein endothelial cells (HUVEC and human aortic endothelial cells (HAEC down-regulated the protein level of nucleolin in a dose- and time-dependent manner. ADP treatment did not decrease the transcript level of nucloelin, suggesting that ADP might induce nucleolin protein degradation. HUVEC and HAEC expressed ADP receptor P2Y13 receptor, but did not express P2Y1 or P2Y12 receptors. However, P2Y1, 12, 13 receptor antagonists MRS2179, PSB0739, MRS2211 did not inhibit ADP-induced down-regulation of nucleolin. Moreover, MRS2211 itself down-regulated nucleolin protein level. In addition, 2-MeSADP, an agonist for P2Y1, 12 and 13 receptors, did not down-regulate nucleolin protein. These results suggested that ADP-induced nucleolin down-regulation was not due to the activation of P2Y1, 12, or 13 receptors. We also found that ADP treatment induced cell cycle arrest in S phase, cell apoptosis and cell proliferation inhibition via nucleolin down-regulation. The over-expression of nucleolin by gene transfer partly reversed ADP-induced cell cycle arrest, cell apoptosis and cell proliferation inhibition. Furthermore, ADP sensitized HUVEC to cisplatin-induced cell death by the down-regulation of Bcl-2 expression. Taken together, we found, for the first time to our knowledge, a novel mechanism by which ADP regulates cell proliferation by induction of cell cycle arrest and cell apoptosis via targeting nucelolin.

  7. Apoptosis induced by genipin in human leukemia K562 cells:involvement of C-Jun N-terminal kinase in G2/M arrest

    Institute of Scientific and Technical Information of China (English)

    Qian FENG; Hou-li CAO; Wei XU; Xiao-rong LI; Yan-qin REN; Lin-fang DU

    2011-01-01

    Aim:To investigate the effect of genipin on apoptosis in human leukemia K562 cells in vitro and elucidate the underlying mechanisms.Methods:The effect of genipin on K562 cell viability was measured using trypan blue dye exclusion and cell counting.Morphological changes were detected using phase-contrast microscopy.Apoptosis was analyzed using DNA ladder, propidium iodide(PI)-labeled flow cytometry(FCM)and Hoechst 33258 staining.The infiuence of genipin on cell cycle distribution was determined using Plstaining.Caspase 3 activity was analyzed to detect apoptosis at different time points.Protein levels of phospho-c-Jun,phosphor-C-Jun N-terminal kinase(p-JNK).phosphor-p38-Fas-L,p63,and Bax and the release of cytochrome c were detected using Western blot analysis.Results:Genipin reduced the viability of K562 cells with an IC50 value of approximately 250 μmol/L.Genipin 200-400 μmol/L induced formation of typicaI apoptotic bodies and DNA fragmentation.Additionally,genipin 400 μmol/L significantly increased the caspase 3activity from 8-24 h and arrested the cells in the G2/M phase.After stimulation with genipin 500 μmol/L, the levels of p-JNK, p-c-Jun.Fas-L,Bax.and cytochrome c were remarkably upregulated,but there were no obvious changes of p-p38.Genipin 200-500 μmol/Lsignificantly upregulated the Fas-L expression and downregulated p63 expression.Dicoumarol 100 μmol/L.a JNK1/2 inhibitor,markedly suppressed the formation of apoptotic bodies and JNK activation induced by genipin 400 μmol/L.Conclusion:These results suggest that genipin inhibits the proliferation of K562 cells and induces apoptosis through the activation of JNK and induction of the Fas ligand.

  8. Acidosis promotes Bcl-2 family-mediated evasion of apoptosis: involvement of acid-sensing G protein-coupled receptor Gpr65 signaling to Mek/Erk.

    Science.gov (United States)

    Ryder, Christopher; McColl, Karen; Zhong, Fei; Distelhorst, Clark W

    2012-08-10

    Acidosis arises in solid and lymphoid malignancies secondary to altered nutrient supply and utilization. Tumor acidosis correlates with therapeutic resistance, although the mechanism behind this effect is not fully understood. Here we show that incubation of lymphoma cell lines in acidic conditions (pH 6.5) blocks apoptosis induced by multiple cytotoxic metabolic stresses, including deprivation of glucose or glutamine and treatment with dexamethasone. We sought to examine the role of the Bcl-2 family of apoptosis regulators in this process. Interestingly, we found that acidic culture causes elevation of both Bcl-2 and Bcl-xL, while also attenuating glutamine starvation-induced elevation of p53-up-regulated modulator of apoptosis (PUMA) and Bim. We confirmed with knockdown studies that these shifts direct survival decisions during starvation and acidosis. Importantly, the promotion of a high anti- to pro-apoptotic Bcl-2 family member ratio by acidosis renders cells exquisitely sensitive to the Bcl-2/Bcl-xL antagonist ABT-737, suggesting that acidosis causes Bcl-2 family dependence. This dependence appears to be mediated, in part, by the acid-sensing G protein-coupled receptor, GPR65, via a MEK/ERK pathway. PMID:22685289

  9. 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.)

  10. Evidence for involvement of cytosolic thioredoxin peroxidase in the excessive resistance of Sf9 Lepidopteran insect cells against radiation-induced apoptosis.

    Science.gov (United States)

    Hambarde, Shashank; Singh, Vijaypal; Chandna, Sudhir

    2013-01-01

    Lepidopteran insect cells display 50-100 times higher radioresistance compared to human cells, and reportedly have more efficient antioxidant system that can significantly reduce radiation-induced oxidative stress and cell death. However, the antioxidant mechanisms that contribute substantially to this excessive resistance still need to be understood thoroughly. In this study, we investigated the role of thioredoxin peroxidase (TPx) in high-dose γ-radiation response of Sf9 cell line derived from Spodoptera frugiperda, the Fall armyworm. We identified a TPx orthologue (Sf-TPx) in Spodoptera system, with primarily cytosolic localization. Gamma-irradiation at 500 Gy dose significantly up-regulated Sf-TPx, while higher doses (1000 Gy-2000 Gy) had no such effect. G2/M checkpoint induced following 500 Gy was associated with transition of Sf-TPx decamer into enzymatically active dimer. Same effect was observed during G2/M block induced by 5 nM okadaic acid or 10 µM CDK1 (cycline dependent kinase-1) inhibitor roscovitine, thus indicating that radiation-induced Sf-TPx activity is mediated by CDKs. Accumulation of TPx dimer form during G2/M checkpoint might favour higher peroxidase activity facilitating efficient survival at this dose. Confirming this, higher lethal doses (1000 Gy-2000 Gy) caused significantly less accumulation of dimer form and induced dose-dependent apoptosis. A ∼50% knock-down of Sf-TPx by siRNA caused remarkable increase in radiation-induced ROS as well as caspase-3 dependent radiation-induced apoptosis, clearly implying TPx role in the radioresistance of Sf9 cells. Quite importantly, our study demonstrates for the first time that thioredoxin peroxidase contributes significantly in the radioresistance of Lepidopteran Sf9 insect cells, especially in their exemplary resistance against radiation-induced apoptosis. This is an important insight into the antioxidant mechanisms existing in this highly stress-resistant model cell system. PMID:23505474

  11. A ginseng saponin metabolite-induced apoptosis in HepG2 cells involves a mitochondria-mediated pathway and its downstream caspase-8 activation and Bid cleavage

    International Nuclear Information System (INIS)

    20-O-(β-D-Glucopyranosyl)-20(S)-protopanaxadiol (IH901), an intestinal bacterial metabolite of ginseng saponin formed from ginsenosides Rb1, Rb2, and Rc, is suggested to be a potential chemopreventive agent. Here, we show that IH901 induces apoptosis in human hepatoblastoma HepG2 cells. IH901 led to an early activation of procaspase-3 (12 h posttreatment), and the activation of caspase-8 became evident only later (18 h posttreatment). Caspase activation was a necessary requirement for apoptosis because caspase inhibitors significantly inhibited cell death by IH901. Treatment of HepG2 cells with IH901 also induced the cleavage of cytosolic factors such as Bid and Bax and translocation of truncated Bid (tBid) to mitochondria. A time-dependent release of cytochrome c from mitochondria was observed, which was accompanied by activation of caspase-9. A broad-spectrum caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), and a specific inhibitor for caspase-8, N-benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethylketone (zIETD-fmk), abrogated Bid processing and translocation, and caspase-3 activation. Cytochrome c release was inhibited by zVAD-fmk, however, the inhibition by zIETD-fmk was not complete. The activation of caspase-8 was inhibited not only by zIETD-fmk but also by zVAD-fmk. The results, together with the kinetic change of caspase activation, indicate that activation of caspase-8 occurred downstream of caspase-3 and -9. Our data suggest that the activation of caspase-8 after early caspase-3 activation might act as an amplification loop necessary for successful apoptosis. Primary hepatocytes isolated from normal Sprague-Dawley rats were not affected by IH901 (0-60 μM). The very low toxicity in normal hepatocytes and high activity in hepatoblastoma HepG2 cells suggest that IH901 is a promising experimental cancer chemopreventive agent

  12. Garlic ((Allium sativum)) Fresh Juice Induces Apoptosis in Human Oral Squamous Cell Carcinoma: The Involvement of Caspase-3, Bax and Bcl-2.

    Science.gov (United States)

    Farhadi, Farrokh; Jahanpour, Salar; Hazem, Kameliya; Aghbali, Amirala; Baradran, Behzad; Vahid Pakdel, Seyyed Mahdi

    2015-01-01

    Background and aims. There is no report on the apoptotic impact of Allium sativum L.(Garlic) on the oral squamous cell carcinoma (KB); hence, this study was designed to survey the apoptotic effects of garlic fresh juice (GFJ) on the KB cells. Materials and methods. MTTassay (MicrocultureTetrazolium Assay) was carried out to evaluate the cytotoxicity of GFJ on KB cells. Furthermore, TUNEL(Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling)and DNA fragmentation tests were performed to determine if GFJ is able to induce apoptosis in KB cells. Also a standard kit was used to assess caspase-3 activity in KB cells. Also western blotting was employed to evaluate the effect of GFJ on Bax:Bcl-2 ratio. Results. Significant cytotoxic effects were observed for the minimum used concentration (1μg/mL) as calculated to be 77.97±2.3% for 24 h and 818±3.1% for 36h of incubation (P < 0.001). Furthermore, TUNEL and DNA fragmentation tests corroborated the apoptosis inducing activity of GFJ. Consistently, after treating KB cells with GFJ(1μg/mL), caspase-3 activity and Bax:Bcl-2 ratio were raised by 7.3±0.6 and (P <0.001) folds, respectively. Conclusion. The results of this study advanced that GFJ induces apoptosis in the KB cells through increasing caspase-3 activity and Bax:Bcl2 ratio which could be attributed to its organo-sulfurcomponents. PMID:26889365

  13. Involvement of reactive oxygen species/c-Jun NH2-terminal kinase pathway in kotomolide A induces apoptosis in human breast cancer cells

    International Nuclear Information System (INIS)

    The anticancer effects of kotomolide A (KTA), a new butanolide constituent isolated from the leaves of Cinnamomum kotoense (Lauraceae), on the two human breast cancer cell lines MCF-7 and MDA-MB-231, were first investigated in our study. KTA exhibited selectively antiproliferative effects in cancer cell lines without showing any toxicity in normal mammary epithelial cells. Treatment of cancer cells with KTA to trigger G2/M phase arrest was associated with increased p21/WAF1 levels and reduced amounts of cyclin A, cyclin B1, cdc2 and cdc25C. KTA induced cancer cell death treatment by triggering mitochondrial and death receptor 5 (DR5) apoptotic pathways, but did not act on the Fas receptor. Exposure of MCF-7 and MDA-MB-231 cells to KTA resulted in cellular glutathione reduction and ROS generation, accompanied by JNK activation and apoptosis. Both antioxidants, NAC and catalase, significantly decreased apoptosis by inhibiting the phosphorylation of JNK and subsequently triggering DR5 cell death pathways. The reduction of JNK expression by siRNA decreased KTA-mediated Bim cleavage, DR5 upregulation and apoptosis. Furthermore, daily KTA i.p. injections in nude mice with MDA-MB-231 s.c. tumors resulted in a 50% decrease of mean tumor volume, compared with vehicle-treated controls. Taken together, the data show that cell death of breast cancer cells in response to KTA is dependent upon ROS generation and JNK activation, triggering intrinsic and extrinsic apoptotic pathways. The ROS/JNK pathway could be a useful target for novel approaches in breast cancer chemotherapy

  14. 16-Hydroxycleroda-3,13-dien-15,16-olide deregulates PI3K and Aurora B activities that involve in cancer cell apoptosis

    International Nuclear Information System (INIS)

    Highlights: → Natural product PL3 induced cancer cell apoptosis and cell cycle arrest. → PL3 targeted and de-regulated PI3K pathway activities. → De-activated PI3K pathway caused Aurora B degradation and spindle dysfunction. → PL3 could reverse the drug-resistance of Bcr-ABL T315I-positive cells to Imatinib. -- Abstract: The PI3K-AKT pathway and Aurora kinase play essential roles in such cellular processes as cell survival, angiogenesis, and differentiation, and are usually expressed at maximum levels during cancer cell proliferation. The present study investigated the effect of the natural compound, 16-hydroxycleroda-3,13-dien-15,16-olide (PL3), on regulating the PI3K-AKT pathway and Aurora B, which led to cancer cell apoptosis. PL3 acts as a PI3K inhibitor by influencing cell survival, signaling transduction, and cell cycle progression. It was observed that PL3 targeted and induced dephosphorylation of the PI3K pathway, degradation of Aurora B and mitotic-related gene expressions, and sequentially shut down the cell cycle. This eventually resulted in cell death. As Aurora B was downregulated, spindle dysfunction and destruction of the G2/M phase checkpoint resulted in DNA-damaged cells undergoing apoptosis. Moreover, PL3 also resensitized T315I-mutated Bcr-ABL+ BA/F3 cells to improve the cytotoxicity of Imatinib in Imatinib-resistant cell line. Taken together, PL3 can perturb the PI3K-AKT pathway and Aurora B resulting in gene silencing and cell cycle disturbance. It was demonstrated that PL3 acted like a novel small-molecule PI3K modulator, thereby potentially contributing to cancer chemotherapy and combination medication.

  15. 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.

  16. Cardioprotective effect of pioglitazone in diabetic and non-diabetic rats subjected to acute myocardial infarction involves suppression of AGE-RAGE axis and inhibition of apoptosis.

    Science.gov (United States)

    Khodeer, Dina M; Zaitone, Sawsan A; Farag, Noha E; Moustafa, Yasser M

    2016-05-01

    Insulin resistance increases risk of cardiovascular diseases. This work investigated the protective effect of pioglitazone on myocardial infarction (MI) in non-diabetic and diabetic rats, focusing on its role on advanced glycated endproducts (AGEs) and cardiac apoptotic machinery. Male rats were divided into 2 experiments: experiment I and II (non-diabetic and diabetic rats) were assigned as saline, MI (isoproterenol, 85 mg/kg, daily), and MI+pioglitazone (5, 10, and 20 mg/kg). Injection of isoproterenol in diabetic rats produced greater ECG disturbances compared to non-diabetic rats. Treatment with pioglitazone (5 mg/kg) reduced the infarct size and improved some ECG findings. Pioglitazone (10 mg/kg) enhanced ECG findings, improved the histopathological picture and downregulated apoptosis in cardiac tissues. Whereas the higher dose of pioglitazone (20 mg/kg) did not improve most of the measured parameters but rather worsened some of them, such as proapoptotic markers. Importantly, a positive correlation was found between serum AGEs and cardiac AGE receptors (RAGEs) versus caspase 3 expression in the two experiments. Therefore, the current effect of pioglitazone was, at least in part, mediated through downregulation of AGE-RAGE axis and inhibition of apoptosis. Consequently, these data suggest that pioglitazone, at optimized doses, may have utility in protection from acute MI. PMID:27119311

  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)

    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. Indomethacin-Enhanced Anticancer Effect of Arsenic Trioxide in A549 Cell Line: Involvement of Apoptosis and Phospho-ERK and p38 MAPK Pathways

    Directory of Open Access Journals (Sweden)

    Ali Mandegary

    2013-01-01

    Full Text Available Background. Focusing on novel drug combinations that target different pathways especially apoptosis and MAPK could be a rationale for combination therapy in successful treatment of lung cancer. Concurrent use of cyclooxygenase (COX inhibitors with arsenic trioxide (ATO might be a possible treatment option. Methods. Cytotoxicity of ATO, dexamethasone (Dex, celecoxib (Cel, and Indomethacin (Indo individually or in combination was determined at 24, 48, and 72 hrs in A549 lung cancer cells. The COX-2 gene and protein expression, MAPK pathway proteins, and caspase-3 activity were studied for the most cytotoxic combinations. Results. The IC50s of ATO and Indo were 68.7 μmol/L and 396.5 μmol/L, respectively. Treatment of cells with combinations of clinically relevant concentrations of ATO and Indo resulted in greater growth inhibition and apoptosis induction than did either agent alone. Caspase-3 activity was considerably high in the presence of ATO and Indo but showed no difference in single or combination use. Phosphorylation of p38 and ERK1/2 was remarkable in the concurrent presence of both drugs. Conclusions. Combination therapy with ATO and Indo exerted a very potent in vitro cytotoxic effect against A549 lung cancer cells. Activation of ERK and p38 pathways might be the mechanism of higher cytotoxic effect of ATO-Indo combination.

  19. Long non-coding RNA ZFAS1 interacts with CDK1 and is involved in p53-dependent cell cycle control and apoptosis in colorectal cancer

    Science.gov (United States)

    Thorenoor, Nithyananda; Faltejskova-Vychytilova, Petra; Hombach, Sonja; Mlcochova, Jitka; Kretz, Markus; Svoboda, Marek; Slaby, Ondrej

    2016-01-01

    We determined expression of 83 long non-coding RNAs (lncRNAs) and identified ZFAS1 to be significantly up-regulated in colorectal cancer (CRC) tissue. In cohort of 119 CRC patients we observed that 111 cases displayed at least two-times higher expression of ZFAS1 in CRC compared to paired normal colorectal tissue (P HCT116+/+, HCT116−/− and DLD-1) we showed, that ZFAS1 silencing decreases proliferation through G1-arrest of cell cycle, and also tumorigenicity of CRC cells. We identified Cyclin-dependent kinase 1 (CDK1) as interacting partner of ZFAS1 by pull-down experiment and RNA immunoprecipitation. Further, we have predicted by bioinformatics approach ZFAS1 to sponge miR-590-3p, which was proved to target CDK1. Levels of CDK1 were not affected by ZFAS1 silencing, but cyclin B1 was decreased in both cell lines. We observed significant increase in p53 levels and PARP cleavage in CRC cell lines after ZFAS1 silencing indicating increase in apoptosis. Our data suggest that ZFAS1 may function as oncogene in CRC by two main actions: (i) via destabilization of p53 and through (ii) interaction with CDK1/cyclin B1 complex leading to cell cycle progression and inhibition of apoptosis. However, molecular mechanisms behind these interactions have to be further clarified. PMID:26506418

  20. Economic Analysis of Constitutions

    OpenAIRE

    Roger B. Myerson

    2000-01-01

    This paper is a preliminary draft of an article to appear in Chicago Law Review (2000), as part of a symposium reviewing two new books on economic analysis of constitutions: Dennis Mueller's Constitutional Democracy and Robert Cooter's Strategic Constitution. Some of the basic questions of constitutional analysis are introduced, and the importance of work in this area is shown as one of the major new developments in social theory. The methods of economic theory are then shown to be particular...

  1. Conventional Constitutional Law

    OpenAIRE

    2015-01-01

    Judges share conventional understandings about what the Constitution requires, both of themselves and of other constitutional actors. These informal conventions lead to formal decisions, which are then centrally enforced by the state in the same manner as all other judicial decisions. This recognition of conventional constitutional law has three critical implications for our understanding, critique and reform of constitutional law. First, it is unlikely that judges will refer e...

  2. Caspase Family Proteases and Apoptosis

    Institute of Scientific and Technical Information of China (English)

    Ting-Jun FAN; Li-Hui HAN; Ri-Shan CONG; Jin LIANG

    2005-01-01

    Apoptosis, or programmed cell death, is an essential physiological process that plays a critical role in development and tissue homeostasis. The progress of apoptosis is regulated in an orderly way by a series of signal cascades under certain circumstances. The caspase-cascade system plays vital roles in the induction, transduction and amplification of intracellular apoptotic signals. Caspases, closely associated with apoptosis, are aspartate-specific cysteine proteases and members of the interleukin-1β-converting enzyme family. The activation and function of caspases, involved in the delicate caspase-cascade system, are regulated by various kinds of molecules, such as the inhibitor of apoptosis protein, Bcl-2 family proteins, calpain,and Ca2+. Based on the latest research, the members of the caspase family, caspase-cascade system and caspase-regulating molecules involved in apoptosis are reviewed.

  3. Involvement of mitochondria in apoptosis of cancer cells induced by photodynamic therapy Envolvimento da mitocôndria em apoptose de células cancerígenas induzida por terapia fotodinâmica

    Directory of Open Access Journals (Sweden)

    Joselito Nardy Ribeiro

    2004-12-01

    Full Text Available Photodynamic therapy (PDT, a promising cancer treatment that employs a combination of a photosensitizing chemical, oxygen, and visible light, induces apoptosis in tumor cells. However, the precise mechanism of PDT-induced apoptosis is not well characterized. Many of the photosensitizers currently in clinical or pre-clinical studies of PDT are localized in or have a major influence on mitochondria. The treatment with PDT causes mitochondrial damage and induces apoptosis through the release of cytochrome c (cyt c, apoptosis-inducing factor (AIF, Smac/DIABLO and certain procaspases. Proapoptotic and antiapoptotic members of BcL-2 family regulate the release of these proteins from mitochondria. The purpose of this mini-review is to present some recent publications that focus on the involvement of the mitochondria in apoptosis of cancer cells induced by PDT.A terapia fotodinâmica (TFD é um promissor tratamento clínico que emprega a combinação de luz visível, oxigênio e uma substância fotossensibilizadora para tratar doenças de caráter oncológico. Esse tipo de tratamento induz a morte celular programada (apoptose em tecido tumoral. No entanto, o mecanismo de indução de apoptose por TFD não está bem caracterizado. Muitos fotossensibilizadores possuem como alvo principal a mitocôndria. O tratamento com TFD causa danos nessa organela e induz a apoptose através da liberação de citocromo c, fator de indução de apoptose, Smac/DIABLO e certas pró-caspases. A liberação dessas proteínas, a partir da mitocôndria, é regulada por uma família de proteínas pró e antiapoptóticas, conhecida como família BCL-2. A proposta dessa minirrevisão é apresentar algumas publicações recentes que focalizam o envolvimento da mitocôndria em apoptose de células cancerígenas induzida por TFD.

  4. 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

  5. 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; Odum, Niels; Claesson, M H

    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......-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....... In addition, the transcription factor Stat-3 was tyrosine phosphorylated in the cytoplasm and subsequently translocated to the cell nucleus. Data obtained by electrophoretic mobility shift assay suggested that the activated Stat-3 protein associates with the human serum-inducible element (hSIE) DNA...

  6. The role of GSH in microcystin-induced apoptosis in rat liver: Involvement of oxidative stress and NF-κB.

    Science.gov (United States)

    Chen, Liang; Li, Shangchun; Guo, Xiaochun; Xie, Ping; Chen, Jun

    2016-05-01

    Microcystins (MCs) are potent and specific hepatotoxins produced by cyanobacteria in eutrophic waters, representing a health hazard to animals and humans. The objectives of this study are to determine the relationship between oxidative stress and NF-κB activity in MC-induced apoptosis in rat liver and the role of glutathione (GSH). Sprague-Dawley rats were intraperitoneally (i.p.) injected with microcystin-LR (MC-LR) at 0.25 and 0.5 LD50 with or without pretreatment of buthionine-(S,R)-sulfoximine (BSO), a specific GSH synthesis inhibitor. MC-LR induced time-dependent alterations of GSH levels in rat liver. Increased malondialdehyde (MDA) and significant changes of antioxidant enzymes including GSH peroxidase (GPX) and GSH reductase (GR) were also observed, particularly at 24 h post-exposure. The results indicated that acute exposure to MC-LR induced oxidative stress, and GSH depletion (BSO pretreatment) enhanced the level of oxidative stress. Furthermore, the modulation of pro-apoptotic gene p53 and Bax and anti-apoptotic gene Bcl-2 was observed in 0.5 LD50 group at 24 h, and the alteration was more pronounced by BSO injection before MC-LR treatment, suggesting that GSH played a protective role against MC-induced toxicity. Additionally, electrophoretic mobility shift assay (EMSA) showed that NF-κB was induced at 0.25 LD50 but inhibited at 0.5 LD50 . The above results indicated that the possible crosstalk of oxidative stress and NF-κB activity was associated with MC-LR-induced hepatocytes apoptosis in vivo. Our data will provide a new perspective for understanding the mechanisms of MC-induced liver injury. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 552-560, 2016. PMID:25410294

  7. Involvement of mitochondria and caspase pathways in N-demethyl-clarithromycin-induced apoptosis in human cervical cancer HeLa cell

    Institute of Scientific and Technical Information of China (English)

    Ai-min QIAO; Takashi IKEJIMA; Shini-chi TASHIRO; Satoshi ONODERA; Wei-ge ZHANG; Ying-liang WU

    2006-01-01

    Aim: To study the mechanisms by which N-demethyl-clarithromycin (NDC) induces human cervical cancer HeLa cell apoptosis in vitro. Methods: The viability of N-demethyl-clarithromycin-induced HeLa cells was measured by MTT assay. Apoptotic cells with condensed nuclei were visualized by phase contrast microscopy. Nucleosomal DNA fragmentation was assayed by agarose gel electrophoresis. Measurement of mitochondrial transmembrane potential was analyzed by a FACScan flowcytometer. Caspase-3, poly-(ADP-ribose) polymerase (PARP), caspase-activated DNase (ICAD), Bcl-2, Bax, p53, and SIRT1 protein expression and the release of cytochrome c were detected by Western blot analysis. Results: N-demethyl-clarithromycin, an anti-inflammatory substance, inhibited HeLa cell growth in a dose- and time-dependent manner.N-demethyl-clarithromycin induced HeLa cell death through the apoptotic pathways. The pan-caspase inhibitor (z-VAD-fmk), caspase-3 inhibitor (z-DEVD-fmk) and the caspase-9 inhibitor (z-LEHD-fmk) partially enhanced cell viability induced by N-demethyl-clarithromycin, but the caspase-8 inhibitor (z-IETD-fmk) had almost no effect. Caspase-3 was activated then followed by the degradation of caspase-3 substrates, the inhibitor of ICAD and PARP. Simultaneously, mitochondrial transmembrane potential was markedly reduced and the release of cytochrome c in the cytosol was increased.N-demethyl-clarithromycin upregulated the expression ratio of mitochondrial Bax/Bcl-2, and significantly increased the expression of the p53 protein. It also downregulated anti-apoptotic protein SIRT1 expression. Conclusion: N-demethyl-clarithromycin induced apoptosis in HeLa cells via the mitochondrial pathway.

  8. 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

  9. Kenya's New Constitution

    OpenAIRE

    Kramon, Eric; Posner, Daniel N

    2011-01-01

    On 4 August 2010, Kenyans voted to adopt a new constitution, culminating a process that began as part of a resolution to the violent conflict that followed the December 2007 elections. By reducing executive power, devolving authority, and guaranteeing rights to women, minorities, and marginalized communities, the constitution has the potential to transform Kenyan politics. Political and logistical obstacles will, however, pose a challenge to implementation. Yet that the constitution has been ...

  10. The constitutive modeling of shape memory alloys

    OpenAIRE

    Liang, Chen

    1990-01-01

    This dissertation presents a one-dimensional thermomechanical constitutive model for shape memory alloys based on basic concepts of thermodynamics and phase transformation kinetics. Compared with other developed constitutive relations, this thermomechanical constitutive relation not only reflects the physical essence of shape memory alloys, i.e., the martensitic phase transformation involved, but also provides an easy-to-use design tool for engineers. It can predict and describ...

