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71.
Goldman A Chen H Khan MR Roesly H Hill KA Shahidullah M Mandal A Delamere NA Dvorak K 《PloS one》2011,6(8):e23835
Apoptosis resistance is a hallmark of cancer cells. Typically, bile acids induce apoptosis. However during gastrointestinal (GI) tumorigenesis the cancer cells develop resistance to bile acid-induced cell death. To understand how bile acids induce apoptosis resistance we first need to identify the molecular pathways that initiate apoptosis in response to bile acid exposure. In this study we examined the mechanism of deoxycholic acid (DCA)-induced apoptosis, specifically the role of Na(+)/H(+) exchanger (NHE) and Na(+) influx in esophageal cells. In vitro studies revealed that the exposure of esophageal cells (JH-EsoAd1, CP-A) to DCA (0.2 mM-0.5 mM) caused lysosomal membrane perturbation and transient cytoplasmic acidification. Fluorescence microscopy in conjunction with atomic absorption spectrophotometry demonstrated that this effect on lysosomes correlated with influx of Na(+), subsequent loss of intracellular K(+), an increase of Ca(2+) and apoptosis. However, ethylisopropyl-amiloride (EIPA), a selective inhibitor of NHE, prevented Na(+), K(+) and Ca(2+) changes and caspase 3/7 activation induced by DCA. Ouabain and amphotericin B, two drugs that increase intracellular Na(+) levels, induced similar changes as DCA (ion imbalance, caspase3/7 activation). On the contrary, DCA-induced cell death was inhibited by medium with low a Na(+) concentrations. In the same experiments, we exposed rat ileum ex-vivo to DCA with or without EIPA. Severe tissue damage and caspase-3 activation was observed after DCA treatment, but EIPA almost fully prevented this response. In summary, NHE-mediated Na(+) influx is a critical step leading to DCA-induced apoptosis. Cells tolerate acidification but evade DCA-induced apoptosis if NHE is inhibited. Our data suggests that suppression of NHE by endogenous or exogenous inhibitors may lead to apoptosis resistance during GI tumorigenesis. 相似文献
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BACKGROUND: and Aims Free-flowing surface exudates at the stigmatic (wet versus dry stigma) and adaxial epidermis at the site of angiospermy in carpels of Chloranthaceous species have been proposed to comprise a continuous extracellular matrix (ECM) operating in pollen tube transmission to the ovary. The aim of this research was to establish the spatial distribution and histo/immunochemical composition of the ECM involved in pollen tube growth in Sarcandra glabra and Chloranthus japonicus (Chloranthaceae). METHODS: Following confirmation of the pollen tube pathway, the histo/immunochemical make-up of the ECM was determined with histochemistry on fresh tissue to detect cuticle, esterase, proteins, pectins, and lipids and immunolocalization at the level of the TEM on sections from cryofixed/freeze-substituted tissue to detect molecules recognized by antibodies to homogalacturonans (JIM7, 5), arabinogalactan-proteins (JIM13) and cysteine-rich adhesion (SCA). KEY RESULTS: Pollen germinability is low in both species. When grains germinate, they do so on an ECM comprised of an esterase-positive cuticle proper (dry versus wet stigma). Pollen tubes do not track the surface ECM of stigma or adaxial epidermal cells at the site of angiospermy. Instead, tubes grow between stigmatic cells and subsequently along the inner tangential walls of the stigmatic and adaxial carpel cells at the site of angiospermy. Pollen tubes enter the ovary locule at the base of the funiculus. The stigmatic ECM is distinct by virtue of the presence of anti-JIM5 aggregates, lipids, and a protein recognized by anti-SCA. CONCLUSIONS: The Chloranthaceae joins a growing number of basal angiosperm taxa whereby pollen tubes germinate on a dry versus wet stigma to subsequently grow intercellularly en route to the ovary thereby challenging traditional views that the archetype pollen tube pathway was composed of the surface of stigma and adaxial epidermal cells covered with a free-flowing exudate. 相似文献
74.
Zhang J Bao S Furumai R Kucera KS Ali A Dean NM Wang XF 《Molecular and cellular biology》2005,25(22):9910-9919
In response to DNA damage or replication stress, the protein kinase ATR is activated and subsequently transduces genotoxic signals to cell cycle control and DNA repair machinery through phosphorylation of a number of downstream substrates. Very little is known about the molecular mechanism by which ATR is activated in response to genotoxic insults. In this report, we demonstrate that protein phosphatase 5 (PP5) is required for the ATR-mediated checkpoint activation. PP5 forms a complex with ATR in a genotoxic stress-inducible manner. Interference with the expression or the activity of PP5 leads to impairment of the ATR-mediated phosphorylation of hRad17 and Chk1 after UV or hydroxyurea treatment. Similar results are obtained in ATM-deficient cells, suggesting that the observed defect in checkpoint signaling is the consequence of impaired functional interaction between ATR and PP5. In cells exposed to UV irradiation, PP5 is required to elicit an appropriate S-phase checkpoint response. In addition, loss of PP5 leads to premature mitosis after hydroxyurea treatment. Interestingly, reduced PP5 activity exerts differential effects on the formation of intranuclear foci by ATR and replication protein A, implicating a functional role for PP5 in a specific stage of the checkpoint signaling pathway. Taken together, our results suggest that PP5 plays a critical role in the ATR-mediated checkpoint activation. 相似文献
75.
