149 research outputs found
Activation of human neutrophils by type I collagen. Requirement of two different sequences
Critical Role of Gap Junction Coupled K(ATP) Channel Activity for Regulated Insulin Secretion
Pancreatic β-cells secrete insulin in response to closure of ATP-sensitive K(+) (K(ATP)) channels, which causes membrane depolarization and a concomitant rise in intracellular Ca(2+) (Ca(i)). In intact islets, β-cells are coupled by gap junctions, which are proposed to synchronize electrical activity and Ca(i) oscillations after exposure to stimulatory glucose (>7 mM). To determine the significance of this coupling in regulating insulin secretion, we examined islets and β-cells from transgenic mice that express zero functional K(ATP) channels in approximately 70% of their β-cells, but normal K(ATP) channel density in the remainder. We found that K(ATP) channel activity from approximately 30% of the β-cells is sufficient to maintain strong glucose dependence of metabolism, Ca(i), membrane potential, and insulin secretion from intact islets, but that glucose dependence is lost in isolated transgenic cells. Further, inhibition of gap junctions caused loss of glucose sensitivity specifically in transgenic islets. These data demonstrate a critical role of gap junctional coupling of K(ATP) channel activity in control of membrane potential across the islet. Control via coupling lessens the effects of cell–cell variation and provides resistance to defects in excitability that would otherwise lead to a profound diabetic state, such as occurs in persistent neonatal diabetes mellitus
Gliclazide may have an antiapoptotic effect related to its antioxidant properties in human normal and cancer cells
Experimental and clinical studies suggest that gliclazide may protect pancreatic β-cells from apoptosis induced by an oxidative stress. However, the precise mechanism(s) of this action are not fully understood and requires further clarification. Therefore, using human normal and cancer cells we examined whether the anti-apoptotic effects of this sulfonylurea is due to its free radical scavenger properties. Hydrogen peroxide (H2O2) as a model trigger of oxidative stress was used to induce cell death. Our experiments were performed on human normal cell line (human umbilical vein endothelial cell line, HUVEC-c) and human cancer cell lines (human mammary gland cell line, Hs578T; human pancreatic duct epithelioid carcinoma cell line, PANC-1). To assess the effect of gliclazide the cells were pre-treated with the drug. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay was employed to measure the impact of gliclazide on cell viability. Generation of reactive oxygen species, mitochondrial membrane potential (∆Ψm), and intracellular Ca2+ concentration [Ca2+] were monitored. Furthermore, the morphological changes associated with apoptosis were determined using double staining with Hoechst 33258-propidium iodide (PI). Gliclazide protects the tested cells from H2O2-induced cell death most likely throughout the inhibition of ROS production. Moreover, the drug restored loss of ΔΨm and diminished intracellular [Ca2+] evoked by H2O2. Double staining with Hoechst 33258-PI revealed that pre-treatment with gliclazide diminished the number of apoptotic cells. Our findings indicate that gliclazide may protect both normal and cancer human cells against apoptosis induced by H2O2. It appears that the anti-apoptotic effect of the drug is most likely associated with reduction of oxidative stress
The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model
Tumour drug-resistant ABCB1 gene expression is regulated at the chromatin level through epigenetic mechanisms. We examined the effects of the histone deacetylase inhibitor trichostatin A (TSA) on ABCB1 gene expression in small cell lung carcinoma (SCLC) drug-sensitive (H69WT) or etoposide-resistant (H69VP) cells. We found that TSA induced an increase in ABCB1 expression in drug-sensitive cells, but strongly decreased it in drug-resistant cells. These up- and downregulations occurred at the transcriptional level. Protein synthesis inhibition reduced these modulations, but did not completely suppress them. Differential temporal patterns of histone acetylation were observed at the ABCB1 promoter: increase in H4 acetylation in both cell lines, but different H3 acetylation with a progressive increase in H69WT cells but a transient one in H69VP cells. ABCB1 regulations were not related with the methylation status of the promoter −50GC, −110GC, and Inr sites, and did not result in further changes to these methylation profiles. Trichostatin A treatment did not modify MBD1 binding to the ABCB1 promoter and similarly increased PCAF binding in both H69 cell lines. Our results suggest that in H69 drug-resistant SCLC cell line TSA induces downregulation of ABCB1 expression through a transcriptional mechanism, independently of promoter methylation, and MBD1 or PCAF recruitment
The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer
This study was supported by financial support from the University of Edinburgh/China Scholarship Council joint Scholarship Scheme. We are also grateful to support from the Scottish Funding Council.Chromatin undergoes structural changes in response to extracellular and environmental signals. We observed changes in nuclear morphology in cancer tissue biopsied after chemotherapy and hypothesised that these DNA damage-induced changes are mediated by histone deacetylases (HDACs). Nuclear morphological changes in cell lines and a xenograft model (OV1002) weremeasured in response to platinum chemotherapy by image analysis of nuclear texture. HDAC2 expression increased in PEO1 cells treated with cisplatin at 24h, which was accompanied by increased expression of heterochromatin protein 1 (HP1). HDAC2 and HP1 expression were also increased after carboplatin treatment in the OV1002 carboplatin-sensitive xenograft model but notin the insensitive HOX424 model. Expression of DNA damage response pathways (pBRCA1, γH2AX, pATM, pATR) showed time-dependent changes after cisplatin treatment. HDAC2 knockdown by siRNA reduced HP1 expression, induced DNA double strand breaks (DSB) measured by γH2AX, and interfered with the activation of DNA damage responses induced by cisplatin. Furthermore, HDAC2depletion affected γH2AX foci formation, cell cycle distribution, and apoptosis triggered by cisplatin and was additive to the inhibitory effect of cisplatin in cell lines. By inhibiting HDAC2 expression, reversible alterations in chromatin patterns during cisplatin treatment were observed. These results demonstrate quantifiable alterations in nuclear morphology after chemotherapy and implicateHDAC2 in higher-order chromatin changes and cellular DNA damage responses in ovarian cancer cells in vitro and in vivo.Publisher PDFPeer reviewe
Bile acid effects are mediated by ATP release and purinergic signalling in exocrine pancreatic cells
Clinical applications of image cytometry to human tumour analysis
Image cytometry (ICM) is widely applied to the automated screening, the detection, the diagnosis, the classification, the prognosis and the therapeutic followup of different types of cancers (breast, bladder, cervix,. . .). This review describes the analysis methods and the applications of nuclear image analysis, the determination of DNA content and the analysis of morphometry and of nuclear texture. DNA content analysis can contribute to a prognostic information in addition to other prognostic factors for breast, renal and prostate cancers. For ovarian cancer, aneuploidy seems to be related to prognosis. Bladder tumours with DNA aneuploidy were frequently of high malignancy while ploidy was significantly correlated to relapse risk. For digestive cancers, patients presenting DNA diploid tumours show a better survival than patients with aneuploid ones. Morphometry seems to be a more important criterion than other conventional prognostic factors of invasive breast and digestive carcinomas. A differential diagnosis between normal and neoplastic thyroids is more precise when based on a quantitative evaluation of texture associated to morphometry. Textural parameters permit the discrimination of two populations of patients having a different prognosis and could thus be an aid for prognosis in prostatic cancers. Morphonuclear parameters contribute to separate low and high grade bladder carcinomas. Although ICM was frequently reported, results from the reported examples were not always obvious. In conclusion, the measurements obtained with ICM could be helpful for a decision in several cancers but could not be a substitute for the classical approach of the pathologist
Le journal Le Devoir : cas de politique générale d'entreprise
L'analyse de la politique générale du quotidien Le Devoir est le sujet de ce mémoire. Celui-ci se présente sous la forme d'un cas. Cette présentation, peu conventionnelle, a été adoptée en accord avec monsieur Roger Miller, alors directeur du programme de maîtrise en administration. Les raisons en sont les suivantes : 1. Devant enseigner la gestion, à l'issue de ses études à la Faculté d'administration, l'auteur de ce mémoire était appelé à privilégier cet incomparable instrument pédagogique qu'est l'étude de cas : au-delà d'une réflexion approfondie sur la méthode, la rédaction d'un cas s'appliquant au niveau le plus élevé d'une organisation constituait à ses yeux une étape indispensable. 2. Monsieur Miller, dans le cadre du cours de Politique d'entreprise (Business Policy) qu'il donnait à la Faculté, souhaitait disposer de cas se rapportant au contexte québécois. 3. Enfin, il paraissait particulièrement intéressant de faire ressortir l'influence des facteurs personnels dans la définition et la mise en oeuvre de la politique de Compagnie. Or la présentation de l'étude sous la forme d'un cas permettrait de rapporter de la manière la plus impersonnelle les différentes opinions exprimées à ce sujet par les responsables de l'entreprise; le rapprochement avec les autres paramètres de la gestion n'en serait que plus significatif. [...
Le journal Le Devoir : cas de politique générale d'entreprise
L'analyse de la politique générale du quotidien Le Devoir est le sujet de ce mémoire. Celui-ci se présente sous la forme d'un cas. Cette présentation, peu conventionnelle, a été adoptée en accord avec monsieur Roger Miller, alors directeur du programme de maîtrise en administration. Les raisons en sont les suivantes : 1. Devant enseigner la gestion, à l'issue de ses études à la Faculté d'administration, l'auteur de ce mémoire était appelé à privilégier cet incomparable instrument pédagogique qu'est l'étude de cas : au-delà d'une réflexion approfondie sur la méthode, la rédaction d'un cas s'appliquant au niveau le plus élevé d'une organisation constituait à ses yeux une étape indispensable. 2. Monsieur Miller, dans le cadre du cours de Politique d'entreprise (Business Policy) qu'il donnait à la Faculté, souhaitait disposer de cas se rapportant au contexte québécois. 3. Enfin, il paraissait particulièrement intéressant de faire ressortir l'influence des facteurs personnels dans la définition et la mise en oeuvre de la politique de Compagnie. Or la présentation de l'étude sous la forme d'un cas permettrait de rapporter de la manière la plus impersonnelle les différentes opinions exprimées à ce sujet par les responsables de l'entreprise; le rapprochement avec les autres paramètres de la gestion n'en serait que plus significatif. [...
Nouvelles approches thérapeutiques de la leucémie lymphoïde chronique
REIMS-BU Santé (514542104) / SudocSudocFranceF
- …