  11. Analysis of the expression of genes involved in proliferation and apoptosis in cervical intraepithelial neoplasias and cancer of the cervix uteri

    Directory of Open Access Journals (Sweden)

    V. K. Bozhenko

    2014-08-01

    Full Text Available The viral nature of many female genital cancers is now beyond question. By taking into account this fact, the problem of qualitative assessment ofthenatureofcervicalintraepithelialneoplasia(CINanditsfocusonprogressiontoinvasivecarcinomabecomesquitenatu ral.Studiesof a number of biological markers of carcinogenesis have recently provided a possibility for prospective prediction. The paper con siders the as- pects of importance of the molecular biological markers of proliferation and apoptosis in the etiopathogenesis of genital cancers. It gives the results of examinations of 16 patients with histologically verified squamous cell carcinoma of the cervix uteri, 40 patients di agnosed as having CIN of different grades (CIN-1, CIN-2, CIN-3 — squamous cell carcinoma in situ, and 6 patients with the morphologically unaltered cervi- calepithelium,whosecervicalscrapeswereanalyzedfortheexpressionofthemRNAgenesССNB1,Ki-67,BA G,BCL-2,ESR1,andPRG. It is shown that the molecular genetic findings may be new prognostic markers that reflect the possible disease developmental pathways, sug- gesting the need for further investigation of biomarkers in order to prevent malignancies and to reduce their morbidity.

  12. Rituximab enhances radiation-triggered apoptosis in non-Hodgkin's lymphoma cells via caspase-dependent and - independent mechanisms

    International Nuclear Information System (INIS)

    Rituximab (RTX), a chimeric human anti-CD20 monoclonal antibody, is currently employed in the treatment of malignant non-Hodgkin's lymphoma (NHL) either alone or in combination with other cytotoxic approaches. The present study examines the effects of ionizing radiation in combination with RTX on proliferation and apoptosis development in B-lymphoma RL and Raji cells. RTX was used at a concentration of 10 μg/mL 24 hours prior to irradiation at a single dose of 9 Gy. CD20 expression, cell viability, apoptosis, mitochondrial membrane potential and apoptosis-related proteins were evaluated in the treated B cells. The constitutive level of CD20 expression in RL and Raji lymphoma cells did not play an essential role in RTX-induced cell growth delay. Both lymphoma cells showed similar inhibition of cell proliferation without apoptosis development in response to RTX treatment. Exposure to ionizing radiation induced cell growth delay and apoptosis in RL cells, whereas Raji cells showed moderate radio-resistance and activation of cell growth at 24 hours after irradiation, which was accompanied by increased radiation-triggered CD20 expression. The simultaneous exposure of lymphoma cells to ionizing radiation and RTX abrogated radioresistance of Raji cells and significantly enhanced cell growth delay and apoptosis in RL cells. X-linked inhibitor of apoptosis protein (XIAP) and the inducible form of heat shock protein 70 (Hsp70) were positively modulated by RTX in combination with ionizing radiation in order to induce apoptosis. Furthermore, it was demonstrated that mitochondrial membrane potential dissipation is not an essential component to induce apoptosis-inducing factor (AIF) maturation and apoptosis. Our results show that RTX-triggered enhancement of radiation-induced apoptosis and cell growth delay is achieved by modulation of proteins involved in programmed cell death. (author)

  13. 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 participate…

  14. 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)

  15. Bioactive compounds of Eriocaulon sieboldianum blocking proliferation and inducing apoptosis of HepG2 cells might be involved in Aurora kinase inhibition.

    Science.gov (United States)

    Fan, Yanhua; Lu, Hongyuan; Ma, Hongda; Feng, Fan; Hu, Xiaolong; Zhang, Qiao; Wang, Jian; Xu, Yongnan; Zhao, Qingchun

    2015-12-01

    Eriocaulon sieboldianum (Sieb. & Zucc. ex Steud.) is an edible and medicinal plant used in traditional Chinese medicine. Often in combination with other herbs, it is processed into healthcare beverages for expelling wind-heat, protecting eyes, and reducing blood lipids. Besides, its water decoction together with other herbs has been utilized to treat cancer in China. However, the active ingredients and the precise cellular mechanisms of E. sieboldianum remain to be elucidated. The Aurora kinase family plays critical roles in the regulation of cell division and has attracted great attention to the identification of small-molecule Aurora kinase inhibitors for potential treatment of cancer. A molecular docking study was employed for docking of the most bioactive compounds. Hispidulin (HPDL) and quercetin-3-O-(6''-O-galloyl)-β-D-galactopyranoside (QGGP) were singled out as potent inhibitors of Aurora kinase. Their inhibitory activity towards Aurora kinase was further confirmed by the obvious decrease in autophosphorylation of Aurora-A (Thr288) and Aurora-B (Thr232). Moreover, the induction of cell cycle arrest in HepG2 cells and the suppressed phosphorylation of histone H3 were also consistent with the inhibition of Aurora kinase. The data indicate that the E. sieboldianum extract and its two active compounds, HPDL and QGGP, could effectively induce apoptosis via p53, MAPKs and the mitochondrial apoptotic pathways. These findings could improve the understanding and enhance the development of drugs based on E. sieboldianum and raise its application value in anticancer therapy or prevention. In addition, our results indicated that Aurora kinase might be a novel target of HPDL and QGGP. PMID:26369427

  16. 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.

  17. Mitochondrial dynamics and apoptosis

    OpenAIRE

    Suen, Der-Fen; Norris, Kristi L.; Youle, Richard J.

    2008-01-01

    In healthy cells, mitochondria continually divide and fuse to form a dynamic interconnecting network. The molecular machinery that mediates this organelle fission and fusion is necessary to maintain mitochondrial integrity, perhaps by facilitating DNA or protein quality control. This network disintegrates during apoptosis at the time of cytochrome c release and prior to caspase activation, yielding more numerous and smaller mitochondria. Recent work shows that proteins involved in mitochondri...

  18. 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

  19. 9-cis-retinoic acid inhibits activation-driven T-cell apoptosis: implications for retinoid X receptor involvement in thymocyte development.

    OpenAIRE

    Yang, Y.; Vacchio, M S; Ashwell, J D

    1993-01-01

    Retinoic acid is a morphogenetic signaling molecule derived from vitamin A and involved in vertebrate development. Two groups of receptors, retinoic acid receptors and retinoid X receptors (RXRs), have been identified. All-trans-retinoic acid is the high-affinity ligand for retinoic acid receptors, and 9-cis-retinoic acid additionally binds RXRs with high affinity. Here we report that although retinoic acid has little inhibitory effect on activation-induced T-cell proliferation, it specifical...

  20. The role of apoptosis in pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    B. D. Uhal

    2008-12-01

    Full Text Available Apoptosis has been defined as "gene-directed cellular self-destruction" and is an active process that is tightly regulated by a number of gene products, which promote or block cell death. Apoptotic death can be triggered by a wide variety of stimuli and, importantly, not all cells necessarily undergo apoptosis in response to the same stimulus. Abnormal regulation of apoptosis has been implicated in a wide range of diseases and approaches to modifying apoptosis represent important future therapeutic strategies. Idiopathic pulmonary fibrosis (IPF is a progressive and relentless disease involving scarring of the lung, which has been recognised as the most lethal interstitial lung disease. In the lungs of IPF patients, increased epithelial apoptosis, together with decreased apoptosis of myofibroblasts, represents persistent findings (particularly in areas of collagen deposition supporting an interaction between altered apoptosis and the pathogenesis of the disease. Data from human tissues and animal models are refining current knowledge of the processes involved in this pathogenesis. This has challenged the dogma that IPF is purely a disease of unresolved inflammation by emphasising the central roles played by the alveolar epithelial cell and myofibroblasts and, as part of that role, the importance of altered apoptosis. Evidence suggests blockade of epithelial cell apoptosis can prevent subsequent collagen deposition, and induction of myofibroblast apoptosis, at least theoretically, would be expected to resolve ongoing fibrosis. These two concepts raise the prospect of therapeutic intervention aimed at modifying apoptosis and, thus, fibrosis in idiopathic pulmonary fibrosis.

  1. ACCESS METHODS CONCERNING THE CONSTITUTIONAL CONTROL OF THE CONSTITUTIONAL COURT

    OpenAIRE

    Gabriela NEMTOI

    2009-01-01

    The study concerning the laws’ constitutionality represents the reason of constitutional warranty on judicial standards, which governs a democratic state. The supremacy of constitution is only a principle, which has to be doubled by establishing a mechanism creating consistency to it. In order to assure the supremacy of constitution, the doctrine and constitutional practice have created efficient judicial institutions, the control of laws’ constitutionality by the competency of Constitutional...

  2. Modulation of the chaperone heat shock cognate 70 by embryonic (pro)insulin correlates with prevention of apoptosis

    OpenAIRE

    De La Rosa, Enrique J; Vega-Núñez, Elena; Morales, Aixa V.; Serna, José; Rubio, Eva; Pablo, Flora de

    1998-01-01

    Insights have emerged concerning insulin function during development, from the finding that apoptosis during chicken embryo neurulation is prevented by prepancreatic (pro)insulin. While characterizing the molecules involved in this survival effect of insulin, we found insulin-dependent regulation of the molecular chaperone heat shock cognate 70 kDa (Hsc70), whose cloning in chicken is reported here. This chaperone, generally considered constitutively expressed, showed regulation of its mRNA a...

  3. The constitutive sofa cushion

    DEFF Research Database (Denmark)

    Hanghøj, Sara

    2009-01-01

      Full Paper presented by Sara Hanghøj 24.9.2008 at the International Conference "Crafticulation &Education"  University of Helsinki 23.-26.  September 2008 Session: Gendered Textiles     THE CONSTITUTIVE SOFA CUSHION - MATERIALIZATION ANALYSED FROM A CULTURAL PERSPECTIVE   Abstract How can...... 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...... female handcraft-teachers, was generated and constituted with the sofa cushion as one of many actors.      ...

  4. Transnational Governance and Constitutionalism

    DEFF Research Database (Denmark)

    Joerges, Christian; Sand, Inger-Johanne; Teubner, Gunther

    challenging the type of governance which constitutional states were supposed to represent and ensure. They also provoke old questions: Who bears the responsibility for governance without a government? Can accountability be ensured? The term 'constitutionalism' is still widely identified with statal form of......The term transnational governance designates untraditional types of international and regional collaboration among both public and private actors. These legally-structured or less formal arrangements link economic, scientific and technological spheres with political and legal processes. They are...... democratic governance. The book refers to this term as a yardstick to which then contributors feel committed even where they plead for a reconceptualisation of constitutionalism or a discussion of its functional equivalents. 'Transnational governance' is neither public nor private, nor purely international...

  5. 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.

  6. Involvement of mitochondria in apoptosis of cancer cells induced by photodynamic therapy Envolvimento da mitocôndria em apoptose de células cancerígenas induzida por terapia fotodinâmica

    OpenAIRE

    Joselito Nardy Ribeiro; André Romero da Silva; Renato Atilio Jorge

    2004-01-01

    Photodynamic therapy (PDT), a promising cancer treatment that employs a combination of a photosensitizing chemical, oxygen, and visible light, induces apoptosis in tumor cells. However, the precise mechanism of PDT-induced apoptosis is not well characterized. Many of the photosensitizers currently in clinical or pre-clinical studies of PDT are localized in or have a major influence on mitochondria. The treatment with PDT causes mitochondrial damage and induces apoptosis through the release of...

  7. DNA degradation and Apoptosis : DNA degradation

    OpenAIRE

    Torriglia, Alicia; Padron, Laura

    2005-01-01

    Apoptosis, is a form of programmed cell death essential for the development and maintenance of multicellular organisms. DNA degradation is one of the hallmarks of apoptosis. The central component of the apoptotic machinery is a proteolytic system involving caspases and non-caspases proteases. CAD, a caspase-activated DNase, is the endonuclease responsible for DNA degradation during caspase-dependent apoptosis. The relationship between non-caspase proteases and endonucleases is less clear and ...

  8. 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...

  9. Disputing the Constitution.

    Science.gov (United States)

    Pyle, Christopher H.

    1987-01-01

    Constitutional law is a good way to introduce students to fundamental debates over means and ends, over what means work and at what costs, and over what ends are not merely desirable, but may be legitimately achieved even through the application of collective force. It also offers an exciting way to teach logic. (MLW)

  10. Constituting children's bodily integrity.

    Science.gov (United States)

    Hill, B Jessie

    2015-04-01

    Children have a constitutional right to bodily integrity. Courts do not hesitate to vindicate that right when children are abused by state actors. Moreover, in at least some cases, a child's right to bodily integrity applies within the family, giving the child the right to avoid unwanted physical intrusions regardless of the parents' wishes. Nonetheless, the scope of this right vis-à-vis the parents is unclear; the extent to which it applies beyond the narrow context of abortion and contraception has been almost entirely unexplored and untheorized. This Article is the first in the legal literature to analyze the constitutional right of minors to bodily integrity within the family by spanning traditionally disparate doctrinal categories such as abortion rights; corporal punishment; medical decisionmaking; and nontherapeutic physical interventions such as tattooing, piercing, and circumcision. However, the constitutional right of minors to bodily integrity raises complex philosophical questions concerning the proper relationship between family and state, as well as difficult doctrinal and theoretical issues concerning the ever-murky idea of state action. This Article canvasses those issues with the ultimate goal of delineating a constitutional right of bodily security and autonomy for children. PMID:26016017

  11. The Constitution Debate

    Directory of Open Access Journals (Sweden)

    Heinrich Schneider

    2003-03-01

    Full Text Available The paper deals with certain questions and problems of the constitutionalization of the European Union which did not receive very much attention from the ‘Convention on the Future of Europe’ and from the observers of that Convention’s work, but which, nevertheless, may be relevant whenever the results of the Convention’s work are assessed and evaluated. The paper mainly deals with ‘background’ problems associated with traditions of political thought in general and with basic understandings of European integration in particular. The paper also expounds on how the more recent constitution discussion, initiated due to the founding of the European Union, manifests continuities with the debates that have taken place over the past decades (since the start of the integration policy based on the ‘Community method’. However, it shows that the discussion context has become more complex. In the last section of the paper, the relationship of ‘statics’ and ‘dynamics’ in relation to European constitutional conceptions is treated as a subject. The question arises as to whether and to what extent the constitution concept itself is in doubt and whether or not, in connection with this, important functions, whose very performance is expected of a constitution of the European Union, remain unfulfilled.

  12. Crushed Salt Constitutive Model

    International Nuclear Information System (INIS)

    The constitutive model used to describe the deformation of crushed salt is presented in this report. Two mechanisms -- dislocation creep and grain boundary diffusional pressure solution -- 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. Upon complete consolidation, the crushed-salt model reproduces the Multimechanism Deformation (M-D) model typically used for the Waste Isolation Pilot Plant (WIPP) host geological formation salt. New shear consolidation tests are combined with an existing database that includes hydrostatic consolidation and shear consolidation tests conducted on WIPP and southeastern New Mexico salt. Nonlinear least-squares model fitting to the database produced two sets of material parameter values for the model -- one for the shear consolidation tests and one for a combination of the shear and hydrostatic consolidation tests. Using the parameter values determined from the fitted database, the constitutive model is validated against constant strain-rate tests. Shaft seal problems are analyzed to demonstrate model-predicted consolidation of the shaft seal crushed-salt component. Based on the fitting statistics, the ability of the model to predict the test data, and the ability of the model to predict load paths and test data outside of the fitted database, the model appears to capture the creep consolidation behavior of crushed salt reasonably well

  13. Judiciary on Russian Constitutional System

    Directory of Open Access Journals (Sweden)

    Vladislav Arkhipov

    2013-12-01

    Full Text Available This article is about new constitutional order in Russia emphasizing fundamental areas as the role of judiciary in the Russian Constitutional System from 1993 Constitution, the one which replaced the 1978 Russian Soviet Federative Socialist Republic Constitution based on communist ideology. Therefore, it is intended to examine the principle of separation of powers, constitutionally recognized human rights and liberties, relationship between international bodies’ case law of human rights and the Russian Constitutional Court, among others issues.

  14. Constitutional appeals refused

    International Nuclear Information System (INIS)

    Already in the three-judge-appointed preliminary commission, the Fed. Constitutional Court, in several cases unanimously, refused a constitutional appeal against decisions in court cases regarding nuclear power plants with the substantiation that they have no sufficient prospects for success, or that they are inadmissable. These decisions are incontestable. The following orders were issued: 1) Churches must also pay for electricity produced by nuclear power plants. 2) Construction of the Grohnde nuclear power plant will not be interrupted. 3) Limited right of action against nuclear power plant licences (here: Stade) 4) Confirmation of the preliminary site approval for Kruemmel nuclear power plant. The essential reasons for the decisions are given. (orig./HP)

  15. 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.'

  16. Invertebrate Iridovirus Modulation of Apoptosis

    Institute of Scientific and Technical Information of China (English)

    Trevor Williams; Nllesh S. Chitnis; Sh(a)n L. Bilimoria

    2009-01-01

    Programmed cell death (apoptosis) is a key host response to virus infection. Viruses that can modulate host apoptotic responses are likely to gain important opportunities for transmission. Here we review recent studies that demonstrate that particles of Invertebrate iridescent virus 6 (IIV-6) (Iridoviridae, genus Iridovirus), or an IIV-6 virion protein extract, are capable of inducing apoptosis in lepidopteran and coleopteran cells, at concentrations 1000-fold lower than that required to shut-off host macromolecular synthesis. Induction of apoptosis depends on endocytosis of one or more heat-sensitive virion component(s). Studies with a JNK inh ibitor(SP600125) indicated that the JNK signaling pathway is significantly involved in apoptosis in IIV-6 infections of Choristoneurafumiferana ceils. The genome of IIV-6 codes for an inhibitor of apoptosis iap gene (193R) that encodes a protein of 208 aa with 15% identity and 28% similarity in its amino acid sequence to IAP-3 from Cydia pomonella ganulovirus (CpGV). Transcription of IIV-6 iap did not require prior DNA or protein synthesis, indicating that it is an immediate-early class gene. Transient expression and gene knockdown studies have confirmed the functional nature of the IIV-6 iap gene. We present a tentative model for IIV-6 induction and inhibition of apoptosis in insect cells and discuss the potential applications of these findings in insect pest control.

  17. The denied constitution

    OpenAIRE

    Borja, Miguel

    2014-01-01

    The present article examines the luck of the proposals presented by indigenous and afro-Colombian communities, during the National Constituent Assembly of 1991. These proposals were aimed to define a new territorial organization of the State, but they were discarded from the Constitution and the subsequent legislative development. We are, therefore, front of the lack of knowledge of one of the most important realities of the country: the construction of space by the indigenous and afro-Colomb...

  18. [Constitutional requirements of rationing].

    Science.gov (United States)

    Kluth, Winfried

    2008-01-01

    Rationing is an emotive issue in the field of public health. This complicates the rational discourse, which is indispensable for analyzing the rationing conditions as set out by constitutional law and which requires manifold differentiation and consideration that shall briefly be outlined in the following short contribution. Of central significance is the distinction between indirect and direct rationing as well as the reference to the essential responsibility of legislators for rationing decisions. PMID:19004184

  19. What constitutes information integrity?

    OpenAIRE

    S. Flowerday; R. von Solms

    2008-01-01

    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 securit...

  20. What constitutes information integrity?

    OpenAIRE

    S. Flowerday; R. von Solms

    2007-01-01

    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 securit...

  1. 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.

  2. [The comeback of mitochondria in Drosophila apoptosis].

    Science.gov (United States)

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

    2016-05-01

    The role of the mitochondrion in mammalian cell apoptosis has been established since the mid-1990s. However, the importance of this organelle in non-mammalian apoptosis has long been regarded as minor, notably because of the absence of a crucial role for cytochrome c in caspase activation. Recent results indicate that the control of caspase activation and apoptosis in Drosophila cell death occurs at the mitochondrial level. Numerous proteins that appear key for Drosophila apoptosis regulation constitutively or transiently bind to mitochondria. They participate in the cell death process at different levels such as degradation of an IAP caspase inhibitor, production of mitochondrial reactive oxygen species or stimulation of the mitochondrial fission machinery. The aim of this review is to take stock of these events that might have their counterpart in humans. PMID:27225920

  3. Ethics and constitutional government.

    Science.gov (United States)

    Albright, James A

    2007-01-01

    The term ethics refers to a set of principles that govern acceptable, proper conduct. Attacks on the Constitution of the United States pose the most serious breach of ethics today. Our country was founded as a republic, not as a democracy. Our Founding Fathers' main concern was to protect citizens from the power of the federal government, so constitutionally, the central government has little or no authority over individual citizens except on federal property. One of the major problems today is the fact that we now have professional politicians. This is due in large part to the lure of financial gain from countless special interest groups. This would change under constitutional law because the federal budget would decrease drastically. Article 1 states that all legislative power is vested in Congress. Congress has only 18 enumerated powers, and almost half of these pertain to defense of the country. Many of our current problems are due to regulatory agencies that have become independent fiefdoms with unconstitutional legislative, as well as executive and judicial, powers. The regulatory agency most relevant to medicine, both clinical care and research, is the FDA. It is now obvious that its basic structure needs to be changed or abolished because its actions are identical to those inherent in authoritarian systems. Constructive change could come from Congress, but it would be most desirable if the Supreme Court would take the lead and reestablish the authority of the Constitution as the Supreme Law of the Land. The FDA's function could be limited to the determination of safety, but preferably its mission would be altered to that of product certification. Defenders of the current system claim that such a drastic change would be too dangerous and their prime example is thalidomide. But it is now known that the market has already solved that problem prior to the government-imposed sanctions. Realistically, market forces and their ramifications, including our legal

  4. 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.

  5. 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.

  6. Environment, constitution, administration

    International Nuclear Information System (INIS)

    This issue contains papers delivered at the 13th congress of the Institute for Energy Law at Cologne University. The titles of the essays are as follows: The Implementation of governmental decisions as a constitutional problem; Protection of the environment within the system of judicial order; The compromise in harmonizing goals as part of the judicial order; The burden of proof as lever of the politics of law and order especially within the limits of the Emission Control Law; The protection of the law and the setting of standards by governmental and private channels; The legal Emission control provisions as prerequisite for licensing; Protection of established power installations. All essays are concerned with environmental problems. (HSCH)

  7. Cell shrinkage as a signal to apoptosis in NIH 3T3 fibroblasts

    DEFF Research Database (Denmark)

    Friis, Martin B; Friborg, Christel R; Schneider, Linda;

    2005-01-01

    Cell shrinkage is a hallmark of the apoptotic mode of programmed cell death, but it is as yet unclear whether a reduction in cell volume is a primary activation signal of apoptosis. Here we studied the effect of an acute elevation of osmolarity (NaCl or sucrose additions, final osmolarity 687...... mosmol l(-1)) on NIH 3T3 fibroblasts to identify components involved in the signal transduction from shrinkage to apoptosis. After 1.5 h the activity of caspase-3 started to increase followed after 3 h by the appearance of many apoptotic-like bodies. The caspase-3 activity increase was greatly enhanced...... in cells expressing a constitutively active G protein, Rac (RacV12A3 cell), indicating that Rac acts upstream to caspase-3 activation. The stress-activated protein kinase, p38, was significantly activated by phosphorylation within 30 min after induction of osmotic shrinkage, the phosphorylation being...

  8. 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

  9. Preprogrammed and programmed cell death mechanisms of apoptosis: UV-induced immediate and delayed apoptosis

    International Nuclear Information System (INIS)

    Equitoxic doses (10% clonogenic survival) of UV radiation (UVR) from the three waveband regions, i.e. UVA1 (340-400 nm), UVB (290-320 nm) and UVC (200-290 nm), were shown to induce immediate or delayed apoptosis in L5178Y-R murine lymphoma cells. Membrane and DNA damage were shown to be the most probable initiators of UVA1-induced immediate or UVR-induced delayed apoptosis, respectively. These UV-induced apoptotic processes appeared to utilize two different ''core'' biochemical mechanisms; however, one core mechanism could be initiated at two distinct sites (e.g. membrane or DNA) and result in disparate kinetics. In an attempt to resolve this mechanistic issue, the dependence on macromolecular synthesis of each UV-induced apoptotic mechanism was investigated. In the absence of UVR, inhibition of either transcription (actinomycin D) or translation (cycloheximide) induced apoptosis in a concentration-and time-dependent manner. These results suggest that an apoptotic mechanism exists that does not require macromolecular synthesis postinsult (constitutive). The UVR data demonstrate that UVA-1 induced immediate apoptosis utilizes this constitutive mechanism (preprogrammed), while UVR-induced delayed apoptosis utilizes the well-known inducible mechanism (programmed). Therefore, there are two different core biochemical mechanisms of apoptotic death available to each cell: preprogrammed (constitutive) and programmed (inducible) cell death. (Author)

  10. The Constitution and American Diversity.

    Science.gov (United States)

    Glazer, Nathan

    1987-01-01

    Diversity in American constitutional law refers to differences among the laws of the states. However, key phrases in the Constitution have been used to ensure individual rights. The expansion of those rights has led to conflict between community needs and those of the individual, with each side referring to the Constitution for support. (PS)

  11. Cooperative Interaction of trp Melastatin Channel TRPM2 with its Splice Variant TRPM2-S is Essential for Endothelial Cell Apoptosis

    Science.gov (United States)

    Hecquet, Claudie M.; Zhang, Min; Mittal, Manish; Vogel, Stephen M.; Di, Anke; Gao, Xiaopei; Bonini, Marcelo G.; Malik, Asrar B.

    2014-01-01

    Rationale: Oxidants generated by activated endothelial cells are known to induce apoptosis, a pathogenic feature of vascular injury and inflammation from multiple etiologies. The melastatin-family transient receptor potential 2 (TRPM2) channel is an oxidant-sensitive Ca2+ permeable channel implicated in mediating apoptosis; however, the mechanisms of gating of the supra-normal Ca2+ influx required for initiating of apoptosis are not understood. Objective: Here we addressed the role TRPM2 and its interaction with the short splice variant TRPM2-S in mediating the Ca2+ entry burst required for induction of endothelial cell apoptosis. Methods and Results: We observed that TRPM2-S was basally associated with TRPM2 in the endothelial plasmalemma and this interaction functioned to constitutively suppress TRPM2-dependent Ca2+ gating. ROS production in endothelial cells or directly applying ROS induced PKCα activation and phosphorylation of TRPM2 at Ser 39. This in turn stimulated a large entry of Ca2+ and activated the apoptosis pathway. A similar TRPM2-dependent endothelial apoptosis mechanism was seen in intact vessels. The PKCα-activated phospho-switch opened the TRPM2 channel to allow large Ca2+ influx by releasing TRPM2-S inhibition of TRPM2, which in turn activated caspase-3 and cleaved the caspase substrate poly(ADP-ribose) polymerase. Conclusions: Here we describs a fundamental mechanism by which activation of the trp super-family TRPM2 channel induces apoptosis of endothelial cells. The signaling mechanism involves ROS-induced PKCα activation resulting in phosphorylation of TRPM2-S that allows enhanced TRPM2-mediated gating of Ca2+ and activation of the apoptosis program. Strategies aimed at preventing the uncoupling of TRPM2-S from TRPM2 and subsequent Ca2+ gating during oxidative stress may mitigate endothelial apoptosis and its consequences in mediating vascular injury and inflammation. PMID:24337049

  12. Constitution-making in the 21st century

    Directory of Open Access Journals (Sweden)

    Cheryl Saunders

    2012-04-01

    Full Text Available Constitutions have been made or changed in major ways in more than half the countries of the world in recent decades. This article deals with contemporary approaches to constitution-making, organising the analysis around three key phases: setting the agenda, in terms of both substance and process; design, drafting and approval; and implementation. It argues that, while all constitution-making processes are different, there are some distinctive features of constitution-making in the 21st century that include popular participation, the need to build trust, internationalisation in its various forms and the importance of process. The article canvasses examples of constitution-making practices that have been or are likely to be influential. It identifies and briefly explores some of the key tensions in constitution-making between, for example, international involvement and domestic ownership of a Constitution and public participation and leadership.