Réty S Sopková-de Oliveira Santos J Dreyfuss L Blondeau K Hofbauerová K Raguénès-Nicol C Kerboeuf D Renouard M Russo-Marie F Lewit-Bentley A 《Journal of molecular biology》2005,345(5):1131-1139
Annexin A8 is a relatively infrequent and poorly studied member of this large family of calcium-binding and membrane-binding proteins. It is, however, associated with a specific disease, acute promyelocytic leukemia. We have solved its three-dimensional structure, which includes a moderately long and intact N terminus. The structure is closest to that of annexin A3 and highlights several important regions of inherent flexibility in the annexin molecule. The N terminus resembles that of annexin A3, as it lies along the concave surface of the molecule and inserts partially into the hydrophilic channel in its centre. Since both annexins A3 and A8 are expressed in promyelocytic cells during their differentiation, the similarity in their structures might suggest a functional relationship. 相似文献
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Nakládalová M Sovová E Ivanová K Kaletová M Lukl J Fialová J 《Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia》2005,149(2):293-295
The aim of the study was to determine the prevalence of risk factors for cardiovascular diseases among physicians at a teaching hospital. In total, 203 men and 167 women were included in the study. The participants filled in a questionnaire; their height, weight, blood pressure, serum cholesterol and glucose levels were added. 19.2 % males and 13.8 % females were smokers, hypertension was diagnosed in 10 % of males and in 6.6 % of females, 52.2 % males and 17.4 % females were overweight, 37 % males and 43.1 % females had hypercholesterolemia. The above findings suggest that Czech physicians have more favourable values of all the studied cardiovascular diseases risk factors than the general Czech population. However, Czech physicians smoke more than those in other countries and their level of cardiovascular diseases risk factors is unsatisfactory and calls for further intensive prevention. Preliminary outcomes of the study repeated after two years show no positive trends as well as physicians' low willingness to actively participate in lowering cardiovascular diseases risk factors. 相似文献
78.
Martic G Karetsou Z Kefala K Politou AS Clapier CR Straub T Papamarcaki T 《The Journal of biological chemistry》2005,280(16):16143-16150
Linker histone H1 is the major factor that stabilizes higher order chromatin structure and modulates the action of chromatin-remodeling enzymes. We have previously shown that parathymosin, an acidic, nuclear protein binds to histone H1 in vitro and in vivo. Confocal laser scanning microscopy reveals a nuclear punctuate staining of the endogenous protein in interphase cells, which is excluded from dense heterochromatic regions. Using an in vitro chromatin reconstitution system under physiological conditions, we show here that parathymosin (ParaT) inhibits the binding of H1 to chromatin in a dose-dependent manner. Consistent with these findings, H1-containing chromatin assembled in the presence of ParaT has reduced nucleosome spacing. These observations suggest that interaction of the two proteins might result in a conformational change of H1. Fluorescence spectroscopy and circular dichroism-based measurements on mixtures of H1 and ParaT confirm this hypothesis. Human sperm nuclei challenged with ParaT become highly decondensed, whereas overexpression of green fluorescent protein- or FLAG-tagged protein in HeLa cells induces global chromatin decondensation and increases the accessibility of chromatin to micrococcal nuclease digestion. Our data suggest a role of parathymosin in the remodeling of higher order chromatin structure through modulation of H1 interaction with nucleosomes and point to its involvement in chromatin-dependent functions. 相似文献
79.
Tabner BJ El-Agnaf OM Turnbull S German MJ Paleologou KE Hayashi Y Cooper LJ Fullwood NJ Allsop D 《The Journal of biological chemistry》2005,280(43):35789-35792
Alzheimer disease and familial British dementia are neurodegenerative diseases that are characterized by the presence of numerous amyloid plaques in the brain. These lesions contain fibrillar deposits of the beta-amyloid peptide (Abeta) and the British dementia peptide (ABri), respectively. Both peptides are toxic to cells in culture, and there is increasing evidence that early "soluble oligomers" are the toxic entity rather than mature amyloid fibrils. The molecular mechanisms responsible for this toxicity are not clear, but in the case of Abeta, one prominent hypothesis is that the peptide can induce oxidative damage via the formation of hydrogen peroxide. We have developed a reliable method, employing electron spin resonance spectroscopy in conjunction with the spin-trapping technique, to detect any hydrogen peroxide generated during the incubation of Abeta and other amyloidogenic peptides. Here, we monitored levels of hydrogen peroxide accumulation during different stages of aggregation of Abeta-(1-40) and ABri and found that in both cases it was generated as a short "burst" early on in the aggregation process. Ultrastructural studies with both peptides revealed that structures resembling "soluble oligomers" or "protofibrils" were present during this early phase of hydrogen peroxide formation. Mature amyloid fibrils derived from Abeta-(1-40) did not generate hydrogen peroxide. We conclude that hydrogen peroxide formation during the early stages of protein aggregation may be a common mechanism of cell death in these (and possibly other) neurodegenerative diseases. 相似文献
80.