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At least 145 records · Page 8Linked to original sources
PubMed1990

Molecular pharmacological aspects of antiarrhythmic activity, II: Interaction of class I compounds with calmodulin.

We have tested the calmodulin (CaM) inhibitory potency of class I antiarrhythmics in the phosphodiesterase (PDE) assay. The lipophilicity of the test compounds has been quantified by two experimental (log P, RM) and two calculative (sigma f, C log P) procedures. Five antiarrhythmics (asocainol, aprindine, lorcainide, propafenone, and ethmozine) exhibit IC50 values less than 250 microM for the inhibition of the CaM-stimulated PDE activity. Lipophilicity seems to be a prime, but not the sole descriptor of CaM inhibitory potency. The functional means of CaM inhibition by the test compounds for their antiarrhythmic properties remains to be clarified in further investigations.

Anti-Arrhythmia Agents↗
PubMed1987

Experimental conditions influence [3H]-dihydroalprenolol binding characteristics to living HeLa cells due to morphological changes: a warning.

Harvesting of plated growing HeLa cells, followed by incubation of these cells without any addition at 37 degrees C was found to cause changes in the cell shape. This phenomenon is accompanied by a diminished binding of the beta-adrenergic antagonist [3H]-dihydroalprenolol and the alpha-adrenergic antagonist phentolamine to a binding compartment not representing beta-adrenergic receptors. These binding sites have a high affinity for hydrophobic agents and most probably represent lipophilic structures in the cellular membrane. Changes in the cell shape obviously cause alterations in the physical properties of the plasma membrane. This might lead to misinterpretations of the results from experiments in which the redistribution of beta-adrenergic receptors is followed during incubation with agonists, as receptor occupation with subsequent receptor redistribution is possibly accompanied by effects on the membrane microviscosity. It is concluded that investigations performed in order to follow physiological events like receptor redistribution and desensitization processes, may be obfuscated by changes in the normal physical state of the living cells.

Adrenergic beta-Agonists↗
PubMed2006

The role of constitutively active signal transducer and activator of transcription 3 in ovarian tumorigenesis and prognosis.

BACKGROUND: Signal transducer and activator of transcription 3 (Stat3), which is a latent transcription factor that participates in the transcriptional activation of apoptosis and cell cycle progression, has been implicated as an oncogene in several neoplastic diseases. However, the specific role of Stat3 in ovarian carcinogenesis remains poorly understood. The objectives of the current study were to examine the effect of Stat3 activation on the phenotypic transformation of an immortalized, nontumorigenic ovarian epithelial cell line and to evaluate the expression of tyrosine-activated Stat3 (pStat3) in tissue microarrays from 303 ovarian carcinomas to determine its prognostic relevance and to correlate its expression with several upstream oncogenes of Stat3 and with the oncogenes involved in apoptosis and proliferation. METHODS: Overexpression of pStat3 was weakly tumorigenic and produced measurable tumors in mice in 1 of 3 clones. Using tissue microarrays from a large group of patients with primary ovarian carcinoma, the expression of pStat3 was correlated with the expression of growth factor receptors (HER-2/neu and epidermal growth factor receptor [EGFR]), interleukin 6, and the proliferation and apoptosis markers Ki-67, Bcl-2, and Bcl-xL and with clinicopathologic variables and patient survival. RESULTS: High pStat3 expression in the tumor tissue microarray was associated with high levels of HER-2/neu, EGFR, and Ki-67. No correlation was observed between overall pStat3 levels and any other clinicopathologic variables tested. High nuclear expression of pStat3 (>10% of positive-stained cells) was linked with poor overall survival. CONCLUSIONS: The activation and translocation of pStat3 to the nucleus are frequent events in ovarian carcinoma that are associated with a poor prognosis. Further studies are needed to elucidate the mechanism of activation of Stat3, its effects on downstream targets, and its role in the neoplastic transformation of epithelial ovarian cells.

Animals↗
PubMed1993

Growth regulation and transformation of ovarian epithelium.

The discovery of peptide growth factors and cancer-causing genes (oncogenes and tumor-suppressor genes) has provided us with the exciting opportunity to begin to understand the molecular pathology of human ovarian cancer. Activation of several genes, including HER-2/neu, myc, ras, and p53 have been described in some ovarian cancers. In addition, some protooncogenes such as the epidermal growth factor receptor (erbB) and the M-CSF receptor (fms) are expressed along with the respective ligands (peptide growth factors) in some ovarian cancers. Although the studies reviewed in this paper represent a promising beginning, we remain far from a comprehensive understanding of growth regulation and transformation of human ovarian epithelium.

Cell Division↗
PubMed1993

Cell growth regulation in epithelial ovarian cancer.