  13. Religion and the Japanese Constitution

    OpenAIRE

    Hardacre, Helen

    2014-01-01

    This paper examines provisions regarding religion in the 1947 Constitution of Japan, showing how they differ from the Meiji constitution of 1889. It examines policies on religion established by the Allied Occupation of Japan (1945‐1952), especially relating to Shinto, their implementation, and their relation to the 1947 constitution. The paper documents the process through which Occupation officials drafted entirely new articles on religion, displacing a Japanese government commission that ...

  14. 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. PMID:26679112

  15. The Role Of Constitutional Justice in Russia in the Process of Interpretation of European Values and the Promotion of European Constitutionalism

    OpenAIRE

    Mouliarova, Ekaterina

    2010-01-01

    This paper conducts a critical analysis of selected cases of the Russian Constitutional Court and High Arbitration Court involving the interpretation of constitutional values underlying the Russian legal order, in this way investigating the role of constitutional justice in Russia in promoting a European type of constitutionalism. The judicial practices of the Constitutional Court are brought into the broader context of the process of transition, state- and nation-building in the ...

  16. Inhibition of autophagy enhances apoptosis involved with intracellular ROS generation in multiple myeloma cells exposed to Oridonin%抑制自噬促进冬凌草甲素诱导的多发性骨髓瘤细胞凋亡涉及胞内ROS产生

    Institute of Scientific and Technical Information of China (English)

    曾蓉; 陈燕; 崔国惠

    2011-01-01

    目的 本实验主要研究冬凌草甲素诱导多发性骨髓瘤发生自噬、凋亡,两者之间的关系以及所涉及的相关机制.方法 利用MTT比色法检测冬凌草甲素对多发性骨髓瘤RPMI8226细胞的增殖活性影响;透视电镜观察细胞内凋亡和自噬的形态学改变;TUNEL检测细胞凋亡;分别利用以下技术检测处理后的细胞内的自噬变化:使用QDs605nm-Anti-LC3荧光探针以及免疫荧光技术定位细胞胞内LC3Ⅰ和LC3Ⅱ蛋白,利用western blot免疫印记技术检测Beclin 1蛋白表达水平;利用DCFH-DA探针以及流式细胞术检测细胞胞内ROS水平.结果 冬凌草甲素能明显抑制RPMI8226细胞增殖,其抑制作用呈时间、剂量依赖性;冬凌草甲素能同时诱发细胞凋亡、自噬和胞内ROS产生;NAC完全抑制胞内ROS产生后冬凌草甲素诱导的细胞凋亡消失;3-MA抑制自噬后,冬凌草甲素诱导的胞内ROS产生进一步增多,凋亡增多.结论 冬凌草甲素能明显抑制RPMI8226细胞增殖;冬凌草甲素同时诱发细胞凋亡和自噬;胞内ROS产生介导冬凌草甲素诱导的凋亡;凋亡为细胞死亡的主要途径,而自噬通过下调胞内ROS产生抑制凋亡.%Objective To explore the oridonin-induced apoptosis and autophagy of multiple myelomacells the relationship between them, and the involved molecular mechanisms. Methods RPM18226 cell vitality was assessed by MTT assay. The morphology of apoptosis and autophagy was observed by TEM.TUNEL assay was used to determine apoptosis. The LC3 localization and the Beclinl protein level indicating autophagy level were analyzed by immunofluorescence analysis using the QDs605nm-AntiLC3 fluorescent probe and western blot assay. The intracellular ROS generation was estimated by FCM using the uorescent probe DCFH-DA. Results Oridonin inhibited the proliferation of RPM18226 cells dose- and time-dependently. Oridonin simultaneously induced apoptosis, autophagy and intracellular ROS generation

  17. Cytochrome c and insect cell apoptosis

    Institute of Scientific and Technical Information of China (English)

    Kai-Yu Liu; Hong Yang; Jian-Xin Peng; Hua-Zhu Hong

    2012-01-01

    The role ofcytochrome c in insect cell apoptosis has drawn considerable attention and has been subject to considerable controversy.In Drosophila,the majority of studies have demonstrated that cytochrome c may not be involved in apoptosis,although there are conflicting reports.Cytochrome c is not released from mitochondria into the cytosol and activation of the initiator caspase Dronc or effector caspase Drice is not associated with cytochrome c during apoptosis in Drosophila SL2 cells or BG2 cells.Cytochrome c failed to induce caspase activation and promote caspase activation in Drosophila cell lysates,but remarkably caused caspase activation in extracts from human cells.Knockdown of cytochrome c does not protect cells from apoptosis and over-expression of cytochrome c also does not promote apoptosis.Structural analysis has revealed that cytochrome c is not required for Dapaf-1 complex assembly.In Lepidoptera,the involvement of cytochrome c in apoptosis has been demonstrated by the accumulating evidence.Cytochrome c release from mitochondria into cytosol has been observed in different cell lines such as Spodoptera frugiperda Sf9,Spodoptera litura S1-1 and Lymantria dispar LdFB.Silencing of cytochrome c expression significantly affected apoptosis and activation of caspase and the addition of cytochrome c to cell-free extracts results in caspase activation,suggesting the activation of caspase is dependent on cytochrome c.Although Apaf- 1 has not been identified in Lepidoptera,the inhibitor of apoptosome formation can inhibit apoptosis and caspase activation.Cytochrome c may be exclusively required for Lepidoptera apoptosis.

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

    Science.gov (United States)

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

    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. PMID:27060196

  19. Targeting early B-cell receptor signaling induces apoptosis in leukemic mantle cell lymphoma

    Directory of Open Access Journals (Sweden)

    Boukhiar Mohand-Akli

    2013-02-01

    Full Text Available Abstract Background We previously showed that B-cell receptor (BCR signaling pathways are important for in vitro survival of mantle cell lymphoma (MCL cells. To further identify early BCR-activated signaling pathways involved in MCL cell survival, we focused our study on BCR-proximal kinases such as LYN whose dysregulations could contribute to the aggressive course of MCL. Methods Primary MCL cells were isolated from 14 leukemic patients. Early BCR-induced genes were identified by qRT-PCR array. The basal and BCR-induced phosphorylation of LYN and JNK were evaluated by immunoblottting. Cell survival signals were evaluated by apoptosis using flow cytometry. Results We showed that LYN was constitutively phosphorylated in MCL cell lines and in 9/10 leukemic MCL cases. Treatment with dasatinib or with a specific inhibitor of Src kinases such as PP2 suppressed constitutive LYN activation and increased in vitro spontaneous apoptosis of primary MCL cells. BCR engagement resulted in an increase of LYN phosphorylation leading to activation of c-JUN NH2-terminal kinase (JNK and over-expression of the early growth response gene-1 (EGR-1. Inhibition of JNK with SP600125 induced apoptosis and reduced level of basal and BCR-induced expression of EGR-1. Furthermore, decreasing EGR1 expression by siRNA reduced BCR-induced cell survival. Treatment with PP2 or with dasatinib suppressed BCR-induced LYN and JNK phosphorylation as well as EGR-1 upregulation and is associated with a decrease of cell survival in all cases analysed. Conclusions This study highlights the importance of BCR signaling in MCL cell survival and points out to the efficiency of kinase inhibitors in suppressing proximal BCR signaling events and in inducing apoptosis.

  20. How Capitalistic Is the Constitution?

    Science.gov (United States)

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

    Second in a three-part series designed to help prepare the nation for a thoughtful observance of the Constitutional bicentennial, this publication contains seven essays on the topic of capitalism and the Constitution. "American Democracy and the Acquisitive Spirit" (Marc F. Plattner) supports the argument that the framers of the Constitution…

  1. Constitutive Effects of Performance Indicators

    DEFF Research Database (Denmark)

    Dahler-Larsen, Peter

    2014-01-01

    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....

  2. Reordering American Constitutional Law Teaching.

    Science.gov (United States)

    Gerber, Scott D.

    1994-01-01

    Maintains that constitutional law is the cornerstone of an undergraduate public law curriculum. Asserts that there is a welcome trend toward teaching the subject over a two-semester sequence, instead of only one. Describes course content and teaching strategies used in a college constitutional law course. (CFR)

  3. Constitutional Law and Liberal Education.

    Science.gov (United States)

    Clor, Harry

    1985-01-01

    By studying constitutional law, students learn about the relationship between democratic theory and practice, one of the main concerns of liberal education. The mind is enlarged when it must apply ethical standards and political ideas to real human problems. How a political science professor teaches constitutional law is discussed. (RM)

  4. 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…

  5. Regulation of apoptosis by peroxisome proliferators.

    Science.gov (United States)

    Roberts, Ruth A; Michel, Cecile; Coyle, Beth; Freathy, Caroline; Cain, Kelvin; Boitier, Eric

    2004-04-01

    Peroxisome proliferators (PPs) constitute a large and chemically diverse family of non-genotoxic rodent hepatocarcinogens that activate the PP-activated receptor alpha (PPARalpha). In order to investigate the hypothesis that PPs elicit their carcinogenic effects through the suppression of apoptosis, we established an in vitro assay for apoptosis using both primary rat hepatocytes and the FaO rat hepatoma cell line. Apoptosis was induced by transforming growth factor beta1 (TGFbeta1), the physiological negative regulator of liver growth. In this system, PPs could suppress both spontaneous and TGFbeta1-induced apoptosis. In order to understand the mechanisms of this regulation of apoptosis, we conducted microarray analysis followed by pathway-specific gene clustering in TGFbeta1-treated cells. After treatment, 76 genes were up-regulated and 185 were down-regulated more than 1.5-fold. Cluster analysis of up-regulated genes revealed three clusters, A-C. Cluster A (4h) was associated with 12% apoptosis and consisted of genes mainly of the cytoskeleton and extracellular matrix such as troponin and the proteoglycan SDC4. In cluster B (8h; 25% apoptosis), there were many pro- and anti-apoptotic genes such as XIAP, BAK1 and BAD, whereas at 16h (40% apoptosis) the regulated genes were mainly those of the cellular stress pathways such as the genes implicated in the activation of the transcription factor NFkappab. Genes found down-regulated in response to TGFbeta1 were mainly those associated with oxidative stress and several genes implicated in glutathione production and maintenance. Thus, TGFbeta1 may induce apoptosis via a down regulation of oxidant defence leading to the generation of reactive oxygen species. The ability of PPs to impact on these apoptosis pathways remains to be determined. To approach this question, we have developed a technique using laser capture microdissection of livers treated with the PP, clofibric acid coupled with gene expression array analysis

  6. Constitutional multicenter bank linked to Sasang constitutional phenotypic data

    OpenAIRE

    Jin, Hee-Jeong; Baek, Younghwa; Kim, Ho-Seok; Ryu, Jonghyang; Lee, Siwoo

    2015-01-01

    Background Biobanks are more important in medical area because they can give researchers data for demonstrating and validating their research. In this study, we developed a biobank called the Korea Constitutional Multicenter Bank (KCMB) based on Sasang Constitutional Medicine (SCM). The aim of the KCMB was a foundation to providing the scientific basis of SCM. Methods The KCMB has been constructed since 2006 in 24 Korean medical clinics with collection of questionnaire data, physical measurem...

  7. Apoptosis in the Retina

    OpenAIRE

    Crisanti, Patricia; Lecain, Eric; Omri, Boubaker

    2007-01-01

    Retinal degenerations are a common cause of blindness in Western countries. Despite various origins of retinal degeneration it is well recognised that. Apoptosis is the final pathway of photoreceptor neuron cell death in these diseases. So that Ivana Scovassi presents the historical development of our knowledge in: apoptosis, its difference with other forms of cell death as necrosis and analyses when and how apoptosis arises, discussing also the molecular markers in this form of cell death. T...

  8. Radioactive waste disposal and constitution

    International Nuclear Information System (INIS)

    The radioactive waste disposal has many dimensions with regard to the constitutional law. The central problem is the corret delimitation between adequate governmental precautions against risks and or the permitted risk which the state can impose on the citizen, and the illegal danger which nobody has to accept. The solution requires to consider all aspects which are relevant to the constitutional law. Therefore, the following analysis deals not only with the constitutional risks and the risks of the nuclear energy, but also with the liberal, overall-economic, social, legal, and democratic aspects of radioactive waste disposal. (HSCH)

  9. Remarks on turbulent constitutive relations

    Science.gov (United States)

    Shih, Tsan-Hsing; Lumley, John L.

    1993-01-01

    The paper demonstrates that the concept of turbulent constitutive relations can be used to construct general models for various turbulent correlations. Some of the Generalized Cayley-Hamilton formulas for relating tensor products of higher extension to tensor products of lower extension are introduced. The combination of dimensional analysis and invariant theory can lead to 'turbulent constitutive relations' (or general turbulence models) for, in principle, any turbulent correlations. As examples, the constitutive relations for Reynolds stresses and scalar fluxes are derived. The results are consistent with ones from Renormalization Group (RNG) theory and two-scale Direct-Interaction Approximation (DIA) method, but with a more general form.

  10. 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

    Energy Technology Data Exchange (ETDEWEB)

    Zhai, Qingna [Department of Clinical Laboratory, Peking University Shenzhen Hospital, Guangdong (China); Shantou University Medical College, Guangdong (China); Zhou, Liang [Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Guangdong (China); Zhao, Chunjuan [Department of Clinical Laboratory, Peking University Shenzhen Hospital, Guangdong (China); Shantou University Medical College, Guangdong (China); Wan, Jun [Section of Biochemistry and Cell Biology, Division of Life Science, The Hong Kong University of Science and Technology (Hong Kong); Yu, Zhendong, E-mail: zhendongyu66@hotmail.com [Department of Clinical Laboratory, Peking University Shenzhen Hospital, Guangdong (China); Guo, Xin; Qin, Jie; Chen, Jing [Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Guangdong (China); Lu, Ruijing [Department of Clinical Laboratory, Peking University Shenzhen Hospital, Guangdong (China); Shantou University Medical College, Guangdong (China)

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer Previous method was the second-generation sequencing technology. Black-Right-Pointing-Pointer miR-508-3p and miR-509-3p were significantly down-regulated in RCC tissues. Black-Right-Pointing-Pointer They can inhibit cell proliferation and migration and promote cell apoptosis. Black-Right-Pointing-Pointer The expression of miR-508-3p was significantly decreased in RCC patients plasma. Black-Right-Pointing-Pointer 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.

  11. 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)

    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.

  12. Histone Modifications in Senescence-Associated Resistance to Apoptosis by Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Yan Y. Sanders

    2013-01-01

    Full Text Available Aging and age-related diseases are associated with cellular senescence that results in variable apoptosis susceptibility to oxidative stress. Although fibroblast senescence has been associated with apoptosis resistance, mechanisms for this have not been well defined. In this report, we studied epigenetic mechanisms involving histone modifications that confer apoptosis resistance to senescent human diploid fibroblasts (HDFs. HDFs that undergo replicative senescence display typical morphological features, express senescence-associated β-galactosidase, and increased levels of the tumor suppressor genes, p16, p21, and caveolin-1. Senescent HDFs are more resistant to oxidative stress (exogenous H2O2-induced apoptosis in comparison to non-senescent (control HDFs; this is associated with constitutively high levels of the anti-apoptotic gene, Bcl-2, and low expression of the pro-apoptotic gene, Bax. Cellular senescence is characterized by global increases in H4K20 trimethylation and decreases in H4K16 acetylation in association with increased activity of Suv420h2 histone methyltransferase (which targets H4K20, decreased activity of the histone acetyltransferase, Mof (which targets H4K16, as well as decreased total histone acetyltransferase activity. In contrast to Bax gene, chromatin immunoprecipitation studies demonstrate marked enrichment of the Bcl-2 gene with H4K16Ac, and depletion with H4K20Me3, predicting active transcription of this gene in senescent HDFs. These data indicate that both global and locus-specific histone modifications of chromatin regulate altered Bcl-2:Bax gene expression in senescent fibroblasts, contributing to its apoptosis-resistant phenotype.

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

    International Nuclear Information System (INIS)

    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)

  14. Cleanup liability and the Constitution

    International Nuclear Information System (INIS)

    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. Are Sanctions on Employers Constitutional?

    Science.gov (United States)

    Gollobin, Ira

    1988-01-01

    Questions the constitutional validity of employer sanctions used to deter illegal immigration under the Immigration Reform and Control Act. Points out the anomaly of using criminal penalties to deter a civil, administrative violation. (FMW)

  16. 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.

  17. 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....

  18. Constitutional aneuploidy and cancer predisposition†

    OpenAIRE

    Ganmore, Ithamar; Smooha, Gil; Izraeli, Shai

    2009-01-01

    Constitutional aneuploidies are rare syndromes associated with multiple developmental abnormalities and the alterations in the risk for specific cancers. Acquired somatic chromosomal aneuploidies are the most common genetic aberrations in sporadic cancers. Thus studies of these rare constitutional aneuploidy syndromes are important not only for patient counseling and clinical management, but also for deciphering the mechanisms by which chromosomal aneuploidy affect cancer initiation and progr...

  19. Constitutional Design and Political Communication

    OpenAIRE

    Xefteris, Dimitrios

    2009-01-01

    This paper models the constitutional design process, and points out the importance of political communication (defined as the level of information about the social distribution of policy preferences that individuals hold, at the time of this process) on the "extent" of "democratic restraints" of the socially preferred constitution and on the welfare derived by the society from its implementation. The results demonstrate that the level of political communication has a positive effect on the le...

  20. Valuation in the constitutional era

    OpenAIRE

    Elmien (WJ) du Plessis

    2015-01-01

    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...

  1. Constitutional orders in multinational firms

    DEFF Research Database (Denmark)

    Hull Kristensen, Peer; Morgan, Glenn

    Multinationals are faced with the problem of how to coordinate different actors and stop `fiefdoms' emerging that inhibits the achievement of transnational cooperation? We identify this as a problem of `constitutional ordering' in the firm. Drawing on Varieties of Capitalism approaches, we explore...... how multinationals from different contexts seek to create constitutional orders. We argue that the models which exist appear to be destructive of coordination. We explore the implications for MNCs....

  2. 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

  3. Oridonin induces apoptosis via PI3K/Akt pathway in cervical carcinoma HeLa cell line

    Institute of Scientific and Technical Information of China (English)

    Hong-zhen HU; Yue-bo YANG; Xiang-dong XU; Hong-wei SHEN; Yi-min SHU; Zi REN; Xiao-mao LI; Hui-ming SHEN; Hai-tao ZENG

    2007-01-01

    Aim:To investigate the apoptosis-inducing effect of oridonin,a diterpenoid isolated from Rabdosia rubescens,in the human cervical carcinoma HeLa cell line.Methods:A morphological analysis,nuclear condensation,and fragmentation of chromatin were monitored using Hoechst 33342 staining. Cell viability was assessed using the 3-(4,5-dimethylthiazol-(2)-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cell apoptosis and the apoptosis-related activation in the HeLa cell line were evaluated by flow cytometry and Western blotting. Results:Oridonin suppressed the proliferation of the HeLa cell line in a dose- and time-dependent fashion. Oridonin treatment downregulated the activation of protein kinase B (Akt),the expression of forkhead box class O (FOXO) transcription factor,and glycogen synthase kinase 3 (GSK3). Oridonin also induced the release of cytochrome c accompanied by the activation of caspase-3 and poly-adenosine diphosphate-ribose polymerase cleavage. In addition,Z-D(OMe)-E(OMe)-V-D(OMe)FMK (z-DEVD-fmk),an inhibitor of caspases,prevented caspase-3 activation and abrogated oridonin-induced cell death. Finally,oridonin treatment of the HeLa cell line downregulated the expression of the inhibitor of the apoptosis protein.Conclusion:Our results showed that oridonin-induced apoptosis involved several molecular pathways. Oridonin may suppress constitutively activated targets of phosphatidylinositol 3-kinase (Akt,FOXO,and GSK3) in the HeLa cell line,inhibiting the proliferation and induction of caspase-dependent apoptosis.

  4. Vitis vinifera seeds extract for the modulation of cytosolic factors BAX-α and NF-kB involved in UVB-induced oxidative stress and apoptosis of human skin cells

    Science.gov (United States)

    DECEAN, HANA; FISCHER-FODOR, EVA; TATOMIR, CORINA; PERDE-SCHREPLER, MARIA; SOMFELEAN, LIDIA; BURZ, CLAUDIA; HODOR, TUDOR; ORASAN, REMUS; VIRAG, PIROSKA

    2016-01-01

    Background and aims The depletion of the ozone layer allows overexposure of the skin to UV radiation, which is prolonged due to the increasing life expectancy, together with inappropriate life habits contribute to the increasing incidence of cutaneous malignancies. Plant extracts with antioxidant capacities are frequently employed as a means to protect skin against ultraviolet (UV) radiations, thus preventing skin cancers. In the present study we assessed a red grape seed extract (GSE) potential capacities to reduce ultraviolet B (UVB) radiation-induced reactive oxygen species (ROS) and subsequent apoptosis in a human keratinocytes cell line (HaCaT). We identified molecules and pathways modulated by the GSE through which this may exert its photoprotective effect. Methods The GSE was standardized according to its polyphenolic content and the most important biologically active compounds, such as epigallocatechin and epicatechin, catechin hydrate, procyanidin B and gallic acid were evidenced by high-performance liquid chromatography. According to the plant extract cytotoxicity on the HaCaT cell line, two concentrations were selected for testing from the non-toxic range: GSE1 (37.5 μgEqGA/ml) and GSE2 (75 μgEqGA/ml). The level of ROS was evaluated with CM-H2DCFDA assay, while apoptosis, Bax-α and NF-kβ p65 proteins with ELISA and confirmed by western-blot. Results Both concentrations of the extract decreased the level of ROS in UVB-irradiated keratinocytes (p<0.001), whereas apoptosis and Bax-α pro-apoptotic protein were only reduced by the higher concentration (GSE2). The NF-kB p65 protein level registered increasing values in time after UVB exposure of the cells, while the tested plant extract re-established its level when its smaller concentration was used (GSE1). Conclusion These results encourage further studies on this extract in order to identify other molecules and pathways through which this extract might exert its beneficial effects and also recommend

  5. Constitutive androstane receptor agonist, TCPOBOP, attenuates steatohepatitis in the methionine choline-deficient diet-fed mouse

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To ascertain whether constitutive androstane receptor (CAR) activation by 1,4-bis-[2-(3,5,dichloropyridyloxy)] benzene (TCPOBOP) modulates steatohepatitis in the methionine choline-deficient (MCD) diet-fed animal. METHODS: C57/BL6 wild-type mice were fed the MCD or standard diet for 2 wk and were treated with either the CAR agonist, TCPOBOP, or the CAR inverse agonist, androstanol. RESULTS: Expression of CYP2B10 and CYP3A11, known CAR target genes, increased 30-fold and 45-fold, respectively, in TCPOBOP-treated mice fed the MCD diet. TCPOBOP treatment reduced hepatic steatosis (44.6 ± 5.4% vs 30.4 ± 4.5%, P < 0.05) and serum triglyceride levels (48 ± 8 vs 20 ± 1 mg/Dl, P < 0.05) in MCD dietfed mice as compared with the standard diet-fed mice. This reduction in hepatic steatosis was accompanied by an increase in enzymes involved in fatty acid microsomal ω-oxidation and peroxisomal β-oxidation, namely CYP4A10, LPBE, and 3-ketoacyl-CoA thiolase. The reduction in steatosis was also accompanied by a reduction in liver cell apoptosis and inflammation. In contrast, androstanol was without effect on any of the above parameters. CONCLUSION: CAR activation stimulates induction of genes involved in fatty acid oxidation, and ameliorates hepatic steatosis, apoptosis and inflammation.

  6. Constitutional compatibility of energy systems

    International Nuclear Information System (INIS)

    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)

  7. Epithelial Cell Apoptosis and Lung Remodeling

    Institute of Scientific and Technical Information of China (English)

    Kazuyoshi Kuwano

    2007-01-01

    Lung epithelium is the primary site of lung damage in various lung diseases. Epithelial cell apoptosis has been considered to be initial event in various lung diseases. Apoptosis signaling is classically composed of two principle pathways. One is a direct pathway from death receptor ligation to caspase cascade activation and cell death. The other pathway triggered by stresses such as drugs, radiation, infectious agents and reactive oxygen species is mediated by mitochondria. Endoplasmic reticulum has also been shown to be the organelle to mediate apoptosis.Epithelial cell death is followed by remodeling processes, which consist of epithelial and fibroblast activation,cytokine production, activation of coagulation pathway, neoangiogenesis, re-epithelialization and fibrosis.Epithelial and mesenchymal interaction plays important roles in these processes. Further understanding of apoptosis signaling and its regulation by novel strategies may lead to effective treatments against various lung diseases. We review the recent advances in the understanding of apoptosis signaling and discuss the involvement of apoptosis in lung remodeling.

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

    DEFF Research Database (Denmark)

    Abat Ninet, Antoni

    2015-01-01

    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...

  9. The Constitutive Power of Twitter

    DEFF Research Database (Denmark)

    Albu, Oana Brindusa; Etter, Michael Andreas

    constituents. Such focus leaves little knowledge concerning the tensions new ICTs bring to organizational life. For a more nuanced understanding of the constitutive role of new ICTs in organizing, this paper unfolds a communication centered perspective and examines the strategic Twitter use in two...... 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 is the...... process through which an organization is constituted in the interactions of both organizational and non-organizational members in both physical and virtual sites....

  10. A Communicatively Constituted Online Crisis

    DEFF Research Database (Denmark)

    Valentini, Chiara; Romenti, Stefania; Kruckeberg, Dean

    2016-01-01

    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...... by offering suggestions on how to study online critical conversations through the lens of a communicative constitution perspective that could inform how critical issues eventually transform and become crises and how crisis perceptions evolve and are discursively shaped by communicative practices...... mediated, then online crises and their meanings are communicatively constructed. The chapter outlines how online conversations constitute discursive practices that make publics aware of critical situations of which they may or may not know and can even construct reputational crises. The chapter concludes...

  11. 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.

  12. 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.

  13. Trace elements and apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Koudrine, A.V. [Orenburg State Medical Academy, Orenburg (Russian Federation)

    1998-07-01

    It is known that apoptosis is considered to be responsible for selective deletion of cells during embryogenesis, the homeostasis of cell populations in continuously renewing tissues (i.e., serving as a counterbalance to mitosis), and tissue involution in response to chemical or physical stimuli. There are many publications on these questions. On the other hand, the intracellular processes that contribute to apoptosis are incompletely understood. Therefore, the role of apoptosis in the intracellular accumulation and outflow of minerals is of considerable importance in light of both their essential functions and toxic effects. (orig.)

  14. DNA fragmentation in apoptosis

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Cleavage of chromosomal DNA into oligonucleosomal size fragments is an integral part of apoptosis. Elegant biochemical work identified the DNA fragmentation factor (DFF) as a major apoptotic endonuclease for DNA fragmentation in vitro. Genetic studies in mice support the importance of DFF in DNA fragmentation and possibly in apoptosis in vivo. Recent work also suggests the existence of additional endonucleases for DNA degradation. Understanding the roles of individual endonucleases in apoptosis, and how they might coordinate to degrade DNA in different tissues during normal development and homeostasis, as well as in various diseased states, will be a major research focus in the near future.

  15. Constitutional Change Marks Ideological Breakthrough

    Institute of Scientific and Technical Information of China (English)

    2004-01-01

    The amendments to the Constitution of the People'sRepublic of China, the fourth since the constitutionwas promulgated in 1982 and proposed by theCentral Committee of the Communist Party of China(CPC), are expected to enshrine the respect andprotection of human rights, the protection of private

  16. A Venture in Constitutional Law.

    Science.gov (United States)

    Cole, W. Graham; Dillon, Dorothy H.

    1980-01-01

    Senior high girls and boys from two single-sex schools undertook a study of a Supreme Court case that provided insight not only into constitutional law and history but also into how men and women can work together and relate in other ways than dating. (DS)

  17. 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. Cro...

  18. Take Advantage of Constitution Day

    Science.gov (United States)

    McCune, Bonnie F.

    2008-01-01

    The announcement of the mandate for Constitution and Citizenship Day shortly before September, 2005, probably led to groans of dismay. Not another "must-do" for teachers and schools already stressed by federal and state requirements for standardized tests, increasingly rigid curricula, and scrutiny from the public and officials. But the idea and…

  19. Mathematical modeling and the two-phase constitutive equations

    International Nuclear Information System (INIS)

    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

  20. 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.

  1. Dental apoptosis: caspases behind

    Czech Academy of Sciences Publication Activity Database

    Matalová, Eva; Fleischmannová, Jana; Míšek, Ivan; Sharpe, P. T.; Tucker, A. S.

    Ljubljana: ECDO, 2007, s. 26-26. [Euroconference on Apoptosis /15./ and Training Course on Concepts and Methods in Programmed Cell Death /4./. Portorož (SI), 26.10.2007-31.10.2007] R&D Projects: GA MŠk OC B23.001; GA AV ČR KJB500450503 Institutional research plan: CEZ:AV0Z50450515 Keywords : dental apoptosis Subject RIV: FF - HEENT, Dentistry

  2. 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.; J. Jiang; 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...

  3. Apoptosis inhibitor of macrophage (AIM) expression in alveolar macrophages in COPD

    OpenAIRE

    Kojima, Jun; Araya, Jun; Hara, Hiromichi; Ito, Saburo; Takasaka, Naoki; Kobayashi, Kenji; Fujii, Satoko; Tsurushige, Chikako; Numata, Takanori; Ishikawa, Takeo; Shimizu, Kenichiro; Kawaishi, Makoto; Saito, Keisuke; Kamiya, Noriki; Hirano, Jun

    2013-01-01

    Background Marked accumulation of alveolar macrophages (AM) conferred by apoptosis resistance has been implicated in pathogenesis of chronic obstructive pulmonary disease (COPD). Apoptosis inhibitor of macrophage (AIM), has been shown to be produced by mature tissue macrophages and AIM demonstrates anti-apoptotic property against multiple apoptosis-inducing stimuli. Accordingly, we attempt to determine if AIM is expressed in AM and whether AIM is involved in the regulation of apoptosis in the...

  4. Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNalpha

    DEFF Research Database (Denmark)

    Brender, C; Lovato, P; Sommer, V H;

    2005-01-01

    Signal transducer and activator of transcription (Stat)3 is constitutively activated in cutaneous T-cell lymphoma (CTCL), where it protects tumour cells against apoptosis. The constitutive activation of Stat3 leads to a constitutive expression of suppressor of cytokine signalling (SOCS)-3. In...... healthy cells, SOCS-3 is transiently expressed following cytokine stimulation and functions as a negative feedback inhibitor of the Stat3-activating kinases. Here, we attempt to resolve the apparent paradox of a simultaneous SOCS-3 expression and Stat3 activation in the same cells. We show that (i) SOCS-3...... expression in tumour cells is equal to or higher than in cytokine-stimulated nonmalignant T cells, (ii) SOCS-3 is not mutated in CTCL, (iii) overexpression of SOCS-3 blocks IFNalpha-mediated growth inhibition without affecting Stat3 activation, growth, and apoptosis, and (iv) inhibition of SOCS-3 by a...

  5. Farnesol-induced apoptosis in Candida albicans.

    Science.gov (United States)

    Shirtliff, Mark E; Krom, Bastiaan P; Meijering, Roelien A M; Peters, Brian M; Zhu, Jingsong; Scheper, Mark A; Harris, Megan L; Jabra-Rizk, Mary Ann

    2009-06-01

    Farnesol, a precursor in the isoprenoid/sterol pathway, was recently identified as a quorum-sensing molecule produced by the fungal pathogen Candida albicans. Farnesol is involved in the inhibition of germination and biofilm formation by C. albicans and can be cytotoxic at certain concentrations. In addition, we have shown that farnesol can trigger apoptosis in mammalian cells via the classical apoptotic pathways. In order to elucidate the mechanism behind farnesol cytotoxicity in C. albicans, the response to farnesol was investigated, using proteomic analysis. Global protein expression profiles demonstrated significant changes in protein expression resulting from farnesol exposure. Among the downregulated proteins were those involved in metabolism, glycolysis, protein synthesis, and mitochondrial electron transport and the respiratory chain, whereas proteins involved in folding, protection against environmental and oxidative stress, actin cytoskeleton reorganization, and apoptosis were upregulated. Cellular changes that accompany apoptosis (regulated cell death) were further analyzed using fluorescent microscopy and gene expression analysis. The results indicated reactive oxygen species accumulation, mitochondrial degradation, and positive terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) in the farnesol-exposed cells concurrent with increased expression of antioxidant-encoding and drug response genes. More importantly, the results demonstrated farnesol-induced upregulation of the caspase gene MCA1 and the intracellular presence of activated caspases. In conclusion, this study demonstrated that farnesol promotes apoptosis in C. albicans through caspase activation, implying an important physiological role for farnesol in the fungal cell life cycle with important implications for adaptation and survival. PMID:19364863

  6. Technical risks and constitutional law

    International Nuclear Information System (INIS)

    It was particularly by the peaceful use of nuclear energy that the topic has raised the interest of the Constitutional Court. The concepts of averting risks, risk precaution and remaining risks have to be differentiated terminologically. The governmental obligation of protecting the citizens and granting the constitutional rights as far as the limit of acceptable risks, which is difficult to determine, is dominating. When applying unavoidable and vague legal concepts these concepts must be specified not only by technical rules or guidelines, expert committees and the like but also by a newr legal basis so that 'the mechanism of the division of power can be set to rights again in the field of technical risk control'. (orig./HP)

  7. 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.

  8. European constitution and EURATOM treaty

    International Nuclear Information System (INIS)

    The European Council held in Laeken in December 2001 had decided to call a convention preparing the next conference of the heads of state and government which, among other topics, was to deliberate the question of a fully formulated European constitution. Under the presidency of Giscard d'Estaing, all delegates to the European Convention on July 10, 2003 signed the draft treaty for a European constitution. This final document is the basis of the conference of the heads of state and government to begin in October 2003. On this occasion, the draft of a separate chapter on energy could well come up again for examination. This chapter had been introduced only at the end of the deliberations of the convention and adds to the competences of the EU institutions. Also the Euratom Treaty was a topic of the convention preparing the constitution. As the presidency felt that no specific issues had been raised in the Laeken declaration, it is proposed to adapt the Euratom Treaty to the new provisions of the constitution by adding a protocol. This would mean that the European Atomic Energy Community, for the time being, would retain its independent legal status. The contents would have to be examined at some later date. Consequently, the real discussion of the Euratom Treaty is yet to come. Also, the speedy completion of the single market for electricity would make it desirable for the Community to adopt a uniform, positive stance in the use of nuclear power at the best possible safety standards so as to ensure a level playing field. Current events entailing power failures in the United States and the United Kingdom have alerted the public to the problem of the continuity of power supply. This could well be the beginning of a new, unbiased, balanced energy discussion in a bigger Europe. (orig.)

  9. [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. PMID:12287889

  10. CONSTITUTIONAL LANDMARKS OF POLITICAL PLURALISM

    OpenAIRE

    ERHARD NICULESCU

    2013-01-01

    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...

  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

    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

  12. Constitutive modeling for isotropic materials (HOST)

    Science.gov (United States)

    Chan, Kwai S.; Lindholm, Ulric S.; Bodner, S. R.; Hill, Jeff T.; Weber, R. M.; Meyer, T. G.

    1986-01-01

    The results of the third year of work on a program which is part of the NASA Hot Section Technology program (HOST) are presented. The goals of this program are: (1) the development of unified constitutive models for rate dependent isotropic materials; and (2) the demonstration of the use of unified models in structural analyses of hot section components of gas turbine engines. The unified models selected for development and evaluation are those of Bodner-Partom and of Walker. A test procedure was developed for assisting the generation of a data base for the Bodner-Partom model using a relatively small number of specimens. This test procedure involved performing a tensile test at a temperature of interest that involves a succession of strain-rate changes. The results for B1900+Hf indicate that material constants related to hardening and thermal recovery can be obtained on the basis of such a procedure. Strain aging, thermal recovery, and unexpected material variations, however, preluded an accurate determination of the strain-rate sensitivity parameter is this exercise. The effects of casting grain size on the constitutive behavior of B1900+Hf were studied and no particular grain size effect was observed. A systematic procedure was also developed for determining the material constants in the Bodner-Partom model. Both the new test procedure and the method for determining material constants were applied to the alternate material, Mar-M247 . Test data including tensile, creep, cyclic and nonproportional biaxial (tension/torsion) loading were collected. Good correlations were obtained between the Bodner-Partom model and experiments. A literature survey was conducted to assess the effects of thermal history on the constitutive behavior of metals. Thermal history effects are expected to be present at temperature regimes where strain aging and change of microstructure are important. Possible modifications to the Bodner-Partom model to account for these effects are outlined

  13. Apoptosis signaling pathways and lymphocyte homeostasis

    Institute of Scientific and Technical Information of China (English)

    Guangwu Xu; Yufang Shi

    2007-01-01

    It has been almost three decades since the term "apoptosis" was first coined to describe a unique form of cell death that involves orderly, gene-dependent cell disintegration. It is now well accepted that apoptosis is an essential life process for metazoan animals and is critical for the formation and function of tissues and organs. In the adult mammalian body, apoptosis is especially important for proper functioning of the immune system. In recent years, along with the rapid advancement of molecular and cellular biology, great progress has been made in understanding the mechanisms leading to apoptosis. It is generally accepted that there are two major pathways of apoptotic cell death induction: extrinsic signaling through death receptors that leads to the formation of the death-inducing signaling complex (DISC), and intrinsic signaling mainly through mitochondria which leads to the formation of the apoptosome. Formation of the DISC or apoptosome, respectively, activates initiator and common effector caspases that execute the apoptosis process. In the immune system, both pathways operate; however, it is not known whether they are sufficient to maintain lymphocyte homeostasis. Recently, new apoptotic mechanisms including caspase-independent pathways and granzyme-initiated pathways have been shown to exist in lymphocytes. This review will summarize our understanding of the mechanisms that control the homeostasis of various lymphocyte populations.

  14. Ligand-induced TCR down-regulation is not dependent on constitutive TCR cycling

    DEFF Research Database (Denmark)

    Dietrich, Jes; Menné, Charlotte; Lauritsen, Jens Peter H;

    2002-01-01

    is regulated by mechanisms distinct from those involved in constitutive internalization, whereas other studies have suggested that the ligand-induced TCR internalization pathway is identical with the constitutive pathway. To resolve this question, we first identified requirements for constitutive TCR...... ligand-induced internalization of the TCR. In conclusion, ligand-induced TCR internalization and constitutive cycling of the TCR represents two independent pathways regulated by different mechanisms....

  15. The South African Constitutional Court Experience: Reasoning Patterns Based on Foreign Law

    OpenAIRE

    Andrea Lollini

    2012-01-01

    This article aims to analyse the phenomenon of the diffusion of interpretive paradigms or argumentation models between constitutional courts. This phenomenon involves the importation of parameters - defined here as extra-systemic to a specific legal system - and the use of the comparative method in applying constitutional texts.The main subject of this study is the analysis of the first 11 years of South African constitutional jurisprudence, which is a convenient scenario since a constitution...

  16. 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.

  17. Legal Conflicts and Subnational Constitutionalism

    OpenAIRE

    DELLEDONNE, Giacomo; MARTINICO, Giuseppe

    2011-01-01

    Paper presented at the World Conference of the International Association of Constitutional Law, Mexico City, 6-10 December 2010. This paper is the result of joint reflections, however Giuseppe Martinico wrote par. 2, 5, 8 and 9, Giacomo Delledonne wrote par. 3, 4 and 7, while par. 1 and 6 were elaborated jointly. We would like to thank Josep Maria Castellà Andreu, François-Xavier Millet and Robert Williams for their comments and Miguel Poiares Maduro and Ernst-Ulrich Petersmann for their supp...

  18. Technical risks and Constitutional Law

    International Nuclear Information System (INIS)

    The author regards technical risk assessment as a legal problem of increasing importance. He discusses the delimitation of hazard, risk and damage; the protective duty of the state, and security of basic rights; the determination of risk elements; the interpretation of undetermined legal concepts. The essential question is as to what extent the undetermined legal concepts are subject to judicial reviews. A transition from 'subject-related' to 'procedural' reviewing requires corresponding insitutional and procedural rules according to which technical safety rules will be created. Under Constitutional Law, it does not seem to be satisfying to bind the courts to technical rules as long as there are none. (HSCH)

  19. A unified viscoplasticity constitutive model based on irreversible thermodynamics

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    A unified viscoplasticity constitutive model for metal materials is developed within the framework of irreversible thermodynamics, and an expression for the Helmholtz free energy function involving the parameters reflecting kinematic hardening and isotropic hardening is given. At the same time a non-associated flow potential function including the corresponding state variables is also given, from which the flow equation and the evolution equations of the internal state variables are derived. Thus, a general theoretical framework constructing a unified viscoplasticity constitutive model is given. Compared with the typical unified viscoplasticity constitutive models, the presented model evidently satisfies the irreversible thermodynamics laws. Moreover, this method not only provides a new theoretical foundation for further development of the unified viscoplasticity constitutive model, but also gives a new theoretical framework for the stress-strain analysis of more materials.

  20. Apoptosis: una muerte silenciosa

    OpenAIRE

    Isis Casadelvalle Pérez

    2006-01-01

    La apoptosis o muerte celular programada es un tipo de muerte presente en todas las células eucarióticas. Es un proceso ordenado y esencial del desarrollo normal y de mantenimiento de la homeostasis de un organismo. En el presente trabajo se resumen las principales características fisiológicas, bioquímicas y moleculares de la muerte por apoptosis, evento que ocurre de forma apagada o silenciosa, o sea, sin daño celular aparente diferenciándose claramente del proceso de necrosis celular. En es...

  1. [Sphingolipid and apoptosis].

    Science.gov (United States)

    Wang, Jing; Hu, Xiao-Song; Shi, Jie-Ping

    2003-07-01

    Over the last decade, considerable progress has been made in the study of sphingolipids with the development of biological techniques. Sphingolipids play important roles in diverse physiological process, including cytoskeleton migration, angiogenesis, embryonic development and signal transduction. Except for this, the lastest evidence has suggested that sphingolipids and their metabolite (ceramide, sphingosine, sphingosine 1-phosphate) can induce apoptosis in a wide variety of tumor cell lines such as LoVo HT29, Bel7402, A549, CNE2 cells. This paper is attempted to review the recent advances of investigation into the relationship between sphingolipids and apoptosis. PMID:14628466

  2. Nuclear energy as reflected in Constitutional Law

    International Nuclear Information System (INIS)

    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)

  3. Constitutive modeling for isotropic materials

    Science.gov (United States)

    Lindholm, Ulric S.; Chan, Kwai S.

    1986-01-01

    The objective of the program is to evaluate and develop existing constitutive models for use in finite-element structural analysis of turbine engine hot section components. The class of constitutive equation studied is considered unified in that all inelastic deformation including plasticity, creep, and stress relaxation are treated in a single term rather than a classical separation of plasticity (time independent) and creep (time dependent) behavior. The unified theories employed also do not utilize the classical yield surface or plastic potential concept. The models are constructed from an appropriate flow law, a scalar kinetic relation between strain rate, temperature and stress, and evolutionary equations for internal variables describing strain or work hardening, both isotropic and directional (kinematic). This and other studies have shown that the unified approach is particularly suited for determining the cyclic behavior of superalloy type blade and vane materials and is entirely compatible with three-dimensional inelastic finite-element formulations. The behavior was examined of a second nickel-base alloy, MAR-M247, and compared it with the Bodner-Partom model, further examined procedures for determining the material-specific constants in the models, and exercised the MARC code for a turbine blade under simulated flight spectrum loading. Results are summarized.

  4. Constitutive activation of extracellular signal-regulated kinase predisposes diffuse large B-cell lymphoma cell lines to CD40-mediated cell death

    DEFF Research Database (Denmark)

    Hollmann, C Annette; Owens, Trevor; Nalbantoglu, Josephine; Hudson, Thomas J; Sladek, Robert

    2006-01-01

    , including LCK and VAV. In addition, CD40-sensitive DLBCL cell lines also displayed constitutive activation of extracellular signal-regulated kinase (ERK) and failed to undergo apoptosis when ERK phosphorylation was inhibited. In contrast, CD40-resistant lines showed no constitutive activation of ERK and no...

  5. 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.

  6. Constitutive model for overconsolidated clays

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Based on the relationships between the Hvorslev envelope,the current yield sur-face and the reference yield surface,a new constitutive model for overconsolidated clays is proposed. It adopts the unified hardening parameter,to which the potential failure stress ratio and the characteristic state stress ratio are introduced. The model can describe many characteristics of overconsolidated clays,including stress-strain relationships,strain hardening and softening,stress dilatancy,and stress path dependency. Compared with the Cam-clay model,the model only re-quires one additional soil parameter which is the slope of the Hvorslev envelope. Comparisons with data from triaxial drained compression tests for Fujinomori clay show that the proposed model can rationally describe overconsolidated properties. In addition,the model is also used to predict the stress-strain relationship in the isotropic consolidation condition and the stress paths in the undrained triaxial compression tests.

  7. The Constitutive Values of Science

    Directory of Open Access Journals (Sweden)

    Hugh Lacey

    1997-06-01

    Full Text Available Cognitive values are the characteristics that are constitutive of good theories, the criteria to which we appeal when choosing among competing theories. I argue that, in order to count as a cognitive value, a characteristic must be needed to explain actually made theory choices, and its cognitive significance must be well defended especially in view of considerations derived from the objective of science. A number of proposed objectives of science are entertained, and it is argued that adopting a par-ticular objective is dialectically intertwined with commitment to certain social values.Then, the ways in which science is, and is not value free is explored briefly, leading to the identification of a level of analysis where values may influence theory choice without causing paradox or threatening the impartiality of soundly-made scientific judgments.

  8. 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.

  9. 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.

  10. 7,12-Dimethylbenzanthracene induces apoptosis in RL95-2 human endometrial cancer cells: Ligand-selective activation of cytochrome P450 1B1

    International Nuclear Information System (INIS)

    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.

  11. 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.

  12. Social Sciences and Constitutional Rights--the Consequences of Uncertainty

    Science.gov (United States)

    Dworkin, Ronald M.

    1977-01-01

    Discusses the theoretical basis of court decisions involving school integration, analyzing the relationship between education, constitutional law, and the social sciences. Concludes that court decisions dealing with the equal protection clause are based on interpretive judgments, rather than on causal judgments drawn from statistical theory. (JG)

  13. INHIBITION OF SPONTANEOUS APOPTOSIS IN HUMAN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    邵志敏; 江明; 吴炅; 余黎民; 韩企夏; 张延璆; 沈镇宙

    1996-01-01

    Breast tumorigenesis proceeds through an accumulation of specific genetic alteration. Breast malignant transformation is dependent on not only the rate of cell production but also on apoptcsis,a genetically prograined process of autonomous ceil death. We investigated whether breast tumorigenesis involved an altered susceptibility to apoptosis and proliferation by examining normal breast epithelium and breast cancer sampies. We found there is a great inhibition of spontaneous apoptosis in breast cancer ceils compared with normal breast epithelium. The inhibition of apoptosis in breast cancer may contribute to neoplastic transformation.

  14. Non-linear constitutive equations for gravitoelectromagnetism

    OpenAIRE

    Duplij, Steven; Di Grezia, Elisabetta; Esposito, Giampiero; Kotvytskiy, Albert

    2013-01-01

    This paper studies non-linear constitutive equations for gravitoelectromagnetism. Eventually, the problem is solved of finding, for a given particular solution of the gravity-Maxwell equations, the exact form of the corresponding non-linear constitutive equations.

  15. The communicative constitution of representation and exclusion

    NARCIS (Netherlands)

    Wessel, van M.G.J.

    2014-01-01

    In the light of current debate on representation, specifically engaging with literature showing how representation is communicatively constituted, this paper empirically shows how exclusion also can be seen as communicatively constituted. The interpretive approach toward communication employed in th

  16. Written Constitution or None: Which Works Better?

    Science.gov (United States)

    Cowen, Zelman

    1987-01-01

    Explores the differences between the U.S. Constitution and British constitutional law. Specifically examines the concept of the U.S. Bill of Rights in relation to the United Kingdom common law doctrine of parliamentary sovereignty. (BSR)

  17. Cerulein Pancreatitis: Oxidative Stress, Inflammation, and Apoptosis

    OpenAIRE

    Kim, Hyeyoung

    2008-01-01

    Cerulein pancreatitis is similar to human edematous pancreatitis, manifesting with dysregulation of digestive enzyme production and cytoplasmic vacuolization, the death of acinar cells, edema formation, and infiltration of inflammatory cells into the pancreas. Reactive oxygen species are involved in nuclear factor-κB activation, cytokine expression, apoptosis and pathogenesis of pancreatitis. There is recent evidence that cerulein activates NADPH oxidase, which is a major source of reactive o...

  18. Constitution of the White Earth Nation

    OpenAIRE

    Vizenor, Gerald

    2011-01-01

    The Constitution of the White Earth Nation was ratified by sworn delegates on April 4, 2009. The Constitution declares a separation from the current federal constitution that consolidated six Anishinaabe or Chippewa reservations in Minnesota. This federal constitutional association has not served the specific interests of the citizens of the White Earth Reservation. The disposition of treaty land, for instance, and the uses of natural resources cannot equitably be decided by any o...

  19. Constitutions, social rights and sovereign debt states in Europe : a challenging new area of constitutional inquiry

    OpenAIRE

    KILPATRICK, Claire

    2015-01-01

    Constitutions, social rights and sovereign debt states in Europe is a rich new seam of constitutional inquiry that challenges existing constitutional scholarship in various ways. I make five claims about how it expands and challenges existing constitutional and EU scholarship. 1. It is new terrain for constitutional social scholarship. 2. Middle-class and public sector entitlements are a deeply problematic area for constitutional social scholarship. 3. Juristocracy charges cannot be the same ...

  20. 17 CFR 200.54 - Constitutional obligations.

    Science.gov (United States)

    2010-04-01

    ... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false Constitutional obligations... ORGANIZATION; CONDUCT AND ETHICS; AND INFORMATION AND REQUESTS Canons of Ethics § 200.54 Constitutional... against any infringement of the constitutional rights, privileges, or immunities of those who are...

  1. 32 CFR 536.42 - Constitutional torts.

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 3 2010-07-01 2010-07-01 true Constitutional torts. 536.42 Section 536.42... AGAINST THE UNITED STATES Investigation and Processing of Claims § 536.42 Constitutional torts. A claim... any subpart. A constitutional claim will be scrutinized in order to determine whether it is totally...

  2. The Constitutional Politics of Charitable Choice.

    Science.gov (United States)

    Knippenberg, Joseph M.

    2003-01-01

    Clarifies the constitutional issue raised by government efforts to cooperate with faith-based organizations, noting that while programs can be constitutional without necessarily being good public policy, too frequently political and constitutional controversies mix these two considerations, thus confusing those trying to understand and resolve…

  3. 7 CFR 718.201 - Farm constitution.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 7 2010-01-01 2010-01-01 false Farm constitution. 718.201 Section 718.201 Agriculture... Reconstitution of Farms, Allotments, Quotas, and Bases § 718.201 Farm constitution. (a) In order to implement... this section. The constitution and identification of land as a farm for the first time and...

  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. 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

  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. 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.

  8. Apoptosis: una muerte silenciosa

    Directory of Open Access Journals (Sweden)

    Isis Casadelvalle Pérez

    2006-01-01

    Full Text Available La apoptosis o muerte celular programada es un tipo de muerte presente en todas las células eucarióticas. Es un proceso ordenado y esencial del desarrollo normal y de mantenimiento de la homeostasis de un organismo. En el presente trabajo se resumen las principales características fisiológicas, bioquímicas y moleculares de la muerte por apoptosis, evento que ocurre de forma apagada o silenciosa, o sea, sin daño celular aparente diferenciándose claramente del proceso de necrosis celular. En ese proceso se destaca la mitocondria, como organelo celular donde mediado por la activación de las caspasas se inicia el paso hacia la muerte celular programada. En el momento actual, la apoptosis ha cobrado un verdadero valor para la mejor comprensión de los procesos biológicos normales en los que este evento está involucrado y que con anterioridad no era tomado en cuenta. En este sentido, se comentan las principales técnicas de detección de muerte celular programada y se aclara que la elección de algunas de ellas depende del modelo de estudio. Tambi én se dan a conocer algunas de las patologías generales en las que este proceso representa un papel determinante y se discute acerca de cómo algunas alteraciones en los mecanismos de regulación de la apoptosis inducen la aparici ón de varias enfermedades, incluyendo aquellos desórdenes en los que ocurre acumulación celular (cáncer, alteración cardiaca, neurodegeneración y SIDA. El estudio y caracterización de este complejo mecanismo ha cambiado profundamente la comprensión de numerosas patologías en los organismos eucariotas.

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

    International Nuclear Information System (INIS)

    To analyze the involvement of apoptosis regulatory genes p53, p21waf1/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, p21waf1/cip1, and the bcl-2/bax ratio was decreased. In HCa-I radiation increased the expression of both p53 and p21waf1/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 p21waf1/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 p21waf1/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)

  10. Who and What does involvement

    DEFF Research Database (Denmark)

    Hansen, Jeppe Oute; Petersen, Anders; Huniche, Lotte

    2016-01-01

    theoretical perspective laid out by Ernesto Laclau and Chantal Mouffe, the aim of this study is to show how the dominant discourse about involvement at the political and clinical sites is constituted by understandings of mentally ill individuals and by political objectives of involvement. The analysis...

  11. 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.

  12. 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)

  13. 3 CFR 8418 - Proclamation 8418 of September 16, 2009. Constitution Day and Citizenship Day, Constitution Week...

    Science.gov (United States)

    2010-01-01

    ... through September 23, 2009, as Constitution Week. I encourage Federal, State, and local officials, as well.... Constitution Day and Citizenship Day, Constitution Week, 2009 8418 Proclamation 8418 Presidential Documents Proclamations Proclamation 8418 of September 16, 2009 Proc. 8418 Constitution Day and Citizenship...

  14. CLDN6-induced apoptosis via regulating ASK1-p38/JNK signaling in breast cancer MCF-7 cells.

    Science.gov (United States)

    Guo, Yaxiong; Lin, Dongjing; Zhang, Mingzi; Zhang, Xiaowei; Li, Yanru; Yang, Ruan; Lu, Yan; Jin, Xiangshu; Yang, Minlan; Wang, Miaomiao; Zhao, Shuai; Quan, Chengshi

    2016-06-01

    Claudin 6 (CLDN6), a member of tight junction protein claudin (CLDN) family, inhibits proliferation and induces apoptosis of MCF-7 breast cancer cells. However, these molecular mechanisms of CLDN6-induced apoptosis remain largely elusive. We previously found that restoration of human CLDN6 gene expression was correlated with the expression level of apoptosis signal-regulating kinase 1 (ASK1) using cDNA array and bioinformatics analysis. ASK1, a mitogen-activated protein kinase kinase kinase, is involved in environmental stress-activation of the c-jun N-terminal kinase (JNK) and p38 pathways, which contribute to apoptosis-associated tumor cell death. In the present study, we show that the restoration of CLDN6 gene expression in MCF-7 cells marhedly decreased ASK1 phosphorylation at Ser967. Activated ASK1ser967 further induced the activation of downstream targets, JNK and p38 kinase. MCF-7/CLDN6 stable transfection cell clone treated with TRX1, an ASK1 inhibitor, showed suppressed JNK and p38 activation, and showed substantially increased survival and colony formation and reduced percent of apoptotic cells using TUNEL staining and DNA ladder. Furthermore, TRX1 treatment increased Bcl-2/Bax ratio and reduced caspase-3 cleavage in MCF-7/CLDN6 stable transfection cell clone. Therefore, these data show that CLDN6 mediates ASK1-p38/JNK apoptotic signaling in MCF-7 cells, and it is correlated with constitutive deregulation of the balance of Bcl-2 family proteins and activation of caspase-3. PMID:27035750

  15. Control of apoptosis by asymmetric cell division.

    Science.gov (United States)

    Hatzold, Julia; Conradt, Barbara

    2008-04-01

    Asymmetric cell division and apoptosis (programmed cell death) are two fundamental processes that are important for the development and function of multicellular organisms. We have found that the processes of asymmetric cell division and apoptosis can be functionally linked. Specifically, we show that asymmetric cell division in the nematode Caenorhabditis elegans is mediated by a pathway involving three genes, dnj-11 MIDA1, ces-2 HLF, and ces-1 Snail, that directly control the enzymatic machinery responsible for apoptosis. Interestingly, the MIDA1-like protein GlsA of the alga Volvox carteri, as well as the Snail-related proteins Snail, Escargot, and Worniu of Drosophila melanogaster, have previously been implicated in asymmetric cell division. Therefore, C. elegans dnj-11 MIDA1, ces-2 HLF, and ces-1 Snail may be components of a pathway involved in asymmetric cell division that is conserved throughout the plant and animal kingdoms. Furthermore, based on our results, we propose that this pathway directly controls the apoptotic fate in C. elegans, and possibly other animals as well. PMID:18399720

  16. Detecting constitutive activity and protean agonism at cannabinoid-2 receptor.

    Science.gov (United States)

    Beltramo, Massimiliano; Brusa, Rossella; Mancini, Isabella; Scandroglio, Paola

    2010-01-01

    Since the cannabinoid system is involved in regulating several physiological functions such as locomotor activity, cognition, nociception, food intake, and inflammatory reaction, it has been the subject of intense study. Research on the pharmacology of this system has enormously progressed in the last 20years. One intriguing aspect that emerged from this research is that cannabinoid receptors (CBs) express a high level of constitutive activity. Investigation on this particular aspect of receptor pharmacology has largely focused on CB1, the CB subtype highly expressed in several brain regions. More recently, research on constitutive activity on the other CB subtype, CB2, was stimulated by the increasing interest on its potential as target for the treatment of various pathologies (e.g., pain and inflammation). There are several possible implications of constitutive activity on the therapeutic action of both agonists and antagonists, and consequently, it is important to have valuable methods to study this aspect of CB2 pharmacology. In the present chapter, we describe three methods to study constitutive activity at CB2: two classical methods relying on the detection of changes in cAMP level and GTPγS binding and a new one based on cell impedance measurement. In addition, we also included a section on detection of protean agonism, which is an interesting pharmacological phenomenon strictly linked to constitutive activity. PMID:21036225

  17. SMC3 knockdown triggers genomic instability and p53-dependent apoptosis in human and zebrafish cells

    Directory of Open Access Journals (Sweden)

    Ghiselli Giancarlo

    2006-11-01

    Full Text Available Abstract Background The structural maintenance of chromosome 3 (SMC3 protein is a constituent of a number of nuclear multimeric protein complexes that are involved in DNA recombination and repair in addition to chromosomal segregation. Overexpression of SMC3 activates a tumorigenic cascade through which mammalian cells acquire a transformed phenotype. This has led us to examine in depth how SMC3 level affects cell growth and genomic stability. In this paper the effect of SMC3 knockdown has been investigated. Results Mammalian cells that are SMC3 deficient fail to expand in a clonal population. In order to shed light on the underlying mechanism, experiments were conducted in zebrafish embryos in which cell competence to undergo apoptosis is acquired at specific stages of development and affects tissue morphogenesis. Zebrafish Smc3 is 95% identical to the human protein, is maternally contributed, and is expressed ubiquitously at all developmental stages. Antisense-mediated loss of Smc3 function leads to increased apoptosis in Smc3 expressing cells of the developing tail and notocord causing morphological malformations. The apoptosis and the ensuing phenotype can be suppressed by injection of a p53-specific MO that blocks the generation of endogenous p53 protein. Results in human cells constitutively lacking p53 or BAX, confirmed that a p53-dependent pathway mediates apoptosis in SMC3-deficient cells. A population of aneuploid cells accumulated in zebrafish embryos following Smc3-knockdown whereas in human cells the transient downregulation of SMC3 level lead to the generation of cells with amplified centrosome number. Conclusion Smc3 is required for normal embryonic development. Its deficiency affects the morphogenesis of tissues with high mitotic index by triggering an apoptotic cascade involving p53 and the downstream p53 target gene bax. Cells with low SMC3 level display centrosome abnormalities that can lead to or are the consequence of

  18. Apoptosis and the target genes of microRNA-21

    Institute of Scientific and Technical Information of China (English)

    Lindsey E. Becker Buscaglia; Yong Li

    2011-01-01

    MicroRNA-21 (miR-21) is frequently up-regulated in cancer and the majodty of its reported targets are tumor suppressors. Through functional suppression, miR-21 is implicated in practically every walk of oncogenic life: the promotion of cell proliferation, invasion and metastasis, genome instability and mutation, inflammation, replicative immortalization, abnormal metabolism, angiogenesis, and evading apoptosis, immune destruction, and growth suppressors. In particular, miR-21 is strongly involved in apoptosis. In this article, we reviewed the experimentally validated targets of miR-21 and found that two thirds are linked to intrinsic and/or extrinsic pathways of cellular apoptosis. This suggests that miR-21 is an oncogene which plays a key role in resisting programmed cell death in cancer cells and that targeting apoptosis is a viable therapeutic option against cancers expressing miR-21.

  19. Apoptosis in astrovirus-infected CaCo-2 cells

    International Nuclear Information System (INIS)

    Cell death processes during human astrovirus replication in CaCo-2 cells and their underlying mechanisms were investigated. Morphological and biochemical alterations typical of apoptosis were analyzed in infected cells using a combination of techniques, including DAPI staining, the sub-G0/G1 technique and the TUNEL assay. The onset of apoptosis was directly proportional to the virus multiplicity of infection. Transient expression experiments showed a direct link between astrovirus ORF1a encoded proteins and apoptosis induction. A computer analysis of the astrovirus genome revealed the presence of a death domain in the nonstructural protein p38 of unknown function, encoded in ORF1a. Apoptosis inhibition experiments suggested the involvement of caspase 8 in the apoptotic response, and led to a reduction in the infectivity of the virus progeny released to the supernatant. We conclude that apoptotic death of host cells seems necessary for efficient human astrovirus replication and particle maturation

  20. Apoptosis in the Medaka Embryo in the Early Developmental Stage

    International Nuclear Information System (INIS)

    Apoptosis is an important event of the development of various organs. In this study, we used in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) to visualize the temporal and spatial distribution of apoptosis in the developing medaka embryo, which is a useful model for developmental biology and genetics. Most of the apoptotic cells were distributed in the central nervous system and tailbud. In the brain and retina, most of the apoptosis occurred in the restricted period. In situ hybridization against caspase 3A and caspase 3B showed that these were distributed in the tailbud and the head, respectively. These results suggested that two types of caspase 3 were involved in apoptosis in different areas

  1. Apoptosis and DNA Methylation

    Directory of Open Access Journals (Sweden)

    Richard R. Meehan

    2011-04-01

    Full Text Available 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.

  2. Is There a Constitutional Right to Clone?

    OpenAIRE

    Sunstein, Cass Robert

    2002-01-01

    Recent scientific innovations, and proposed legislation, have raised questions about the nature of the constitutional right to reproductive freedom, and in particular about whether there is a constitutional “right to clone.” This essay urges that as a matter of substantive due process, rationality review is probably appropriate, and that restrictions on both reproductive and therapeutic cloning would and should survive constitutional scrutiny. At the same time, many of the arguments for banni...

  3. The constitutional control system in Colombia

    OpenAIRE

    Luis Javier Moreno Ortiz

    2010-01-01

    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 ...

  4. POWER OF TAXATION CONCEPT FROM CONSTITUTION PERSPECTIVE

    OpenAIRE

    KARTALCI, Kadir; DOĞAN, Mübeyna

    2013-01-01

    Today, for advanced democracies internalizing social law state, it seems impossible to tax without depending on the constitution. The terms of taxing and the power of taxing were put into the constitutions during republican period of our country. Hence, in 1982 constitution, article 73, subclause 3, the sentence`all taxes and fees are enacted, changed and repealed by law` emphasizes the legality of taxing.However, in a country experiencing martial laws and state emergencies heavily, by inter...

  5. Enslaved Constitution: Obstructing the Freedom to Travel

    OpenAIRE

    Mitchell F. Crusto

    2008-01-01

    Does the Constitution protect a citizen’s intra-state travel (within a state) from unjustified state prohibition? To date, the Supreme Court has not ruled directly on the issue, and many federal courts believe that the right to intrastate travel is not constitutionally protected. This Article explores the constitutional right of intra-state travel that is free from wrongful state infringement along public roadways by law-abiding citizens. Using critical legal history, this Article poses...

  6. Trimetazidine protects against hypoxia-reperfusion-induced cardiomyocyte apoptosis by increasing microRNA-21 expression

    OpenAIRE

    Yang, Qiong; Yang, Kan; Li, An-Ying

    2015-01-01

    Myocardial tissue injury caused by ischemia and hypoxia is a major cause of fatal diseases, including coronary atherosclerosis resulting from myocardial infarction and stroke. Trimetazidine (TMZ), as an anti-ischemic and antioxidant agent, has been demonstrated to preventing ischemia/reperfusion-induced cardiomyocyte apoptosis. However, the anti-apoptosis mechanism of TMZ has not been fully elucidated. The present study demonstrated that miR-21 involved trimetazidine-induced anti-apoptosis du...

  7. Epithelial apoptosis in mechanistically distinct methods of injury in the murine small intestine

    OpenAIRE

    Vyas, D.; Robertson, C M; Stromberg, P.E.; J. R. Martin; Dunne, W. M.; Houchen, C.W.; Barrett, T A; Ayala, A; Perl, M.; Buchman, T G; Coopersmith, C.M.

    2007-01-01

    Gut epithelial apoptosis is involved in the pathophysiology of multiple diseases. This study characterized intestinal apoptosis in three mechanistically distinct injuries with different kinetics of cell death. FVB/N mice were subjected to gamma radiation, Pseudomonas aeruginosa pneumonia or injection of monoclonal anti-CD3 antibody and sacrificed 4, 12, or 24 hours post-injury (n=10/time point). Apoptosis was quantified in the jejunum by hematoxylin and eosin (H&E), active caspase-3, terminal...

  8. Statistical Constitutive Equation of Aramid Fiber Bundles

    Institute of Scientific and Technical Information of China (English)

    熊杰; 顾伯洪; 王善元

    2003-01-01

    Tensile impact tests of aramid (Twaron) fiber bundles were carried om under high strain rates with a wide range of 0. 01/s~1000/s by using MTS and bar-bar tensile impact apparatus. Based on the statistical constitutive model of fiber bundles, statistical constitutive equations of aramid fiber bundles are derived from statistical analysis of test data at different strain rates. Comparison between the theoretical predictions and experimental data indicates statistical constitutive equations fit well with the experimental data, and statistical constitutive equations of fiber bundles at different strain rates are valid.

  9. Improvements to constitutive material model for fabrics

    Science.gov (United States)

    Morea, Mihai I.

    2011-12-01

    The high strength to weight ratio of woven fabric offers a cost effective solution to be used in a containment system for aircraft propulsion engines. Currently, Kevlar is the only Federal Aviation Administration (FAA) approved fabric for usage in systems intended to mitigate fan blade-out events. This research builds on an earlier constitutive model of Kevlar 49 fabric developed at Arizona State University (ASU) with the addition of new and improved modeling details. Latest stress strain experiments provided new and valuable data used to modify the material model post peak behavior. These changes reveal an overall improvement of the Finite Element (FE) model's ability to predict experimental results. First, the steel projectile is modeled using Johnson-Cook material model and provides a more realistic behavior in the FE ballistic models. This is particularly noticeable when comparing FE models with laboratory tests where large deformations in projectiles are observed. Second, follow-up analysis of the results obtained through the new picture frame tests conducted at ASU provides new values for the shear moduli and corresponding strains. The new approach for analysis of data from picture frame tests combines digital image analysis and a two-level factorial optimization formulation. Finally, an additional improvement in the material model for Kevlar involves checking the convergence at variation of mesh density of fabrics. The study performed and described herein shows the converging trend, therefore validating the FE model.

  10. How Does Astronomy Constitute A Learning Community?

    Science.gov (United States)

    Dogan, Yasemin; Sengul, R.; Unat, O.; Aknil, A.; Gurel, Z.

    2010-01-01

    This study was conducted in Turkey within an interdisciplinary project called "From a windowless home to a skyscraper: Let's build a home". It was realized through collaboration between a public university and a private high school. Researchers from Physics Education Department and volunteer teachers from high school, each studying on a different discipline, and volunteer high school students, all from an urban area of the country, conducted the project in a rural small town with resident secondary school students. It was implemented on the basis of history, through the use of different fields such as science, mathematics, geography, art, handcraft, architecture, engineering and astronomy in August 2008. The purpose of this study was to present the effect of the astronomical activities involved in the project. These implementations constructed a scientific and social base for the framework of astronomical activities of IYA2009, including building an amateur observatory. Since today's people are not so much acquainted with the issues of space and astronomy as much as the people of Antiquity, we attached special importance to the efforts in this field. The project, proceeded by a preparatory and informative period, involved night sky observation, initially with naked eye, followed by observation through telescope. Not only the students but also countless people, old or young, participated in our work in the field of astronomy. It provided a chance for all the people participating in or connected to the project to discover the sky. Astronomical activities aroused curiosity among students and the community and made a difference by inducing an awareness of the sky. The participants of the study had completely different social and cultural backgrounds, and this study removed all these differences bringing them together under the overarching astronomical and historical aspect. Moreover the community revealed all the characteristics that constitute a learning community.

  11. Apoptosis Resistance in Endometriosis

    Directory of Open Access Journals (Sweden)

    Liselotte Mettler

    2011-08-01

    Full Text Available Introduction: In a cytological analysis of endometriotic lesions neither granulocytes nor cytotoxic T-cells appear in an appreciable number. Based on this observation we aimed to know, whether programmed cell death plays an essential role in the destruction of dystopic endometrium. Disturbances of the physiological mechanisms of apoptosis, a persistence of endometrial tissue could explain the disease. Another aspect of this consideration is the proliferation competence of the dystopic mucous membrane. Methods: Endometriotic lesions of 15 patients were examined through a combined measurement of apoptosis activity with the TUNEL technique (terminal deoxyribosyltransferase mediated dUTP Nick End Labeling and the proliferation activity (with the help of the Ki-67-Antigens using the monoclonal antibody Ki-S5. Results: Twelve out of 15 women studied showed a positive apoptotic activity of 3-47% with a proliferation activity of 2-25% of epithelial cells. Therefore we concluded that the persistence of dystopic endometrium requires proliferative epithelial cells from middle to lower endometrial layers. Conclusion: A dystopia misalignment of the epithelia of the upper layers of the functionalism can be rapidly eliminated by apoptotic procedures.

  12. THE CONSTITUTIONAL COURT – AN INNOVATION IN THE ROMANIAN CONSTITUTIONAL SYSTEM

    OpenAIRE

    Daniela Cristina VALEA

    2010-01-01

    The control of constitutionality has an extremely important role in the functioning of the state of law. The premise for the birth of the control of constitutionality and the outlining of a control of constitutionality system is the necessity to guarantee ‘the supremacy of the law’, or ‘the supremacy of the Constitution’. In the constitutional systems in which the judge’s role of ‘constitutional judge’ was not recognized or assumed, the control of constitutionality was entrusted to a speciali...

  13. Freedom of Conscience and Conviction in the Spanish Constitutional System

    OpenAIRE

    José María Contreras Mazarío

    2007-01-01

    This text analyses the constitutional principles of the Spanish legal system in the area of religion: freedom of religion, religious equality, the laicity of the State and co-operation with religious denominations. It is based on these criteria that Spain defines freedom of conscience and conviction as a fundamental right. The author suggests that safeguarding these basic rights involves positive action on the part of all of the public powers, with the objective of guaranteeing the real, effe...

  14. The Constitution of the Nonprofit Enterprise: Ideals, Conformism and Reciprocity

    OpenAIRE

    Gianluca Grimalda; Lorenzo Sacconi

    2002-01-01

    We provide an account of the non profit enterprise based on the motivations of the agents involved. Our main idea is that these are ex -post motivated by both self-interest and a conditional willingness to conform to their ex ante accepted constitutional ideology, which are weighed up in a comprehensive utility function. Ideology is shaped as the result of a hypothetical ‘social' contract between the relevant figures participating in the venture, in particular an entrepreneur, a worker, and a...

  15. Mechanisms of constitutional control: a preliminary observation of the Ethiopian system

    Directory of Open Access Journals (Sweden)

    G. Kassa

    2007-01-01

    Full Text Available The present mechanism of constitutional adjudication in Ethiopia demonstrates unique features. The mechanism does not belong to any of the constitutional adjudication models operating in other countries. However, a well-developed system of constitutional adjudication is lacking in actual practice. The federal and regional state organs that exercise the power of constitutional control, i.e. the Council of Constitutional Inquiry and the House of Federation at the federal level and the Constitutional Interpretation Commissions, Council of Nationalities and Councils of Constitutional Inquiry at the regional level, are not functioning fully and, moreover, are not moving at equal pace. In some regional states, the institutions competent for constitutional control, though mentioned in the regional constitutions, are not even established yet. In other regions, these institutions have been established, but are not operating in practice. Besides, a challenge of judicial overlap is likely to emerge when the regional organs start to execute their task of constitutional control. Since no mechanism is devised to delimit the respective competences of the federal and state organs, overlap between federal and state institutions is inevitable. Furthermore, there is no clear guidance with regards to the role of the judiciary on matters that involve determination of constitutionality.

  16. Apoptosis : Target of cancer therapy

    NARCIS (Netherlands)

    Ferreira, CG; Epping, M; Kruyt, FAE; Giaccone, G

    2002-01-01

    Recent knowledge on apoptosis has made it possible to devise novel approaches, which exploit this process to treat cancer. In this review, we discuss in detail approaches to induce tumor cell apoptosis, their mechanism of action, stage of development, and possible drawbacks. Finally, the obstacles y

  17. Nuclear Apoptosis Contributes to Sarcopenia

    OpenAIRE

    Alway, Stephen E.; Parco M. Siu

    2008-01-01

    Apoptosis results in DNA fragmentation and, subsequently, destruction of cells containing a single nucleus. Our hypothesis is that multinucleated cells such as muscle fibers can experience apoptotic-induced loss of single nuclei (nuclear apoptosis) without destruction of the entire fiber. The loss of nuclei likely contributes to atrophy and sarcopenia. Furthermore, increased chronic activity attenuates apoptotic signaling, which may reduce sarcopenia.

  18. Culture (and religion in constitutional adjudication

    Directory of Open Access Journals (Sweden)

    C Rautenbach

    2003-10-01

    Full Text Available 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, socio-economic and cultural considerations on the constitutional court’s interpretation and application of the Bill of Rights. The second aim is to develop practical guidelines (based on the findings during the analysing process for South African courts confronted with issues of a political, socio-economic and cultural nature. This article is concerned with initiating discussions of the decisions of the constitutional court with regard to cultural and religious rights.Before we can explore the role of political, socio-economic and cultural (and religious rights in the decisions of the constitutional court it is important to discuss a few preliminary issues. In this article the meaning of culture and religion within the South African context receives some attention. Secondly, some preliminary comments regarding constitutional protection of culturally and religiously based rights will be made.We are well aware that this is a daunting task, not only in view of the seemingly abysmal gap between the applicable constitutional rights and values enshrined in the 1996 Constitution that, in some instances over centuries, brought about customs and practices within “traditional” communities which, seemingly, infringe on certain constitutional values and rights.

  19. Constitutional Provisions for Community Junior Colleges.

    Science.gov (United States)

    McLeod, Marshall W.

    1983-01-01

    Examines the role of the federal and state constitutions in community college law. Discusses the lack of state constitutional law pertaining explicitly to these institutions and suggests a probable reason for this void. Gives examples of extant state laws and discusses implications for the community college field. (AYC)

  20. Lipid Metabolism, Apoptosis and Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Chunfa Huang

    2015-01-01

    Full Text Available Lipid metabolism is regulated by multiple signaling pathways, and generates a variety of bioactive lipid molecules. These bioactive lipid molecules known as signaling molecules, such as fatty acid, eicosanoids, diacylglycerol, phosphatidic acid, lysophophatidic acid, ceramide, sphingosine, sphingosine-1-phosphate, phosphatidylinositol-3 phosphate, and cholesterol, are involved in the activation or regulation of different signaling pathways. Lipid metabolism participates in the regulation of many cellular processes such as cell growth, proliferation, differentiation, survival, apoptosis, inflammation, motility, membrane homeostasis, chemotherapy response, and drug resistance. Bioactive lipid molecules promote apoptosis via the intrinsic pathway by modulating mitochondrial membrane permeability and activating different enzymes including caspases. In this review, we discuss recent data in the fields of lipid metabolism, lipid-mediated apoptosis, and cancer therapy. In conclusion, understanding the underlying molecular mechanism of lipid metabolism and the function of different lipid molecules could provide the basis for cancer cell death rationale, discover novel and potential targets, and develop new anticancer drugs for cancer therapy.

  1. Analysis of apoptosis on chip - Why the move to chip technology

    NARCIS (Netherlands)

    Wolbers, Floor; Haanen, Clemens; Andersson, Helene; Berg, van den Albert; Vermes, István; Andersson, Helene; Berg, van den Albert

    2004-01-01

    Apoptosis refers to a specific form of programmed cell death, which guarantees the welfare of the whole organism through the elimination of unwanted cells. The duration of apoptosis is short, involves single cells with morphological changes only after the point of no return, ending with phagocytosis

  2. CONSTITUTIONAL TRADITIONALISM IN THE ROBERTS COURT

    Directory of Open Access Journals (Sweden)

    Louis J Virelli III

    2011-05-01

    Full Text Available The debate over the role of traditionalism in constitutional interpretation has itself become a tradition. It remains a popular and controversial topic among constitutional scholars and presents normative questions that are as divisive, difficult, and important today as at the Founding. Missing from the discussion, however, is a comprehensive account of how the Supreme Court has employed traditionalism-an approach that looks for meaning in present manifestations of longstanding practices or beliefs-in its constitutional jurisprudence. This project is the first to fill this gap by providing an exhaustive and systematic analysis of the Court's use of constitutional traditionalism. This article focuses on the Roberts Court's first five terms to provide an empirical foundation that will not only offer previously unavailable insights into the Court's current traditionalist practices, but will also set forth a useful framework for the ongoing normative debate over traditionalism. This project uses content analysis of key terms to identify every instance in which the Roberts Court employed traditionalism to interpret the Constitution. More specifically, this project set out to answer the following three questions: First, how frequently does the Roberts Court employ traditionalism in its constitutional jurisprudence? Second, how robust is the Court's use of traditionalism (i.e., is it used to interpret a broad or narrow range of constitutional provisions? And finally, how often and in what contexts do individual Justices on the Roberts Court rely on traditionalism in their own constitutional opinions? The research provided here suggests answers to all three of these questions. First, the data indicate that traditionalism has been relied upon regularly by the Roberts Court, appearing in nearly half of the Court's constitutional cases. Second, traditionalism is frequently applied to a wide variety of constitutional provisions: Two-thirds of the

  3. Constitutional Interpretation as Constitutional Creation: The 1999-2000 Harry Eckstein Lecture

    OpenAIRE

    Murphy, Walter

    2000-01-01

    This paper starts from what I take as two plain facts of political life: First, the maintenance of any constitutional order whatsoever requires some constitutional interpretation; and, second, the complex normative bases of constitutional democracy cause this necessity to operate especially often. Next comes the gist of the paper, the argument that, in a constitutional democracy, interpreters must exercise a wide range of discretion that inevitably allows, in fact frequently requires, a degre...

  4. Paclitaxel sensitizes gastric cancer cells to TRAIL-induced apoptosis

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Objective:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds promise for cancer therapy as it has unique capacity to selectively trigger apoptosis in cancer cells. We reported here that paclitaxel sensitized gastric cancer cells to TRAIL-induced apoptosis.Methods: After drug exposure, apoptosis rate and caspase activation were examined. Various proteins were detected by western blot. Several interventions, including pharmacological inhibitors and siRNA transfection were used. hTe growth inhibition of tumors was evaluated in SGC-7901-implanted nude mice model.Results:We found gastric cancer cellsshowed a mixed response to TRAIL. Combined treatment with paclitaxel markedly enhanced TARIL-induced apoptosis in vitro and in vivo. The underlying mechanisms involved in synergistical activation of caspase proteins, up-regulation of receptors, down-regulation of antiapoptotic proteins and inactivation of MAPKs.Conclusion:TRAIL-induced cytotoxicity and apoptosis can be synergistically enhanced by paclitaxel, suggesting the therapeutic potential of combining TARIL plus paclitaxel in gastric cancer treatment.

  5. 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.

  6. Cerebral ischemia—induced neuronal apoptosis mediated by nitric oxide

    Institute of Scientific and Technical Information of China (English)

    NomuY

    2002-01-01

    To elucidate the cellular and molecular mechanism of cerebral ischemia-induced neuronal apoptosis mediated by nitric oxide (NO) in the brain,we investigated:(1)cell death in hippocampal CA1 neurons of rats after a rransient four vessel occlusion (4VO)/reperfusion and (2) apoptosis induced by NOC18(NO releaser) using SHSY5Y cells,a human neuroblastoma cell line.We found that 4VO caused expression of inducible type of NO synthase (iNOS) in glial cells and neuronal apoptosis in CA1 region of rats.Next we examined in vitro apoptotic effects of NOC18 on SHSY5Y cells and suggest that NO decrease mitochondrial membrane potential,release cytochrome C from mitochondria,activates caspase-3,degrade inhibitor of caspase-activated DNase(Icad),and activated DNase translocate into nucleus and induce DNA fragmentation.Thus we conclude that the excess amount of NO produced by glial iNOS at cerebral ischemia could be involved in neuronal apoptosis in CA1 region.Regarding NO action on neurons,we further obtained that NO propects neuronal apoptosis in PC12 cells perhaps by nitrosylation of caspase,subsequent reduction of proteolytic activity.Taken together,we suggest that NO seem to exert dual effects(toxic and beneficial) on neuronal apoptosis,the one (toxic);apoptosis-induction throuth the decrease in mitochondrial membrane potentials and cytochrome C release and the othe (beneficial);protection against apoptosis through the inhibition of caspase activity.

  7. Nonlinear constitutive behavior of ferroelectric materials

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The ferroelectric specimen is considered as an aggregation of many randomly oriented domains. According to this mechanism,a multi-domain mechanical model is developed in this paper. Each domain is represented by one element. The applied stress and electric field are taken to be the stress and electric field in the formula of the driving force of domain switching for each element in the specimen. It means that the macroscopic switching criterion is used for calculating the volume fraction of domain switching for each element. By using the hardening relation between the driving force of domain switching and the volume fraction of domain switching calibrated,the volume fraction of domain switching for each element is calculated. Substituting the stress and electric field and the volume fraction of domain switching into the constitutive equation of ferroelectric material,one can easily get the strain and electric displacement for each element. The macroscopic behavior of the ferroelectric specimen is then directly calculated by volume averaging. Mean-while,the nonlinear finite element analysis for the ferroelectric specimen is carried out. In the finite element simulation,the volume fraction of domain switching for each element is calculated by using the same method mentioned above. The in-teraction between different elements is taken into account in the finite element simulation and the local stress and electric field for each element is obtained. The macroscopic behavior of the specimen is then calculated by volume averaging. The computation results involve the electric butterfly shaped curves of axial strain versus the axial electric field and the hysteresis loops of electric displacement versus the electric field for ferroelectric specimens under the uniaxial coupled stress and electric field loading. The present theoretical prediction agrees reasonably with the experimental results.

  8. Nonlinear constitutive behavior of ferroelectric materials

    Institute of Scientific and Technical Information of China (English)

    LI HaiJun; LIU Feng; WANG TzuChiang

    2008-01-01

    The ferroelectric specimen is considered as an aggregation of many randomly oriented domains. According to this mechanism, a multi-domain mechanical model is developed in this paper. Each domain is represented by one element. The applied stress and electric field are taken to be the stress and electric field in the formula of the driving force of domain switching for each element in the specimen. It means that the macroscopic switching criterion is used for calculating the volume fraction of domain switching for each element. By using the hardening relation between the driving force of domain switching and the volume fraction of domain switching calibrated, the volume fraction of domain switching for each element is calculated. Substituting the stress and electric field and the volume fraction of domain switching into the constitutive equation of ferroelectric material, one can easily get the strain and electric displacement for each element. The macroscopic behavior of the ferroelectric specimen is then directly calculated by volume averaging. Mean-while, the nonlinear finite element analysis for the ferroelectric specimen is carried out. In the finite element simulation, the volume fraction of domain switching for each element is calculated by using the same method mentioned above. The in-teraction between different elements is taken into account in the finite element simulation and the local stress and electric field for each element is obtained. The macroscopic behavior of the specimen is then calculated by volume averaging. The computation results involve the electric butterfly shaped curves of axial strain versus the axial electric field and the hysteresis loops of electric displacement versus the electric field for ferroelectric specimens under the uniaxial coupled stress and electric field loading. The present theoretical prediction agrees reasonably with the experimental results.

  9. Modulation of apoptosis during HTLV-1-mediated immortalization process in vitro.

    Science.gov (United States)

    Matteucci, Claudia; Balestrieri, Emanuela; Macchi, Beatrice; Mastino, Antonio

    2004-11-01

    Suppression of apoptosis has been proposed as a mechanism involved in the transforming action of human T-cell leukemia/lymphotropic virus type-1 (HTLV-1). However, there is evidence that HTLV-1 and its protein Tax also induce apoptosis. To resolve this apparent paradox, apoptosis was monitored in primary cultures of peripheral blood lymphocytes (PBLs) from healthy donors, following HTLV-1 infection in vitro. High levels of apoptosis in HTLV-1 infected cultures during the first weeks after infection were detected. Apoptosis was not related to the presence of uninfected cells, as revealed by a fluorescence in situ hybridization assay. Successively, a progressive decrease in apoptosis in infected cultures going towards immortalization, was observed. When IL-2 in the medium was replaced by IL-4, allowing the cells to be efficiently infected by HTLV-1 but not immortalized, apoptosis levels tended to increase, instead of decreasing, with the ongoing time. The caspase cascade was remarkably activated in PBLs recently infected in vitro by HTLV-1, but apoptosis was only partly reduced by caspase inhibitors. Even if spontaneous apoptosis was relatively low in long-term cultures of PBLs immortalized by HTLV-1 in vitro, Fas death-receptor expression and function were well conserved. These observations provide a new rationale for explaining the dual effect of HTLV-1 in controlling apoptosis. PMID:15368513

  10. AIRE-induced apoptosis is associated with nuclear translocation of stress sensor protein GAPDH

    International Nuclear Information System (INIS)

    Highlights: ► AIRE induces apoptosis in epithelial cells. ► CARD domain of AIRE is sufficient for apoptosis induction. ► AIRE induced apoptosis involves GAPDH translocation to the nuclei. ► Deprenyl inhibits AIRE induced apoptosis. -- Abstract: AIRE (Autoimmune Regulator) has a central role in the transcriptional regulation of self-antigens in medullary thymic epithelial cells, which is necessary for negative selection of autoreactive T cells. Recent data have shown that AIRE can also induce apoptosis, which may be linked to cross-presentation of these self-antigens. Here we studied AIRE-induced apoptosis using AIRE over-expression in a thymic epithelial cell line as well as doxycycline-inducible HEK293 cells. We show that the HSR/CARD domain in AIRE together with a nuclear localization signal is sufficient to induce apoptosis. In the nuclei of AIRE-positive cells, we also found an increased accumulation of a glycolytic enzyme, glyceraldehyde-3-phosphate (GAPDH) reflecting cellular stress and apoptosis. Additionally, AIRE-induced apoptosis was inhibited with an anti-apoptotic agent deprenyl that blocks GAPDH nitrosylation and nuclear translocation. We propose that the AIRE-induced apoptosis pathway is associated with GAPDH nuclear translocation and induction of NO-induced cellular stress in AIRE-expressing cells.

  11. AIRE-induced apoptosis is associated with nuclear translocation of stress sensor protein GAPDH

    Energy Technology Data Exchange (ETDEWEB)

    Liiv, Ingrid, E-mail: ingrid.liiv@ut.ee [Molecular Pathology, Institute of General and Molecular Pathology, University of Tartu, Tartu (Estonia); Haljasorg, Uku; Kisand, Kai; Maslovskaja, Julia; Laan, Martti; Peterson, Paert [Molecular Pathology, Institute of General and Molecular Pathology, University of Tartu, Tartu (Estonia)

    2012-06-22

    Highlights: Black-Right-Pointing-Pointer AIRE induces apoptosis in epithelial cells. Black-Right-Pointing-Pointer CARD domain of AIRE is sufficient for apoptosis induction. Black-Right-Pointing-Pointer AIRE induced apoptosis involves GAPDH translocation to the nuclei. Black-Right-Pointing-Pointer Deprenyl inhibits AIRE induced apoptosis. -- Abstract: AIRE (Autoimmune Regulator) has a central role in the transcriptional regulation of self-antigens in medullary thymic epithelial cells, which is necessary for negative selection of autoreactive T cells. Recent data have shown that AIRE can also induce apoptosis, which may be linked to cross-presentation of these self-antigens. Here we studied AIRE-induced apoptosis using AIRE over-expression in a thymic epithelial cell line as well as doxycycline-inducible HEK293 cells. We show that the HSR/CARD domain in AIRE together with a nuclear localization signal is sufficient to induce apoptosis. In the nuclei of AIRE-positive cells, we also found an increased accumulation of a glycolytic enzyme, glyceraldehyde-3-phosphate (GAPDH) reflecting cellular stress and apoptosis. Additionally, AIRE-induced apoptosis was inhibited with an anti-apoptotic agent deprenyl that blocks GAPDH nitrosylation and nuclear translocation. We propose that the AIRE-induced apoptosis pathway is associated with GAPDH nuclear translocation and induction of NO-induced cellular stress in AIRE-expressing cells.

  12. 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.

  13. Elastic-plastic constitutive modeling of concrete

    International Nuclear Information System (INIS)

    The need to understand concrete behavior under high temperatures in the nuclear industry has become rather accute. For this purpose, a constitutive model of concrete especially developed for this severe environment is indispensable. This report reviews the presently available constitutive models of concrete at standard-temperature conditions and considers their advantages and drawbacks. A rather simple but effective approach is selected to treat concrete behavior at high temperatures. Special emphasis is devoted to the modeling of concrete up to and including failure. The derived constitutive model is checked with biaxial and triaxial benchmark experimental results. Very good agreement is obtained

  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. Constitutional notes on the atomic law

    International Nuclear Information System (INIS)

    Both in jurisdiction and in literature increasingly more individuals are doubling the constitutionality of the atomic law, especially its terms concerning permissions, because as they say, the legislator has not made the necessary guiding decisions. The following essay proves that, within the frame of the atomic law, the legislation has made the decisions which are necessary according to the Federal Constitutional Law. This shows that a legal alteration of the terms concerning permissions is not necessary, at least as far as constitutional reasons are concerned. (orig.)

  16. Constitutional and Anatomical Characteristics of Mature Women

    Institute of Scientific and Technical Information of China (English)

    Vladimir NNikolenko; DmitryBNikityuk; SvetlanaVKlochkova; AnastasiaABahmet

    2015-01-01

    Objective To identify the constitutional and anatomical peculiarities of constitution of women of mature age.Methods There was completed comprehensive anthropometric and bio-electrical survey of 651 mature women ( relative norm) living in the Moscow region .Results The quantitative distribution of women by somatotypological affiliation was revealed;anthropometric and body component composition in representatives of different somatotypes were defined .Conclusion Thus, the performed study revealed and quantiely character-ised the distribution of women according to their constitutional types in the studied population of mature age women living in Moscow region under the relative norm conditions .

  17. 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.

  18. Positive and negative regulation of radiation-induced apoptosis by protein kinase C

    International Nuclear Information System (INIS)

    Indicators such as clonogenic survival, transformation, and chromosomal aberrations are used to evaluate the effects of radiation on cells. Apoptosis, another such indicator, is a mode of cell death, and radiation-induced apoptosis contributes to eliminating damaged cells and preventing malformation and carcinogenesis. Understanding radiation-induced apoptosis will assist in radiotherapy for cancer and treatment of patients in accidental radiation exposure. Protein kinase C (PKC) is a serine/threonine kinase that is related to cell proliferation, differentiation, metabolism, and apoptosis, and has many roles in the radiation-induced cellular responses involving apoptosis. This review describes the functions of PKC, including its relationship with other signaling networks and oxidative stress in the regulation of radiation-induced apoptosis. Such information might provide clues for evaluating the effects of radiation and for identifying clinical applications. (author)

  19. The South African Constitutional Court Experience: Reasoning Patterns Based on Foreign Law

    Directory of Open Access Journals (Sweden)

    Andrea Lollini

    2012-05-01

    Full Text Available This article aims to analyse the phenomenon of the diffusion of interpretive paradigms or argumentation models between constitutional courts. This phenomenon involves the importation of parameters - defined here as extra-systemic to a specific legal system - and the use of the comparative method in applying constitutional texts.The main subject of this study is the analysis of the first 11 years of South African constitutional jurisprudence, which is a convenient scenario since a constitutional provision enables the Constitutional Court to 'consider foreign law' when interpreting the Bill of Rights. In fact, this led to the wide use of foreign jurisprudence and legislation (from which were extracted argumentation models, patterns of balancing between principles and sometimes actual normative 'meanings': in other words, extra-systemic legal inferences. This article shows the existence of several patterns of legal argumentation based on foreign law which were developed by the South African Constitutional Court.

  20. Histone deacetylase inhibitors strongly sensitise neuroblastoma cells to TRAIL-induced apoptosis by a caspases-dependent increase of the pro- to anti-apoptotic proteins ratio

    International Nuclear Information System (INIS)

    Neuroblastoma (NB) is the second most common solid childhood tumour, an aggressive disease for which new therapeutic strategies are strongly needed. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in most tumour cells, but not in normal tissues and therefore represents a valuable candidate in apoptosis-inducing therapies. Caspase-8 is silenced in a subset of highly malignant NB cells, which results in full TRAIL resistance. In addition, despite constitutive caspase-8 expression, or its possible restoration by different strategies, NB cells remain weakly sensitive to TRAIL indicating a need to develop strategies to sensitise NB cells to TRAIL. Histone deacetylase inhibitors (HDACIs) are a new class of anti-cancer agent inducing apoptosis or cell cycle arrest in tumour cells with very low toxicity toward normal cells. Although HDACIs were recently shown to increase death induced by TRAIL in weakly TRAIL-sensitive tumour cells, the precise involved sensitisation mechanisms have not been fully identified. NB cell lines were treated with various doses of HDACIs and TRAIL, then cytotoxicity was analysed by MTS/PMS proliferation assays, apoptosis was measured by the Propidium staining method, caspases activity by colorimetric protease assays, and (in)activation of apoptotic proteins by immunoblotting. Sub-toxic doses of HDACIs strongly sensitised caspase-8 positive NB cell lines to TRAIL induced apoptosis in a caspases dependent manner. Combined treatments increased the activation of caspases and Bid, and the inactivation of the anti-apoptotic proteins XIAP, Bcl-x, RIP, and survivin, thereby increasing the pro- to anti-apoptotic protein ratio. It also enhanced the activation of the mitochondrial pathway. Interestingly, the kinetics of caspases activation and inactivation of anti-apoptotic proteins is accelerated by combined treatment with TRAIL and HDACIs compared to TRAIL alone. In contrast, cell surface expression of TRAIL

  1. 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

  2. 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

  3. 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

  4. The moral reading of the British constitution

    OpenAIRE

    Lakin, S. J.

    2009-01-01

    This thesis investigates the philosophical assumptions which underpin established theories of the British constitution, paying particular attention to the influence of traditional (and sometimes outdated) theories of legal positivism. I attempt to identify, analyze and challenge these assumptions, exploring how recent developments in legal theory can inform and enrich our approach to British constitutional theory. Drawing, in particular, on the anti-positivist theory of Ronald Dworkin, I cont...

  5. Conflicts-Law Constitutionalism: Ambitions and Problems

    OpenAIRE

    Joerges, Christian

    2012-01-01

    "Conflicts-law constitutionalism" seeks to defend the rule of law and the idea of law-mediated legitimacy in the postnational constellation. The idea of its "three dimensional" differentiation responds to general developments of legal systems, namely the emergence of legal frameworks for regulatory politics and for governance arrangements. These developments have been observed within constitutional democracies and intensively discussed in the 1970s by legal theorists and sociologists, thereaf...

  6. Spanish Constitution and Education. Parliamentary debates

    OpenAIRE

    Juan Carlos Hernández Beltrán

    2008-01-01

    Alter thirty years of being passed the spanish Constitution in 1978, the aim of this paper try to remind the on-going debates celebrated at the House of Representatives about one of the most controversy issues: the education. Through the parliamentary debates we can take into account the political figh- ting between the differents parties on how education should be set up in Spanish democracy. Finally, the Constitution shows a balance between the recognition of right of education and the free...

  7. Ethnicity and constitutionalism in contemporary Ethiopia

    OpenAIRE

    Abbink, 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 Constitution's explicit reinstatement of ethnicity in law coincides with a politico-economic situation which has made ethnoregional groups more interdependent than ever before, and where the central State ha...

  8. Democracy, Citizen Sovereignty and Constitutional Economics

    OpenAIRE

    Vanberg, Viktor J.

    2006-01-01

    This paper is an exercise in conceptual clarification. Its purpose is to explore the contribution that constitutional economics can make to the theory of democracy. Constitutional economics as the economics of rules is concerned with the study of how the choice of rules in the social, economic and political realm affects the nature of the processes of human interaction that evolve within these rules. The theory of democracy is concerned with institutionalorganizational problems of self-govern...

  9. Constitutional exceptionalism and the common law

    OpenAIRE

    Poole, Thomas

    2008-01-01

    This paper examines the notion of exceptionalism, currently pervasive within constitutional discourse. The term ‘exceptionalist’ is used in this context to indicate a measure which deviates from normal constitutional standards and is, by virtue of that deviation, seen as inappropriate or regrettable. The paper avoids a direct focus on the debate about terrorism, concentrating instead on more conceptual matters – and particularly the ‘fit’ between this discourse and the ‘common law constitutio...

  10. Constitutional Design and Conflict Management in Africa

    OpenAIRE

    Kuperman Alan J.

    2013-01-01

    The CDCM project explores whether and how constitutional reform could reduce political instability and violence in Africa, by addressing the question in three steps. First, case studies of seven African countries identify how at key turning points the domestic political institutions either mitigated – or exacerbated – violent outcomes. Second, an unprecedented database of constitutional design in all of Africa reveals that most countries on the continent have highly centralized political inst...

  11. Towards a Constitutional Theory of Corporate Governance

    OpenAIRE

    Matthias Benz; Frey, Bruno S.

    2006-01-01

    The idea that there is a uniformly �optimal� governance structure for corporations features prominently in current debates and policy proposals. In this paper, we propose a different, constitutional theory of corporate governance: the criterion for a good corporate governance structure is whether it is freely chosen by the shareholders. We illustrate our approach by comparing the constitutional rights of shareholders under US corporate law and Swiss corporate law. Moreover, we discuss the...

  12. Urgency of Attorney Governed by the Constitution

    Directory of Open Access Journals (Sweden)

    Rommy Patra

    2015-12-01

    Full Text Available Attorney existence in the Indonesian constitutional structure has a dilemma for this position. On one side is the Prosecutor’s law enforcement agencies to exercise power independently prosecution while on the other hand is part of a government institution under Law No. 16 of 2004 regarding the Attorney. The position of Attorney as an institution of government has been led to the independence of the Prosecutor is not optimal so that it appears stigma that the Prosecutor merely as a tool of the ruling power. In addition the terms of the arrangement just under the Act, the Attorney General has no legal standing as a constitutional organ that has the constitutional authority so that the current position does not reflect the urgency of its duties and functions. In an effort to organize the next Attorney institutions should be regulated directly by the Constitution. It is intended to make the Attorney as part of the main state organs have the same legal standing as other law enforcement agencies, the police and the courts (Supreme Court and Constitutional Court. As well as to strengthen and clarify the position as a state institution, prosecution authorities are focusing on the Attorney as central of authority, to fix the institutional relations between the members of law enforcement and related agencies and strengthen the independence of the Prosecutor in performing the function of prosecution in the constitutional structure of Indonesia.

  13. Rate constitutive theories for ordered thermofluids

    Science.gov (United States)

    Surana, K. S.; Nunez, D.; Reddy, J. N.; Romkes, A.

    2013-09-01

    The paper considers developments of constitutive theories in Eulerian description for compressible as well as incompressible ordered homogeneous and isotropic thermofluids in which the deviatoric Cauchy stress tensor and the heat vector are functions of density, temperature, temperature gradient, and the convected time derivatives of the strain tensors of up to a desired order. The fluids described by these constitutive theories are called ordered thermofluids due to the fact that the constitutive theories for the deviatoric Cauchy stress tensor and heat vector are dependent on the convected time derivatives of the strain tensor up to a desired order, the highest order of the convected time derivative of the strain tensor in the argument tensors defines the `order of the fluid'. The admissibility requirement necessitates that the constitutive theories for the stress tensor and heat vector satisfy conservation laws, hence, in addition to conservation of mass, balance of momenta, and conservation of energy, the second law of thermodynamics, that is, Clausius-Duhem inequality must also be satisfied by the constitutive theories or be used in their derivations. If we decompose the total Cauchy stress tensor into equilibrium and deviatoric components, then Clausius-Duhem inequality and Helmholtz free energy density can be used to determine the equilibrium stress in terms of thermodynamic pressure for compressible fluids and in terms of mechanical pressure for incompressible fluids, but the second law of thermodynamics provides no mechanism for deriving the constitutive theories for the deviatoric Cauchy stress tensor. In the development of the constitutive theories in Eulerian description, the covariant and contravariant convected coordinate systems, and Jaumann measures are natural choices. Furthermore, the mathematical models for fluids require Eulerian description in which material point displacements are not measurable. This precludes the use of displacement

  14. APOPTOSIS IN WHOLE MOUSE OVARIES

    Science.gov (United States)

    Apoptosis in Whole Mouse Ovaries Robert M. Zucker Susan C. Jeffay and Sally D. Perreault Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, 27711.

  15. Involved Consumers and Advertising Involvement

    OpenAIRE

    Lawlor, Katrina

    1988-01-01

    The question of consumer involvement has at times taken on the appearance of a theoretical quagmire. The proliferation of definitions apart, this confusion has been exacerbated by the failure to distinguish adequately between advertising and consumer involvement. The research outlined in this article attempts to probe the possible relationship between these two discrete entities. It takes as a starting point Kassarjian's postulate of a generalised trait of purchasing involvement. This novel ...

  16. Signaling-based apoptosis therapy: potential for improving the outcome in clinical radiotherapy

    International Nuclear Information System (INIS)

    The most prevalent mechanism of cell kill by radiation in mitosis-dependent and results from lethal DNA double strand breaks and failure to maintain normal replication. Apoptosis is believed to represent a minor component of the clinical effects of radiation. Apoptosis is a pre-programmed death pathway that is constitutively expressed in many cells, albeit in an inactive form, regulated by anti-apoptotic mechanisms. Data will be presented to demonstrate that in irradiated cells, the balance between pro- and anti-apoptotic signaling may determine the apoptotic outcome in vitro and in vivo. This balance can be modulated by pharmacological intervention to produce a more pro-apoptotic phenotype, increasing apoptotic cell kill by radiation in vivo. These studies establish the basic principles of signaling-based apoptosis therapy, designed to overcome the relative resistance to radiation-induced apoptosis and to improve the therapeutic ratio in the treatment of human tumors with fractionated radiation

  17. 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.

  18. Mitochondrial genome depletion in human liver cells abolishes bile acid-induced apoptosis: role of the Akt/mTOR survival pathway and Bcl-2 family proteins.

    Science.gov (United States)

    Marin, Jose J G; Hernandez, Alicia; Revuelta, Isabel E; Gonzalez-Sanchez, Ester; Gonzalez-Buitrago, Jose M; Perez, Maria J

    2013-08-01

    Acute accumulation of bile acids in hepatocytes may cause cell death. However, during long-term exposure due to prolonged cholestasis, hepatocytes may develop a certain degree of chemoresistance to these compounds. Because mitochondrial adaptation to persistent oxidative stress may be involved in this process, here we have investigated the effects of complete mitochondrial genome depletion on the response to bile acid-induced hepatocellular injury. A subline (Rho) of human hepatoma SK-Hep-1 cells totally depleted of mitochondrial DNA (mtDNA) was obtained, and bile acid-induced concentration-dependent activation of apoptosis/necrosis and survival signaling pathways was studied. In the absence of changes in intracellular ATP content, Rho cells were highly resistant to bile acid-induced apoptosis and partially resistant to bile acid-induced necrosis. In Rho cells, both basal and bile acid-induced generation of reactive oxygen species (ROS), such as hydrogen peroxide and superoxide anion, was decreased. Bile acid-induced proapoptotic signals were also decreased, as evidenced by a reduction in the expression ratios Bax-α/Bcl-2, Bcl-xS/Bcl-2, and Bcl-xS/Bcl-xL. This was mainly due to a downregulation of Bax-α and Bcl-xS. Moreover, in these cells the Akt/mTOR pathway was constitutively activated in a ROS-independent manner and remained similarly activated in the presence of bile acid treatment. In contrast, ERK1/2 activation was constitutively reduced and was not activated by incubation with bile acids. In conclusion, these results suggest that impaired mitochondrial function associated with mtDNA alterations, which may occur in liver cells during prolonged cholestasis, may activate mechanisms of cell survival accounting for an enhanced resistance of hepatocytes to bile acid-induced apoptosis. PMID:23597504

  19. Apoptosis in cancer: therapeutic implications

    OpenAIRE

    Negoescu, A.

    2000-01-01

    This review outlines the principal limitations of the mechanisms of active cell death (ACD, apoptosis) as the basis of tumorigenesis and the rationale of almost all therapies of malignancy. The concentration of cancer therapy in the directon of ACD induction is presented as both the result of progressive understanding of the mechanisms of apoptosis and that of the favourable tumor environment for ACD signal transmission. The latter property induces the by-stand...

  20. Ultima Ratio as a Constitutional Principle

    Directory of Open Access Journals (Sweden)

    Kaarlo Tuori

    2013-01-01

    Full Text Available The paper argues the criminal law notion of ultima ratio is an instance of a broader constitutional law principle of proportionality. However, ultima ratio is not the only principle relevant in a constitutional assessment of criminalization. The role of ultima ratio is to impose limitations on criminalization. But constitutional doctrines also exist which call for criminalization and might even be seen as establishing a criminalization obligation. The paper examines three constitutional counter weights to ultima ratio. The first of these is discussed in the context of state constitutions. This is the cluster of the interrelated constitutional doctrines of the horizontal effect of fundamental rights and the protective duty of the state, as well as the understanding of collective security as a basic right. These doctrines are analysed in the light of the praxis of the German Constitutional Court and the Finnish Constitutional Law Committee. The two other constitutional counterweights are discussed at the level of the transnational, European constitution. These are the principles of precaution and effectiveness. Este artículo defiende que el concepto de ultima ratio es una instancia más amplia del principio de proporcionalidad dentro del derecho constitucional. Sin embargo, el ultima ratio no es el único principio relevante en la valoración constitucional de la criminalización. El papel del ultima ratio es imponer límites a la criminalización. Pero también existen doctrinas constitucionales que exigen la criminalización e incluso dan pie a entender que obligan a establecer una pena. El documento examina tres contrapesos constitucionales al ultima ratio. En primer lugar, se analiza en el contexto de las constituciones estatales. Este es el conjunto de las doctrinas constitucionales interrelacionadas entre el efecto horizontal de los derechos fundamentales y el deber de protección del Estado, así como la asunción de la seguridad colectiva

  1. Role of apoptosis-inducing factor, proline dehydrogenase, and NADPH oxidase in apoptosis and oxidative stress

    Directory of Open Access Journals (Sweden)

    Becker DF

    2012-02-01

    Full Text Available Sathish Kumar Natarajan, Donald F BeckerDepartment of Biochemistry and Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NEAbstract: Flavoproteins catalyze a variety of reactions utilizing flavin mononucleotide or flavin adenine dinucleotide as cofactors. The oxidoreductase properties of flavoenzymes implicate them in redox homeostasis, oxidative stress, and various cellular processes, including programmed cell death. Here we explore three critical flavoproteins involved in apoptosis and redox signaling, ie, apoptosis-inducing factor (AIF, proline dehydrogenase, and NADPH oxidase. These proteins have diverse biochemical functions and influence apoptotic signaling by unique mechanisms. The role of AIF in apoptotic signaling is two-fold, with AIF changing intracellular location from the inner mitochondrial membrane space to the nucleus upon exposure of cells to apoptotic stimuli. In the mitochondria, AIF enhances mitochondrial bioenergetics and complex I activity/assembly to help maintain proper cellular redox homeostasis. After translocating to the nucleus, AIF forms a chromatin degrading complex with other proteins, such as cyclophilin A. AIF translocation from the mitochondria to the nucleus is triggered by oxidative stress, implicating AIF as a mitochondrial redox sensor. Proline dehydrogenase is a membrane-associated flavoenzyme in the mitochondrion that catalyzes the rate-limiting step of proline oxidation. Upregulation of proline dehydrogenase by the tumor suppressor, p53, leads to enhanced mitochondrial reactive oxygen species that induce the intrinsic apoptotic pathway. NADPH oxidases are a group of enzymes that generate reactive oxygen species for oxidative stress and signaling purposes. Upon activation, NADPH oxidase 2 generates a burst of superoxide in neutrophils that leads to killing of microbes during phagocytosis. NADPH oxidases also participate in redox signaling that involves hydrogen peroxide-mediated activation of

  2. Enslaved Constitution: Obstructing the Freedom to Travel

    Directory of Open Access Journals (Sweden)

    Mitchell F. Crusto

    2008-04-01

    Full Text Available Does the Constitution protect a citizen’s intra-state travel (within a state from unjustified state prohibition? To date, the Supreme Court has not ruled directly on the issue, and many federal courts believe that the right to intrastate travel is not constitutionally protected. This Article explores the constitutional right of intra-state travel that is free from wrongful state infringement along public roadways by law-abiding citizens. Using critical legal history, this Article poses that federal courts’ denial of the right to intrastate travel consciously or unconsciously reflects the antebellum, Southern legal doctrine of people as property, which regulated the travel of enslaved African descendants.The constitutionality of intra-state travel arose most recently during the Hurricane Katrina Crisis when the City of Greta, Louisiana police barricaded a federal highway, denying would-be evacuees the ability to flee from the flooding City of New Orleans. In an ensuing action for infringement of the would-be evacuees’ constitutional right to intra-state travel, Federal District Judge Mary Ann Vial Lemmon dismissed the matter in Dickerson v. City of Gretna, holding that “[w]hile there is no doubt that a fundamental right of interstate travel exists, the Supreme Court has not ruled on whether a right of intra[-]state travel exists. This Court declines to find that there is a fundamental right to intra[-]state travel.” The Fifth Circuit affirmed the ruling.This Article recommends that when federal courts assess whether there is a constitutional right to intra-state travel, they should embrace the American paradigm of liberty and abandon the antebellum, Southern paradigm of enslavement. Consistent with Professor Derrick Bell’s “interestconvergence” principle, all Americans benefit when the Constitution protects the human rights of the least powerful American.

  3. PUMA Promotes Bax Translocation by Both Directly Interacting with Bax and by Competitive Binding to Bcl-XL during UV-induced Apoptosis

    OpenAIRE

    Zhang, Yingjie; Xing, Da; Liu, Lei

    2009-01-01

    Cell apoptosis induced by UV irradiation is a highly complex process in which different molecular signaling pathways are involved. p53 up-regulated modulator of apoptosis (PUMA) has been proposed as an important regulator in UV irradiation-induced apoptosis. However, the molecular mechanism through which PUMA regulates apoptosis, especially how PUMA activates Bcl-2-associated X protein (Bax) in response to UV irradiation is still controversial. In this study, by using real-time single-cell an...

  4. 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

  5. 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. PMID:23262771

  6. 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).

  7. Linguistic Diversity within the Integrated Constitutional Space

    Directory of Open Access Journals (Sweden)

    Francesco Palermo

    2006-11-01

    Full Text Available The language issue within the European constitutional space is one of the most fascinating challenges to supranational integration. On the one hand, the principle of equal standing of all official and working languages is constantly reaffirmed; on the other hand the necessity to simplify the European Babel on the basis of a more functional consideration of the language issue seems unavoidable. Several solutions have been proposed both by scholars and by European institutions. The paper argues that there is an intimate contradiction in today’s linguistic policy in the EU, oscillating between the need to simplification and the constitutional duty to respect linguistic pluralism as imposed by the member states. In fact, the language issue is just the mirror of the constitutional law of integration as a whole. Looking closer at the constitutional dimension of supranational integration cal help better address the language issue too. The analysis is divided in four parts, dealing respectively with the role and the limits of law in matters of language, the present allocation of competences in language-issues, the development of the concept of “integrated constitutional space”, and its legal nature under the viewpoint of the language dimension, elaborating some tentative proposals.

  8. Nuclear energy and the constitutional state

    International Nuclear Information System (INIS)

    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)

  9. The constitutional momentum of European contract law (II): The DCFR and the European constitutional order

    OpenAIRE

    Mak, C.

    2009-01-01

    This paper analyses the potential impact of the recently published Draft Common Frame of Reference for European contract law (DCFR) on the European constitutional process. Looking at the combination of characteristics of codification and aspects of constitutionalism reflected in the DCFR, it is submitted that the further harmonisation of European contract law may contribute to the definition of the European constitutional order both on the institutional level (regarding the forms in which Eur...

  10. 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

  11. Cultural, social and economic rights in the Constitution corpus and Constitutional Court’s Case Law

    OpenAIRE

    Patricio Rubio

    2013-01-01

    This article deals with Cultural, Social and Economic Rights established in the Constitution and in Constitutional Case Law. So, after explaining its nature, state’s role according preservation and enforceability,relationship with other fundamental rights, among other key points, it isi ntended to answer, dealing with those rights, which of two scenarios have prevailed: internationalization of constitutional law or constitutionalization of international law.

  12. Constitutionality of the Atomic Energy Act

    International Nuclear Information System (INIS)

    Roma locuta, causa finita. The Federal Constitutional Court declared in its decree of 8 August 1978 the peaceful uses of nuclear energy (Paragraph 7 sub-section 1 and 2 Atomic Energy Act) in NPPs of the so-called fast breeder type as constitutional for the time being. The excellent simplicity of the explanations, namely about the anavoidability and social adequancy of the so-called residual risk in a highly technical society and about the determining influence of practical ratio as a measure for the estimation of the residual risk which must be born by all citizens, creates a good clarification on the level of constitutional law. However, it remains, to be seen whether the decree can give the administrative courts any orientation help in the future and whether it will lead to an improved legal protection of all participants and a more effective handling of administrative processes. (orig.)

  13. Acoustomechanical constitutive theory for soft materials

    Science.gov (United States)

    Xin, Fengxian; Lu, Tian Jian

    2016-07-01

    Acoustic wave propagation from surrounding medium into a soft material can generate acoustic radiation stress due to acoustic momentum transfer inside the medium and material, as well as at the interface between the two. To analyze acoustic-induced deformation of soft materials, we establish an acoustomechanical constitutive theory by combining the acoustic radiation stress theory and the nonlinear elasticity theory for soft materials. The acoustic radiation stress tensor is formulated by time averaging the momentum equation of particle motion, which is then introduced into the nonlinear elasticity constitutive relation to construct the acoustomechanical constitutive theory for soft materials. Considering a specified case of soft material sheet subjected to two counter-propagating acoustic waves, we demonstrate the nonlinear large deformation of the soft material and analyze the interaction between acoustic waves and material deformation under the conditions of total reflection, acoustic transparency, and acoustic mismatch.

  14. Inhibition of p53 deSUMOylation Exacerbates Puromycin Aminonucleoside-Induced Apoptosis in Podocytes

    Directory of Open Access Journals (Sweden)

    Lingyu Wang

    2014-11-01

    Full Text Available Apoptosis is a major cause of reduced podocyte numbers, which leads to proteinuria and/or glomerulosclerosis. Emerging evidence has indicated that deSUMOylation, a dynamic post-translational modification that reverses SUMOylation, is involved in the apoptosis of Burkitt’s lymphoma cells and cardiomyocytes; however, the impact of deSUMOylation on podocyte apoptosis remains unexplored. The p53 protein plays a major role in the pathogenesis of podocyte apoptosis, and p53 can be SUMOylated. Therefore, in the present study, we evaluated the effect of p53 deSUMOylation, which is regulated by sentrin/SUMO-specific protease 1 (SENP1, on podocyte apoptosis. Our results showed that SENP1 deficiency significantly increases puromycin aminonucleoside (PAN-induced podocyte apoptosis. Moreover, SENP1 knockdown results in the accumulation of SUMOylated p53 protein and the increased expression of the p53 target pro-apoptotic genes, BAX, Noxa and PUMA, in podocytes during PAN stimulation. Thus, SENP1 may be essential for preventing podocyte apoptosis, at least partly through regulating the functions of p53 protein via deSUMOylation. The regulation of deSUMOylation may provide a novel strategy for the treatment of glomerular disorders that involve podocyte apoptosis.

  15. 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. PMID:22797774

  16. 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...... 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...

  17. Antiproliferation of berberine is mediated by epigenetic modification of constitutive androstane receptor (CAR) metabolic pathway in hepatoma cells

    OpenAIRE

    Lei Zhang; Xiao-Jie Miao; Xin Wang; Hai-Hui Pan; Pu Li; Hong Ren; Yong-Rui Jia; Chuang Lu; Hong-Bing Wang; Lan Yuan; Guo-Liang Zhang

    2016-01-01

    Constitutive androstane receptor (CAR) regulates hepatic xenobiotic and energy metabolism, as well as promotes cell growth and hepatocarcinogenesis. Berberine is an ancient multipotent alkaloid drug which derived from Coptis chinensis plants. Here we report that berberine is able to be cellular uptake and accessible to chromatin in human hepatoma HepG2 cells. Berberine induces more apoptosis, cell cycle arrest, but less ROS production in CAR overexpressed mCAR-HepG2 cells. Moreover, berberine...

  18. Human B Cell-Derived Lymphoblastoid Cell Lines Constitutively Produce Fas Ligand and Secrete MHCII+FasL+ Killer Exosomes

    OpenAIRE

    Klinker, Matthew W.; Lizzio, Vincent; Reed, Tamra J.; Fox, David A.; Lundy, Steven K.

    2014-01-01

    Immune suppression mediated by exosomes is an emerging concept with potentially immense utility for immunotherapy in a variety of inflammatory contexts, including allogeneic transplantation. Exosomes containing the apoptosis-inducing molecule Fas ligand (FasL) have demonstrated efficacy in inhibiting antigen-specific immune responses upon adoptive transfer in animal models. We report here that a very high frequency of human B cell-derived lymphoblastoid cell lines (LCL) constitutively produce...

  19. The negotiation of The Constitution of Romania of 1923 and The Constitution of Romania of 1991

    OpenAIRE

    Ivona-Arina Raef

    2012-01-01

    In the present study the author is trying to find if there was a negotiation between main parties regarding The Constitution of Romania of 1923 and The Constitution Of Romania of 1991 or if there was a project imposed by one party to the others.

  20. 77 FR 57981 - Constitution Day and Citizenship Day, Constitution Week, 2012

    Science.gov (United States)

    2012-09-18

    ..., Constitution Week, 2012 #0; #0; #0; Presidential Documents #0; #0; #0;#0;Federal Register / Vol. 77 , No. 181... Citizenship Day, and September 17 through September 23, 2012, as Constitution Week. I encourage Federal, State... of the United States of America the two hundred and thirty- seventh. (Presidential Sig.) [FR...

  1. 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.

  2. Constitutive model with time-dependent deformations

    DEFF Research Database (Denmark)

    Krogsbøll, Anette

    1998-01-01

    common in time as well as size. This problem is adressed by means of a new constitutive model for soils. It is able to describe the behavior of soils at different deformation rates. The model defines time-dependent and stress-related deformations separately. They are related to each other and they occur...

  3. 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-regulation and...

  4. 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…

  5. Constitutive behavior of reconsolidating crushed salt

    International Nuclear Information System (INIS)

    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

  6. Crushed-salt constitutive model update

    International Nuclear Information System (INIS)

    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

  7. The Constitutionality of DNA Sampling of Arrestees

    Directory of Open Access Journals (Sweden)

    Anip Patel

    2012-12-01

    Full Text Available This article addresses whether the DNA Act (which requires DNA samples from arrestees passes constitutional muster. I argue that the act is constitutional and that if society believes the collection of DNA from arrestees violates an individual’s privacy, it should seek legislative resolution and not seek the protection of the Fourth Amendment of the Constitution. Throughout my analysis, I demonstrate why DNA collection is constitutional and how it is necessary. Part I of this article examines the history of DNA sampling, case law establishing an arrestee’s expectation of privacy, and the applicable Fourth Amendment tests. Part II examines the arguments for and against DNA sampling by considering case law at the state and federal level, and explores the significance of junk DNA and the treatment of abandoned DNA. Part III is the personal analysis section, which argues that the totality of circumstances test is the proper test. I apply the test to determine that there is minimal intrusion of an arrestee’s expectation of privacy through DNA sampling, a legitimate governmental interest, and that warrants are unnecessary. Further, the section demonstrates why DNA sampling is a natural progression from fingerprint collection, and the section analyzes abandoned DNA and DNA sampling. Part IV concludes the article by stating that the Fourth Amendment is not violated and that society must turn to Congress to seek greater protection.

  8. Globalization of Constitutional Law and Civil Rights.

    Science.gov (United States)

    Weissbrodt, David

    1993-01-01

    Two issues are discussed: (1) reasons for raising global and international human rights issues in constitutional law, civil rights, and administrative law courses in United States law schools; and (2) barriers to globalization of courses and ways to overcome them. (MSE)

  9. A New Perspective on Teaching Constitutional Law

    Science.gov (United States)

    Rosenblum, Robert

    1977-01-01

    The author suggests that a major failure of most law schools and traditional undergraduate constitutional law courses is that they omit an adequate analysis of the political nature of the judicial process. Political influences on a variety of court cases are discussed. (LBH)

  10. Children's Constitutional Rights: Interpretations and Implications.

    Science.gov (United States)

    Sametz, Lynn; And Others

    1983-01-01

    Discusses a brief historical overview of constitutional law as it applies to children, delineated in the First, Fourth, Fifth, Sixth, Eighth, and Fourteenth Amendments. Emphasizes the need for school psychologists and educators to have an understanding of children's developing legal rights. Specific court cases are cited. (Author/JAC)

  11. 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)

  12. 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…

  13. Ethnicity and constitutionalism in contemporary Ethiopia

    NARCIS (Netherlands)

    Abbink, 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 Constituti

  14. Metal-induced apoptosis: mechanisms

    International Nuclear Information System (INIS)

    The past decade has seen an intense focus on mechanisms of apoptosis. Many important observations on the various signaling pathways mediating apoptotic cell death have been made and our understanding of the importance of apoptosis in both normal growth and development and pathophysiology has greatly increased. In addition, mechanisms of metal-induced toxicity continue to be of interest given the ubiquitous nature of these contaminants. The purpose of this review is to summarize our current understanding of the apoptotic pathways that are initiated by metals, mainly established (arsenic, cadmium, chromium, nickel, beryllium) and possible (lead, antimony, cobalt) human carcinogens. Increased understanding of metal-induced apoptosis is critical to illuminate mechanisms of metal-induced carcinogenesis, as well as the potential of metal species (arsenic) as chemotherapeutic agents

  15. Comparison of Constitutional Spirit Between United States and China

    Institute of Scientific and Technical Information of China (English)

    杨琅琅

    2007-01-01

    This paper compares the differences in constitutional spirit between United States and China, and then brings out the influence of the constitutional spirit in United States to the constitutional spirit in China.

  16. 78 FR 39721 - Constitution Pipeline Company, LLC; Notice of Application

    Science.gov (United States)

    2013-07-02

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Constitution Pipeline Company, LLC; Notice of Application Take notice that on June 13, 2013, Constitution Pipeline Company, LLC (Constitution), having its principal place...

  17. Monitoring apoptosis in real time.

    Science.gov (United States)

    Green, Allan M; Steinmetz, Neil D

    2002-01-01

    Many therapeutically active anticancer treatments exert their effect by the induction of apoptosis and necrosis. Serial biopsies in breast cancer patients have suggested that response to therapy correlates with early posttreatment increases in tumor apoptotic index. Radiolabeled technetium Tc 99m-recombinant human (rh) annexin V provides a noninvasive technique for imaging treatment-induced cell death. Annexin V is a naturally occurring human protein that binds avidly to membrane-associated phosphatidylserine (PS). PS is normally found only on the inner leaflet of the cell membrane double layer, but it is actively transported to the outer layer as an early event in apoptosis and becomes available for annexin binding. Annexin also gains access to PS as a result of the membrane fragmentation associated with necrosis. In vitro studies of apoptosis using fluorescein annexin have shown good correlation with assessments of apoptosis documented by nuclear DNA degradation and caspase activation. In vivo localization of intravenously administered Tc 99m-annexin V has been demonstrated in numerous preclinical models of apoptosis, including anti-Fas-mediated hepatic apoptosis, rejection of allogeneic heterotopic cardiac allografts, cyclophosphamide treatment of murine lymphoma, cyclophosphamide-induced apoptosis in bone marrow, and leukocyte apoptosis associated with abscess formation. Scintigraphic studies in humans using Tc 99m-rh annexin V have demonstrated the feasibility of imaging cell death in acute myocardial infarction, in tumors with a high apoptotic index, and in response to anti-tumor chemotherapy of non-small cell lung cancer, small-cell lung cancer, breast cancer, lymphoma, and sarcoma. Increased localization of Tc 99m-rh annexin V within 1 to 3 days of chemotherapy has been noted in some, but not all, subjects with these tumors. To date, most subjects showing increased Tc 99m-rh annexin V uptake after the first course of chemotherapy have shown objective

  18. Cardiomyocytic apoptosis and heart failure

    Institute of Scientific and Technical Information of China (English)

    Quanzhou Feng

    2008-01-01

    Heart failure is a major disease seriously threatening human health.Once left ventricular dysfunction develops,cardiac function usually deteriorates and progresses to congestive heart failure in several months or years even if no factors which accelerate the deterioration repeatedly exist.Mechanism through which cardiac function continually deteriorates is still unclear.Cardiomyocytic apoptosis can occur in acute stage of ischemic heart diseases and the compensated stage of cardiac dysfunction.In this review,we summarize recent advances in understanding the role of cardiomyocytic apoptosis in heart failure.

  19. Thermo-plasticity of soils at various saturation states : a constitutive model

    OpenAIRE

    François, Bertrand; LALOUI, Lyesse

    2008-01-01

    This paper presents a highly-coupled thermo-plasticity model for unsaturated soils. The effect of temperature on the mechanics of unsaturated soils is briefly addressed. Then the equations of the developed model, so-called ACMEG-TS, are detailed. Finally, the model is validated by the means of comparisons with experiments. This constitutive model constitutes an effective tool for modelling the thermo-hydro-mechanical (THM) behaviour of geomaterials involved in the confinement of nuclear waste...

  20. Transgenic mice expressing constitutive active MAPKAPK5 display gender-dependent differences in exploration and activity

    OpenAIRE

    Moens Ugo; Van, Belle Werner; Gerits Nancy

    2007-01-01

    Abstract Background The mitogen-activated protein kinases, MAPKs for short, constitute cascades of signalling pathways involved in the regulation of several cellular processes that include cell proliferation, differentiation and motility. They also intervene in neurological processes like fear conditioning and memory. Since little remains known about the MAPK-Activated Protein Kinase, MAPKAPK5, we constructed the first MAPKAPK knockin mouse model, using a constitutive active variant of MAPKAP...

  1. DECREASED APOPTOSIS DURING CAR-MEDIATED HEPATOPROTECTION AGAINST LITHOCHOLIC ACID-INDUCED LIVER INJURY IN MICE

    OpenAIRE

    Beilke, Lisa D.; Aleksunes, Lauren M.; Olson, Erik R.; Besselsen, David G; Klaassen, Curtis D.; Dvorak, Katerina; Cherrington, Nathan J.

    2009-01-01

    Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver against bile acid-induced toxicity and it may have a role in cell death via apoptosis by altering expression of Bcl-2 family proteins such as myeloid cell leukemia-1 (Mcl-1). Our aim was to determine if activation of CAR reduces hepatocellular apoptosis during cholestasis as a mechanism of hepatoprotection. CAR+/+ (WT) and CAR−/−...

  2. Nuclear exclusion of transcription factors associated with apoptosis in developing nervous tissue

    Directory of Open Access Journals (Sweden)

    R. Linden

    1999-07-01

    Full Text Available Programmed cell death in the form of apoptosis involves a network of metabolic events and may be triggered by a variety of stimuli in distinct cells. The nervous system contains several neuron and glial cell types, and developmental events are strongly dependent on selective cell interactions. Retinal explants have been used as a model to investigate apoptosis in nervous tissue. This preparation maintains the structural complexity and cell interactions similar to the retina in situ, and contains cells in all stages of development. We review the finding of nuclear exclusion of several transcription factors during apoptosis in retinal cells. The data reviewed in this paper suggest a link between apoptosis and a failure in the nucleo-cytoplasmic partition of transcription factors. It is argued that the nuclear exclusion of transcription factors may be an integral component of apoptosis both in the nervous system and in other types of cells and tissues.

  3. 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.

  4. Spred2 is involved in imatinib-induced cytotoxicity in chronic myeloid leukemia cells

    International Nuclear Information System (INIS)

    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.

  5. Social apoptosis in honey bee superorganisms.

    Science.gov (United States)

    Page, Paul; Lin, Zheguang; Buawangpong, Ninat; Zheng, Huoqing; Hu, Fuliang; Neumann, Peter; Chantawannakul, Panuwan; Dietemann, Vincent

    2016-01-01

    Eusocial insect colonies form superorganisms, in which nestmates cooperate and use social immunity to combat parasites. However, social immunity may fail in case of emerging diseases. This is the case for the ectoparasitic mite Varroa destructor, which switched hosts from the Eastern honeybee, Apis cerana, to the Western honey bee, Apis mellifera, and currently is the greatest threat to A. mellifera apiculture globally. Here, we show that immature workers of the mite's original host, A. cerana, are more susceptible to V. destructor infestations than those of its new host, thereby enabling more efficient social immunity and contributing to colony survival. This counterintuitive result shows that susceptible individuals can foster superorganism survival, offering empirical support to theoretical arguments about the adaptive value of worker suicide in social insects. Altruistic suicide of immature bees constitutes a social analogue of apoptosis, as it prevents the spread of infections by sacrificing parts of the whole organism, and unveils a novel form of transgenerational social immunity in honey bees. Taking into account the key role of susceptible immature bees in social immunity will improve breeding efforts to mitigate the unsustainably high colony losses of Western honey bees due to V. destructor infestations worldwide. PMID:27264643

  6. 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.

  7. PARP1-Driven Apoptosis in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Panagiotis T. Diamantopoulos

    2014-01-01

    Full Text Available Chronic lymphocytic leukemia (CLL is considered a malignancy resulting from defects in apoptosis. For this reason, targeting apoptotic pathways in CLL may be valuable for its management. Poly [ADP-ribose] polymerase 1 (PARP1 is the main member of a family of nuclear enzymes that act as DNA damage sensors. Through binding on DNA damaged structures, PARP1 recruits repair enzymes and serves as a survival factor, but if the damage is severe enough, its action may lead the cell to apoptosis through caspase activation, or necrosis. We measured the PARP1 mRNA and protein pretreatment levels in 26 patients with CLL and the corresponding posttreatment levels in 15 patients after 3 cycles of immunochemotherapy, as well as in 15 healthy blood donors. No difference was found between the pre- and posttreatment levels of PARP1, but we found a statistically significant relative increase of the 89 kDa fragment of PARP1 that is cleaved by caspases in the posttreatment samples, indicating PARP1-related apoptosis in CLL patients after treatment. Our findings constitute an important step in the field, especially in the era of PARP1 inhibitors, and may serve as a base for future clinical trials with these agents in CLL.

  8. Active Akt and functional p53 modulate apoptosis in Abelson virus-transformed pre-B cells.

    Science.gov (United States)

    Gong, Li; Unnikrishnan, Indira; Raghavan, Anuradha; Parmar, Kalindi; Rosenberg, Naomi

    2004-02-01

    Suppression of apoptosis is an important feature of the Abelson murine leukemia virus (Ab-MLV) transformation process. During multistep transformation, Ab-MLV-infected pre-B cells undergo p53-dependent apoptosis during the crisis phase of transformation. Even once cells are fully transformed, an active v-Abl protein tyrosine kinase is required to suppress apoptosis because cells transformed by temperature-sensitive (ts) kinase mutants undergo rapid apoptosis after a shift to the nonpermissive temperature. However, inactivation of the v-Abl protein by a temperature shift interrupts signals transmitted via multiple pathways, making it difficult to identify those that are critically important for the suppression of apoptosis. To begin to dissect these pathways, we tested the ability of an SH2 domain Ab-MLV mutant, P120/R273K, to rescue aspects of the ts phenotype of pre-B cells transformed by the conditional kinase domain mutant. The P120/R273K mutant suppressed apoptosis at the nonpermissive temperature, a phenotype correlated with its ability to activate Akt. Apoptosis also was suppressed at the nonpermissive temperature by constitutively active Akt and in p53-null pre-B cells transformed with the ts kinase domain mutant. These data indicate that an intact Src homology 2 (SH2) domain is not critical for apoptosis suppression and suggest that signals transmitted through Akt and p53 play an important role in the response. PMID:14747529

  9. Blockade of the BAK hydrophobic groove by inhibitory phosphorylation regulates commitment to apoptosis.

    Directory of Open Access Journals (Sweden)

    Abul Azad

    Full Text Available The BCL-2 family protein BAK is a key regulator of mitochondrial apoptosis. BAK activation first involves N-terminal conformational changes that lead to the transient exposure of the BAK BH3 domain that then inserts into a hydrophobic groove on another BAK molecule to form symmetric dimers. We showed recently that post-translational modifications are important in the regulation of BAK conformational change and multimerization, with dephosphorylation at tyrosine 108 constituting an initial step in the BAK activation process. We now show that dephosphorylation of serine 117 (S117, located in the BAK hydrophobic groove, is also critical for BAK activation to proceed to completion. Phosphorylation of BAK at S117 has two important regulatory functions: first, it occludes the binding of BH3-containing peptides that bind to BAK causing activation and cytochrome c release from mitochondria; second, it prevents BAK-BH3:BAK-Groove interactions that nucleate dimer formation for subsequent multimerization. Hence, BH3-mediated BAK conformational change and subsequent BAK multimerization for cytochrome c release and cell death is intimately linked to, and dependent on, dephosphorylation at S117. Our study reveals important novel mechanistic and structural insights into the temporal sequence of events governing the process of BAK activation in commitment to cell death and how they are regulated.

  10. Constitutional change, legislative performance and institutional consolidation

    Directory of Open Access Journals (Sweden)

    Figueiredo Argelina Cheibub

    2000-01-01

    Full Text Available The article examines the effects of changes in constitutional and internal legislative regulations on the performance of the House of Representatives in law making. It presents an analysis of the flow of bills in the Lower House and the legal output in the post 1988 Constitution period, showing, on the one hand, the importance of the executive in the definition of the legislative agenda and its preponderance in legislative outcomes and, on the other hand, the role of the college of leaders, to the detriment of the standing committees, in the organization of the legislative work. The authors argue, against the conventional wisdom on Brazilian politics, that the legislature cannot be viewed as an obstacle to executive action.

  11. Thermodynamic watershed hydrological model: Constitutive relationship

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The representative elementary watershed (REW) approach proposed by Reggiani et al. was the first attempt to develop scale adaptable equations applicable directly at the macro scale. Tian et al. extended the initial definition of REW for simulating the energy related processes, and re-organized the deriving procedure of balance equations so that additional sub-regions and substances could be easily incorpo-rated. The resultant ordinary differential equation set can simulate various hydro-logical processes in a physically reasonable way. However, constitutive and geo-metric relationships have not been developed for Tian et al.’s equation set, which are necessary for the thermodynamic watershed hydrological model to apply in hydrological modeling practice. In this work, the constitutive equations for mass exchange terms and momentum exchange terms were developed as well as geo-metric relationships. The closed ordinary differential equation set with nine equa-tions was finally obtained.

  12. Canada's constitutional separation of (wind) power

    International Nuclear Information System (INIS)

    This paper investigates the impact that a federal government structure has on strategic selection of renewable energy policy instruments. The context for this study centers on wind power development in Canada. Canada is a nation that is blessed by all the attributes necessary to catalyze global leadership in installed wind power capacity. Unfortunately, the constitutional separation of powers that underpins Canada's federal system impedes the creation of a national wind power development strategy because Canada's provinces have constitutional authority over electricity governance. The insights gleaned from the case study are used to develop a conceptual framework for understanding the impact that federal structure has on policy instrument selection and efficacy under areas of federal, regional and concurrent policy jurisdiction. Finally, this framework is re-applied to identify specific approaches the Canadian federal government could take to resolve what currently amounts to be a fragmented, ineffective approach to wind power development planning.

  13. 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

  14. 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.

  15. Increased apoptosis in gastric mucosa adjacent to intestinal metaplasia

    Science.gov (United States)

    van Grieken, N C T; Meijer, G A; zur Hausen, A; Meuwissen, S G M; Baak, J P A; Kuipers, E J

    2003-01-01

    Background: The biological processes involved in the development of gastric mucosal atrophy and intestinal metaplasia are still incompletely understood. Reports testing the hypothesis that apoptosis leads to atrophy have yielded conflicting results. The availability of new antibodies for the detection of apoptotic cells in tissue sections has facilitated the analysis of the role of apoptosis in the gastritis–atrophy–intestinal metaplasia sequence. Methods: Archival material from 40 gastric resection specimens with normal mucosa (n = 5), chronic active gastritis (n = 17), or intestinal metaplasia (n = 18) was studied. Immunohistochemistry was performed using antibodies directed against cleaved cytokeratin 18 and active caspase 3. Slides were scored on a 0–3 scale for the presence of apoptotic cells. Results: Normal gastric mucosa contained low numbers of apoptotic cells at the surface epithelium (mean score, 0.20). This number was significantly increased in cases with chronic gastritis (mean score, 1.06) and in those with intestinal metaplasia (mean score, 2.56). Within the intestinal metaplasia cases, 44 different foci of intestinal metaplasia were identified. In 39 of these 44 areas, concentrations of apoptotic cells were seen immediately adjacent to the foci of intestinal metaplasia, but not in the metaplastic epithelium itself. Conclusions: Apoptosis is uncommon in normal gastric mucosa. Chronic inflammation and intestinal metaplasia are associated with increased apoptosis, but occur mainly at the mucosal surface and not in the deeper layers. These findings do not support the concept that apoptosis underlies the loss of gastric glands and leads to atrophy, but the observed concentration of apoptotic epithelial cells adjacent to foci of intestinal metaplasia could be related to heterogeneity of epithelial damage, causing apoptosis, to which intestinal metaplasia is a response. PMID:12719456

  16. 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)

  17. The Dynamic Efficiency of Regulatory Constitutions

    OpenAIRE

    Gilbert, Richard J; Newbery, David M.

    1994-01-01

    In this article, we model regulation as a repeated game between a utility facing a random sequence of demands and a regulator tempted to underreward past investment. Rate-of-return regulation designed with a constitutional commitment to an adequate rate of return on capital prudently invested is able to support an efficient investment program as a subgame-perfect Nash equilibrium for a larger set of parameter values than rate-of-return regulation without such a commitment. Furthermore, rate-o...

  18. Tunnel modelling: stress release and constitutive aspects

    OpenAIRE

    Gerheim Souza Dias, Tiago; Bezuijen, Adam

    2014-01-01

    Tunnel construction in soft ground has evolved significantly over the last 20 years, especially on the matter of settlement control. This was achieved by guiding theTBM operation to control the main factors that induced soil displacements, like the face pressure and the soil-lining void closure. However, the design methods and numerical modeling procedures where not adapted to these new conditions, sometimes applying boundary conditions, constitutive parameters or state variables with no phys...

  19. The Eurozone Crisis: A Constitutional Analysis

    OpenAIRE

    Anna Sting

    2015-01-01

    “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 s...

  20. The Eurozone Crisis: A Constitutional Analysis

    OpenAIRE

    Anna Sting

    2015-01-01

    “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 E...

  1. The constitution of the corpus of research

    OpenAIRE

    Reinoldo Marquezan

    2009-01-01

    This study will reflect on the construction of an object of research: the discursive corpus of analysis from the file constituted by the Special Education law. It is anchored in the theoretical device of the french discourse analysis inaugurated by Michel Pêcheux. The construction of a research object requires the consideration of some factors: object, question and research problem. It requires a broad preliminary exploration of the subject to insert the research in a theoretical chart settin...

  2. Unified viscoplastic constitutive equations and their applications

    Science.gov (United States)

    Lindholm, U. S.

    1987-01-01

    Unified constitutive equations for time- and temperature-dependent metallic plastic deformation have been applied in FEM simulations of forming processes; increasingly powerful computational tools and physical models are being used to numerically model complex engineering problems. Once confidence has been gained through adequate verification, these numerical models will increasingly replace experimental models. Attention is presently given to the contributions made by physical metallurgy, continuum mechanics, and computational mechanics.

  3. Linguistic Diversity within the Integrated Constitutional Space

    OpenAIRE

    Francesco Palermo

    2006-01-01

    The language issue within the European constitutional space is one of the most fascinating challenges to supranational integration. On the one hand, the principle of equal standing of all official and working languages is constantly reaffirmed; on the other hand the necessity to simplify the European Babel on the basis of a more functional consideration of the language issue seems unavoidable. Several solutions have been proposed both by scholars and by European institutions. The paper argues...

  4. Black Holes Constitute All Dark Matter

    OpenAIRE

    Frampton, Paul H.

    2010-01-01

    The dimensionless entropy, ${\\cal S} \\equiv S/k$, of the visible universe, taken as a sphere of radius 50 billion light years with the Earth at its "center", is discussed. An upper limit ($10^{112}$), and a lower limit ($10^{102}$), for ${\\cal S}$ are introduced. It is suggested that intermediate-mass black holes (IMBHs) constitute all dark matter, and that they dominate ${\\cal S}$.

  5. 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.

  6. Signal transducer and activator of transcription 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells

    Directory of Open Access Journals (Sweden)

    Qualman Stephen J

    2007-06-01

    Full Text Available Abstract Background Stat3 has been classified as a proto-oncogene and constitutive Stat3 signaling appears to be involved in oncogenesis of human cancers. However, whether constitutive Stat3 signaling plays a role in the survival and growth of osteosarcomas, rhabdomyosarcomas, and soft-tissue sarcomas is still unclear. Methods To examine whether Stat3 is activated in osteosarcomas, rhabdomyosarcomas and other soft-tissue sarcomas we analyzed sarcoma tissue microarray slides and sarcoma cell lines using immunohistochemistry and Western blot analysis, respectively, with a phospho-specific Stat3 antibody. To examine whether the activated Stat3 pathway is important for sarcoma cell growth and survival, adenovirus-mediated expression of a dominant-negative Stat3 (Y705F and a small molecule inhibitor (termed STA-21 were used to inhibit constitutive Stat3 signaling in human sarcoma cell lines expressing elevated levels of Stat3 phosphorylation. Cell viability was determined by MTT assays and induction of apoptosis was analyzed by western blotting using antibodies that specifically recognize cleaved caspases-3, 8, and 9. Results Stat3 phosphorylation is elevated in 19% (21/113 of osteosarcoma, 27% (17/64 of rhabdomyosarcoma, and 15% (22/151 of other soft-tissue sarcoma tissues as well as in sarcoma cell lines. Expression of the dominant-negative Stat3 and treatment of STA-21 inhibited cell viability and growth and induced apoptosis through caspases 3, 8 and 9 pathways in human sarcoma cell lines expressing elevated levels of phosphorylated Stat3. Conclusion This study demonstrates that Stat3 phosphorylation is elevated in human rhabdomyosarcoma, osteosarcomas and soft-tissue sarcomas. Furthermore, the activated Stat3 pathway is important for cell growth and survival of human sarcoma cells.

  7. Association of Sasang Constitutional Type with Sarcopenia.

    Science.gov (United States)

    Lee, Seung Ku; Yoon, Dae Wui; Choi, Kyung-Mee; Lee, Si Woo; Kim, Jong Yeol; Kim, Jin Kwan; Shin, Chol

    2015-01-01

    Sasang constitutional medicine (SCM) is a unique Korean traditional medicine that classifies human beings as four distinct types named Sasang constitutional types (SCTs), based on physiologic, physical, and psychological traits. Accumulating evidence has demonstrated that specific constitutional types are associated with chronic diseases, but no study has investigated the relationship between SCTs and sarcopenia. The aim of this study was to examine the association in a large population-based study. Data from 1,204 participants who completed questionnaires for life style, anthropometric evaluation, and biochemical analysis were analyzed. Classification of the SCTs was done using an integrated diagnostic method. Sarcopenia was defined as appendicular skeletal muscle mass/height(2) less than one standard deviation below the gender-specific normal mean of a younger group. Dual-energy X-ray absorptiometry was used to assess whole body composition. The prevalence of sarcopenia was 8.6% in the Tae-eum (TE) type, 44.7% in the So-eum (SE) type, and 20.7% in the So-yang (SY) type. Multivariate analysis revealed that the SE and SY types had 9.22 (5.06-16.81; P sarcopenia compared to the TE type, respectively. Our results show that the SE and SY types are significantly associated with increased prevalence of sarcopenia. PMID:26649062

  8. 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. PMID:26971070

  9. 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.

  10. 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.

  11. Neem oil limonoids induces p53-independent apoptosis and autophagy.

    Science.gov (United States)

    Srivastava, Pragya; Yadav, Neelu; Lella, Ravi; Schneider, Andrea; Jones, Anthony; Marlowe, Timothy; Lovett, Gabrielle; O'Loughlin, Kieran; Minderman, Hans; Gogada, Raghu; Chandra, Dhyan

    2012-11-01

    Azadirachta indica, commonly known as neem, has a wide range of medicinal properties. Neem extracts and its purified products have been examined for induction of apoptosis in multiple cancer cell types; however, its underlying mechanisms remain undefined. We show that neem oil (i.e., neem), which contains majority of neem limonoids including azadirachtin, induced apoptotic and autophagic cell death. Gene silencing demonstrated that caspase cascade was initiated by the activation of caspase-9, whereas caspase-8 was also activated late during neem-induced apoptosis. Pretreatment of cancer cells with pan caspase inhibitor, z-VAD inhibited activities of both initiator caspases (e.g., caspase-8 and -9) and executioner caspase-3. Neem induced the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria, suggesting the involvement of both caspase-dependent and AIF-mediated apoptosis. p21 deficiency caused an increase in caspase activities at lower doses of neem, whereas p53 deficiency did not modulate neem-induced caspase activation. Additionally, neem treatment resulted in the accumulation of LC3-II in cancer cells, suggesting the involvement of autophagy in neem-induced cancer cell death. Low doses of autophagy inhibitors (i.e., 3-methyladenine and LY294002) did not prevent accumulation of neem-induced LC3-II in cancer cells. Silencing of ATG5 or Beclin-1 further enhanced neem-induced cell death. Phosphoinositide 3-kinase (PI3K) or autophagy inhibitors increased neem-induced caspase-3 activation and inhibition of caspases enhanced neem-induced autophagy. Together, for the first time, we demonstrate that neem induces caspase-dependent and AIF-mediated apoptosis, and autophagy in cancer cells. PMID:22915764

  12. The constitutional implications of the rise of the SNP

    OpenAIRE

    McHarg, Aileen

    2015-01-01

    The UK Constitutional Law Association blog has asked constitutional lawyers to review the main party manifestos ahead of the May elections, drawing out key constitutional proposals. Below Aileen McHarg discussed the constitutional implications of the rise of the SNP.

  13. 29 CFR 402.1 - Labor organization constitution and bylaws.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 2 2010-07-01 2010-07-01 false Labor organization constitution and bylaws. 402.1 Section... constitution and bylaws. Every labor organization shall adopt a constitution and bylaws consistent with the... a constitution and bylaws which it has previously adopted and under which it is operating when...

  14. The Law of the Constitution: A Bicentennial Lecture.

    Science.gov (United States)

    Meese, Edwin, III

    This paper discusses the distinction between the Constitution and constitutional law. The Constitution is the fundamental law of the United States. It creates the institutions of government, enumerates the powers of these institutions, and delineates areas government may not enter. The Constitution is the instrument by which the consent of the…

  15. Power: Constitutional Update. Bar/School Partnership Programs Series.

    Science.gov (United States)

    American Bar Association, Chicago, IL. Special Committee on Youth Education for Citizenship.

    The fourth in a special series of handbooks dealing with constitutional themes, this document looks at power in the context of the U.S. Constitution. "The Constitution's Prescription for Freedom" (L. Peach) examines the separation of powers provided for in the Constitution. "The Concept of Power" (C. Roach) is a series of strategies, some using…

  16. Resveratrol Induces Glioma Cell Apoptosis through Activation of Tristetraprolin

    OpenAIRE

    Ryu, Jinhyun; Yoon, Nal Ae; Seong, Hyemin; Jeong, Joo Yeon; Kang, Seokmin; Park, Nammi; Choi, Jungil; Lee, Dong Hoon; Roh, Gu Seob; Kim, Hyun Joon; Cho, Gyeong Jae; Choi, Wan Sung; Park, Jae-Yong; Park, Jeong Woo; Kang, Sang Soo

    2015-01-01

    Tristetraprolin (TTP) is an AU-rich elements (AREs)-binding protein, which regulates the decay of AREs-containing mRNAs such as proto-oncogenes, anti-apoptotic genes and immune regulatory genes. Despite the low expression of TTP in various human cancers, the mechanism involving suppressed expression of TTP is not fully understood. Here, we demonstrate that Resveratrol (3,5,4′-trihydroxystilbene, Res), a naturally occurring compound, induces glioma cell apoptosis through activation of tristetr...

  17. Apoptosis, autophagy and unfolded proteinresponse pathways in Arbovirus replicationand pathogenesis

    OpenAIRE

    Iranpour, Mahmoud; Moghadam, Adel R; Yazdi, Mina; Ande, Sudharsana R; Alizadeh, Javad; Wiechec, Emilia; Lindsay, Robbin; Drebot, Michael; Coombs, Kevin M; Ghavami, Saeid

    2016-01-01

    Arboviruses are pathogens that widely affect the health of people in different communities around the world. Recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern. The arbovirus infection and replication processes are complex, and many factors are involved in their regulation. Apoptosis, autophagy and the unfolded protei...

  18. 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

  19. 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

  20. Mitogen-Activated Protein Kinase Signaling in Male Germ Cell Apoptosis in the Rat1

    OpenAIRE

    Jia, Yue; Castellanos, Jesse; Wang, Christina; Sinha-Hikim, Indrani; Lue, YanHe; Swerdloff, Ronald S.; Sinha-Hikim, Amiya P.

    2008-01-01

    Programmed germ cell death is critical for functional spermatogenesis. Increased germ cell apoptosis can be triggered by various regulatory stimuli, including testicular hyperthermia or deprivation of gonadotropins and intratesticular testosterone. We have previously shown the involvement of the mitogen-activated protein kinase (MAPK) 14 in apoptotic signaling of male germ cells across species after hormone deprivation. This study investigates the role of MAPK14 in germ cell apoptosis in rats...

  1. Kaposi's Sarcoma Herpesvirus microRNAs Target Caspase 3 and Regulate Apoptosis

    OpenAIRE

    Guillaume Suffert; Georg Malterer; Jean Hausser; Johanna Viiliäinen; Aurélie Fender; Maud Contrant; Tomi Ivacevic; Vladimir Benes; Frédéric Gros; Olivier Voinnet; Mihaela Zavolan; Ojala, Päivi M.; Haas, Juergen G.; Sébastien Pfeffer

    2011-01-01

    Kaposi's sarcoma herpesvirus (KSHV) encodes a cluster of twelve micro (mi)RNAs, which are abundantly expressed during both latent and lytic infection. Previous studies reported that KSHV is able to inhibit apoptosis during latent infection; we thus tested the involvement of viral miRNAs in this process. We found that both HEK293 epithelial cells and DG75 cells stably expressing KSHV miRNAs were protected from apoptosis. Potential cellular targets that were significantly down-regulated upon KS...

  2. SOME ASPECTS OF THE CONSTITUTIONALITY OF LAWS CONF CONTROL

    OpenAIRE

    Luminita DRAGNE

    2010-01-01

    The Constitution is the fundamental law of a State, its supremacy is ensured by a special and complex mechanism called the control of the constitutionality of laws. For this purpose it was created an effective mechanism resulted in a legal institution called review the constitutionality of laws and that includes all procedures that ensure the supremacy of the Constitution. The notion of control of constitutionality of laws means all methods through which the verification of compliance with co...

  3. The new Swaziland constitution and its impact on media freedom

    OpenAIRE

    Richard Rooney

    2011-01-01

    This paper examines media freedom in Swaziland since the kingdom's new constitution came into effect in 2006. Despite the constitution, Swaziland remains a non-democracy and there continues to be a restrictive media environment. The paper tackles three research questions: (i) How repressive were media laws in Swaziland before the constitution came into effect? (ii) What does the 2006 constitution say about media freedom? (iii) To what extent has the constitution improved media freedom? The pa...

  4. 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.

  5. 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

  6. Nosema Tolerant Honeybees (Apis mellifera) Escape Parasitic Manipulation of Apoptosis

    Science.gov (United States)

    Kurze, Christoph; Le Conte, Yves; Dussaubat, Claudia; Erler, Silvio; Kryger, Per; Lewkowski, Oleg; Müller, Thomas; Widder, Miriam; Moritz, Robin F. A.

    2015-01-01

    Apoptosis is not only pivotal for development, but also for pathogen defence in multicellular organisms. Although numerous intracellular pathogens are known to interfere with the host’s apoptotic machinery to overcome this defence, its importance for host-parasite coevolution has been neglected. We conducted three inoculation experiments to investigate in the apoptotic respond during infection with the intracellular gut pathogen Nosema ceranae, which is considered as potential global threat to the honeybee (Apis mellifera) and other bee pollinators, in sensitive and tolerant honeybees. To explore apoptotic processes in the gut epithelium, we visualised apoptotic cells using TUNEL assays and measured the relative expression levels of subset of candidate genes involved in the apoptotic machinery using qPCR. Our results suggest that N. ceranae reduces apoptosis in sensitive honeybees by enhancing inhibitor of apoptosis protein-(iap)-2 gene transcription. Interestingly, this seems not be the case in Nosema tolerant honeybees. We propose that these tolerant honeybees are able to escape the manipulation of apoptosis by N. ceranae, which may have evolved a mechanism to regulate an anti-apoptotic gene as key adaptation for improved host invasion. PMID:26445372

  7. Nosema Tolerant Honeybees (Apis mellifera Escape Parasitic Manipulation of Apoptosis.

    Directory of Open Access Journals (Sweden)

    Christoph Kurze

    Full Text Available Apoptosis is not only pivotal for development, but also for pathogen defence in multicellular organisms. Although numerous intracellular pathogens are known to interfere with the host's apoptotic machinery to overcome this defence, its importance for host-parasite coevolution has been neglected. We conducted three inoculation experiments to investigate in the apoptotic respond during infection with the intracellular gut pathogen Nosema ceranae, which is considered as potential global threat to the honeybee (Apis mellifera and other bee pollinators, in sensitive and tolerant honeybees. To explore apoptotic processes in the gut epithelium, we visualised apoptotic cells using TUNEL assays and measured the relative expression levels of subset of candidate genes involved in the apoptotic machinery using qPCR. Our results suggest that N. ceranae reduces apoptosis in sensitive honeybees by enhancing inhibitor of apoptosis protein-(iap-2 gene transcription. Interestingly, this seems not be the case in Nosema tolerant honeybees. We propose that these tolerant honeybees are able to escape the manipulation of apoptosis by N. ceranae, which may have evolved a mechanism to regulate an anti-apoptotic gene as key adaptation for improved host invasion.

  8. Coxsackievirus B3-induced apoptosis and Caspase-3

    Institute of Scientific and Technical Information of China (English)

    JIAN PING YUAN; WEI ZHAO; HONG TAO WANG; KAI YU WU; TAO LI; XIAO KUI GUO; SHAN QING TONG

    2003-01-01

    Cell death can be classified into two categories: apoptosis and necrosis. Apoptotic pathway can beeither caspase-dependent or caspase-independent. Caspase-independent cytopathic effect (CPE) has beendescribed. In order to evaluate the pattern of HeLa cell death induced by Coxsackievirus B3 (CVB3)and whether apoptosis involves caspase activation, we co-cultivated HeLa cells with CVB3 and detectedthe cytopathic changes, the alteration of mRNA and protein expression of caspase-3 gene plus caspase-3activity, as well as analyzing DNA fragmentation before and after caspase-3 activity inhibition. Accordingto the results, we propose that CVB3 may induce apoptosis and necrosis in HeLa cells, the latter appearingmuch earlier. Caspase-3 is activated at the levels of both transcription and translation, and procaspase-3 isproteolytically cleaved, thus leading to the continuous increasing of both caspase-3 precursor protein and itssubunit. However, besides CPE, apoptosis induced by CVB3 is not a direct consequence of the activationof caspase-3, or caspase-3 is not the only effector molecule in apoptotic cell death, for caspase-3 inhibitorcan not decrease DNA fragmentation. Some other biochemical mechanisms may participate in the process,whose role weakens the effect of inhibiting caspase-3 activity.

  9. Constitutional aspects of a nuclear power phaseout

    International Nuclear Information System (INIS)

    In the current political debate in Germany about the Federal Government's plans to opt out of nuclear power, the time horizon for implementation of the policy and the nuclear power phaseout is a focal point of interest. This aspect is discussed from the angle of German constitutional law. The author analyses in this context the protective scope of Art. 14 GG (German Basic Law), relating to the protection of ownership rights and the principle of legal protection for bona fide acts, which is a vital aspect for the nuclear industry and the power industry. (orig./CB)

  10. Identification of constitutive parameters for fractional viscoelasticity

    Science.gov (United States)

    Xiao, Zhao; Haitian, Yang; Yiqian, He

    2014-01-01

    This paper develops a numerical model to identify constitutive parameters in the fractional viscoelastic field. An explicit semi-analytical numerical model and a finite difference (FD) method based numerical model are derived for solving the direct homogenous and regionally inhomogeneous fractional viscoelastic problems, respectively. A continuous ant colony optimization (ACO) algorithm is employed to solve the inverse problem of identification. The feasibility of the proposed approach is illustrated via the numerical verification of a two-dimensional identification problem formulated by the fractional Kelvin-Voigt model, and the noisy data and regional inhomogeneity etc. are taken into account.

  11. The Right to Water: A Constitutional Perspective

    OpenAIRE

    Kothari, Jayna

    2013-01-01

    Introduction This paper examines the justiciability of social rights, looking particularly at the Right to Water as part of the all encompassing Right to Life. The Right to water in India has been protected as a fundamental human right by the Indian Supreme Court emanating from the Right to Life guaranteed under Article 21 of the constitution. The right to life has been expanded to include the right to health and the right to a clean environment. In India, there have also been significant dev...

  12. Labour’s 'Juridification' of the Constitution.

    OpenAIRE

    Masterman, R.M.W.

    2009-01-01

    This article responds to a number of points made by Mark Bevir in his article ‘The Westminster Model, Governance and Judicial Reform’ [Parliamentary Affairs 61 (2008), 559–77], in which Bevir highlights the ‘increasing role of the courts in the processes of collective decision-making’ which has been the result of, inter alia (but of particular importance to Bevir's argument), the passage and implementation of the Human Rights Act 1998 and the Constitutional Reform Act 2005. This article puts ...

  13. CONSTITUTIONAL VALIDITY OF POLYGRAPH, THE LIEDETECTOR TEST

    OpenAIRE

    M. Madhavi Latha

    2016-01-01

    The main aim of polygraph test is to detect the truth from criminal. polygraph is scientific form of investigating tools. The main object of polygraph test is to go in the root of truth as well as to reduce the criminal behavior in society. But today one of the biggest legal controversies which around this Test are alleged violation of the fundamental rights against self incrimination guaranteed under Article 20(3) of the Indian Constitution. Therefore the researcher has tried to discuss the ...

  14. Retroviral expression of a kinase-defective IGF-I receptor suppresses growth and causes apoptosis of CHO and U87 cells in-vivo

    International Nuclear Information System (INIS)

    Phosphatidylinositol-3,4,5-triphosphate (PtdInsP3) signaling is elevated in many tumors due to loss of the tumor suppressor PTEN, and leads to constitutive activation of Akt, a kinase involved in cell survival. Reintroduction of PTEN in cells suppresses transformation and tumorigenicity. While this approach works in-vitro, it may prove difficult to achieve in-vivo. In this study, we investigated whether inhibition of growth factor signaling would have the same effect as re-expression of PTEN. Dominant negative IGF-I receptors were expressed in CHO and U87 cells by retroviral infection. Cell proliferation, transformation and tumor formation in athymic nude mice were assessed. Inhibition of IGF-IR signaling in a CHO cell model system by expression of a kinase-defective IGF-IR impairs proliferation, transformation and tumor growth. Reduction in tumor growth is associated with an increase in apoptosis in-vivo. The dominant-negative IGF-IRs also prevented growth of U87 PTEN-negative glioblastoma cells when injected into nude mice. Injection of an IGF-IR blocking antibody αIR3 into mice harboring parental U87 tumors inhibits tumor growth and increases apoptosis. Inhibition of an upstream growth factor signal prevents tumor growth of the U87 PTEN-deficient glioma to the same extent as re-introduction of PTEN. This result suggests that growth factor receptor inhibition may be an effective alternative therapy for PTEN-deficient tumors

  15. Investigation on etretin effects on expression of Fas/FasL ligand and apoptosis in cultured human keratinocytes

    Institute of Scientific and Technical Information of China (English)

    Ping Liu; Shunsheng Tan; Yanping Xi; Zhenping Cao

    2005-01-01

    Objective: To further illuminate a possibme mechanism of Fas/FasL in the treatment of psoriasis, the expression of it and apoptosis of KC were investigated. Methods: With cell culture,immunocytochemistry, the expression of Fas/FasL protein after the treatment with etretin was observed in cultured human normal keratinocytes. Then, the state of apoptosis in cultured keratinocyte after stimuwasn't involved in apoptosis in cultured normol human keratinocytes. But during limited period, the apoptosis of KC could be induced by etretin, thus it can antagonize benign proliferate of keratinocytes. Our data showed up-regulation of the expression of Fas/FasL and apoptosis in cultured human keratinocytes stimulated by etretin, and its function may be involved in the therapeutic machanism of psoriasis.

  16. Sorafenib induces growth arrest and apoptosis of human glioblastoma cells via dephosphorylation of STAT3

    OpenAIRE

    Yang, Fan; Brown, Christine; Buettner, Ralf; HEDVAT, MICHAEL; Starr, Renate; Scuto, Anna; Schroeder, Anne; Jensen, Michael; Jove, Richard

    2010-01-01

    Glioblastoma is the most common type of primary brain tumor and is rapidly progressive with few treatment options. Here, we report that sorafenib (≤ 10 μM) inhibited cell proliferation and induced apoptosis in two established cell lines (U87, U251) and two primary cultures (PBT015, PBT022) from human glioblastomas. Effects of sorafenib on these tumor cells were associated with inhibiting phosphorylated STAT3 (Tyr705). Expression of a constitutively activated STAT3 mutant partially blocked the...

  17. Milk fermented by Propionibacterium freudenreichii induces apoptosis of HGT-1 human gastric cancer cells.

    OpenAIRE

    Cousin, Fabien,; Jouan-Lanhouet, Sandrine; Dimanche-Boitrel, Marie-Thérèse; Corcos, Laurent; Jan, Gwénaël

    2012-01-01

    Background: Gastric cancer is one of the most common cancers in the world. The ‘‘economically developed countries’’ life style, including diet, constitutes a risk factor favoring this cancer. Diet modulation may lower digestive cancer incidence. Among promising food components, dairy propionibacteria were shown to trigger apoptosis of human colon cancer cells, via the release of short-chain fatty acids acetate and propionate. [br/] Methodology/Principal Findings: A fermented milk, exclusiv...

  18. Large Deformation Constitutive Laws for Isotropic Thermoelastic Materials

    Energy Technology Data Exchange (ETDEWEB)

    Plohr, Bradley J. [Los Alamos National Laboratory; Plohr, Jeeyeon N. [Los Alamos National Laboratory

    2012-07-25

    We examine the approximations made in using Hooke's law as a constitutive relation for an isotropic thermoelastic material subjected to large deformation by calculating the stress evolution equation from the free energy. For a general thermoelastic material, we employ the volume-preserving part of the deformation gradient to facilitate volumetric/shear strain decompositions of the free energy, its first derivatives (the Cauchy stress and entropy), and its second derivatives (the specific heat, Grueneisen tensor, and elasticity tensor). Specializing to isotropic materials, we calculate these constitutive quantities more explicitly. For deformations with limited shear strain, but possibly large changes in volume, we show that the differential equations for the stress components involve new terms in addition to the traditional Hooke's law terms. These new terms are of the same order in the shear strain as the objective derivative terms needed for frame indifference; unless the latter terms are negligible, the former cannot be neglected. We also demonstrate that accounting for the new terms requires that the deformation gradient be included as a field variable

  19. THE CORPORATE CONSTITUTIONALISM APPROACH IN FORMULATION OF CSR

    Directory of Open Access Journals (Sweden)

    Victor Imanuel Nalle

    2015-04-01

    Full Text Available The 21st century is the era of the development of corporate social responsibility (CSR. It is encouraged by the development of the company as a business and societal entities that balances public and private interests. If there is a balance of public and private interests in the company, the application of CSR should be able to accommodate the public interest. But many companies in Indonesia do not involve the community in the formulation of CSR implementation model. This resulted in the implementation of CSR is often not well targeted. In that context, the theory of corporate constitutionalism becomes relevant theory to answer these problems. The theory of corporate constitutionalism put deliberation as one of the principles to achieve the legitimacy of decision-making in the corporation. Through a process of deliberation formulation of CSR model with the community, not just the interests of shareholders that can be accommodated but also the interests of stakeholders. Thus, CSR can actually be instrumental in the global and local challenges.

  20. New constitutive latex osmotin-like proteins lacking antifungal activity.

    Science.gov (United States)

    Freitas, Cleverson D T; Silva, Maria Z R; Bruno-Moreno, Frederico; Monteiro-Moreira, Ana C O; Moreira, Renato A; Ramos, Márcio V

    2015-11-01

    Proteins that share similar primary sequences to the protein originally described in salt-stressed tobacco cells have been named osmotins. So far, only two osmotin-like proteins were purified and characterized of latex fluids. Osmotin from Carica papaya latex is an inducible protein lacking antifungal activity, whereas the Calotropis procera latex osmotin is a constitutive antifungal protein. To get additional insights into this subject, we investigated osmotins in latex fluids of five species. Two potential osmotin-like proteins in Cryptostegia grandiflora and Plumeria rubra latex were detected by immunological cross-reactivity with polyclonal antibodies produced against the C. procera latex osmotin (CpOsm) by ELISA, Dot Blot and Western Blot assays. Osmotin-like proteins were not detected in the latex of Thevetia peruviana, Himatanthus drasticus and healthy Carica papaya fruits. Later, the two new osmotin-like proteins were purified through immunoaffinity chromatography with anti-CpOsm immobilized antibodies. Worth noting the chromatographic efficiency allowed for the purification of the osmotin-like protein belonging to H. drasticus latex, which was not detectable by immunoassays. The identification of the purified proteins was confirmed after MS/MS analyses of their tryptic digests. It is concluded that the constitutive osmotin-like proteins reported here share structural similarities to CpOsm. However, unlike CpOsm, they did not exhibit antifungal activity against Fusarium solani and Colletotrichum gloeosporioides. These results suggest that osmotins of different latex sources may be involved in distinct physiological or defensive events. PMID:26231325