BACKGROUND: As in the case of other epithelial neoplasms, most ovarian cancers arise from single clones of cells that have undergone multiple genetic alterations. A comparison of normal and malignant ovarian epithelium has identified several differences in growth regulation by peptide growth factors, protooncogenes, and tumor suppressor genes. METHODS: Recent articles and abstracts have been reviewed. RESULTS: The malignant ovarian epithelial phenotype has been associated with (1) autocrine growth stimulation by transforming growth factor-alpha, (2) loss of autocrine growth inhibition by transforming growth factor-beta, (3) mutation or amplification of ras in 2-12% of cases, (4) amplification of myc in 23% of specimens, (5) expression of fms in 56% of cases with potential autocrine stimulation by macrophage colony stimulating factor, (6) paracrine stimulation by macrophage products including interleukin-1, interleukin-6 and tumor necrosis factor, (7) overexpression of c-erbB-2 (HER-2/neu) in 30% of cases, and (8) mutation with consequent overexpression of p53 in 50% of advanced ovarian cancers. A poor clinical prognosis is associated with expression or overexpression of the epidermal growth factor receptor, fms, and HER-2/neu. Antibodies against the extracellular domain of the HER-2/neu gene product p185 inhibit the growth of tumor cells that overexpress HER-2/neu and are associated with marked decreases in diacylglycerol levels. The intracellular kinase domain is required for growth inhibition. Antibodies that inhibit growth stimulate phosphorylation of intracellular substrates. Ricin A chain monoclonal antibody conjugates that react with p185 also inhibit the growth of tumor cells that overexpress p185. The intracellular kinase region is not required for immunotoxin-mediated killing. Coexpression of HER-2/neu and the epidermal growth factor receptor has been observed in 65% of epithelial ovarian cancers and in a limited number of normal tissue from a fraction of donors. CONCLUSIONS: Multiple alterations in growth factors, protooncogenes and growth factors have been detected in different epithelial ovarian cancers. Inappropriate signalling from receptor tyrosine kinases may be particularly important for ovarian oncogenesis. Drugs that affect tyrosine kinase and phosphatase activity deserve attention as potential therapeutic agents for ovarian cancer. The extracellular domains of the HER-2/neu gene product p185 and the epidermal growth factor receptor may provide useful targets for serotherapy.

Carcinoma↗
PubMed2002

Functional aspects of dopamine metabolism in the putative prefrontal cortex analogue and striatum of pigeons (Columba livia).

Dopamine (DA) in mammalian associative structures, such as the prefrontal cortex (PFC), plays a prominent role in learning and memory processes, and its homeostasis differs from that of DA in the striatum, a sensorimotor region. The neostriatum caudolaterale (NCL) of birds resembles the mammalian PFC according to connectional, electrophysiological, and behavioral data. In the present study, DA regulation in the associative NCL and the striatal lobus parolfactorius (LPO) of pigeons was compared to uncover possible differences corresponding to those between mammalian PFC and striatum. Extracellular levels of DA and its metabolites (homovanillic acid [HVA], dihydroxyphenylacetic acid [DOPAC]) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were investigated by in vivo microdialysis of urethane-anesthetized pigeons under basal conditions and after systemic administration of D-amphetamine. DA was reliably determined only in LPO dialysates, and DA metabolite levels were significantly higher in LPO than in NCL. The HVA/DOPAC ratio, indicating extracellular lifetime of DA, was more than twice as high in NCL than in LPO dialysates. After amphetamine, DA increased in LPO while still being undetectable in NCL, and DA metabolites decreased in both regions. 5-HIAA slightly decreased in NCL dialysates. Amphetamine effects were delayed in NCL compared with the striatum. In conclusion, effects of amphetamine on the pigeon's ascending monoamine systems resemble those found in mammals, suggesting similar regulatory properties. The neurochemical differences between NCL and LPO parallel those between associative regions, such as PFC and dorsal striatum in mammals. They may reflect weaker regulation of extracellular DA, favoring DAergic volume transmission, in associative than striatal forebrain regions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1979

Surface Ig on rabbit lymphocytes. Rabbit B and T cells are distinct populations.

Rabbit peripheral blood lymphocytes (PBL) were analyzed by immunofluorescence using anti-T cell conjugates and anti-Fab, anti-a1 allotype, anti-IgM and anti-IgA conjugates. In addition, T cells were demonstrated by rosetting with papain-treated homologous erythrocytes. Control experiments, using acid treatment and incubation at 37 degrees C for 18 h after or without pronase treatment, revealed the endogenous origin of all surface determinants tested. A good correlation was found between results obtained with the two anti-T cell conjugates used and the T rosette test on PBL and on lymphoid cells isolated from various organs. In lymphocytes isolated from peripheral blood and from various lymphoid organs, the percentages of T and B cells were respectively 45 and 38 for PBL, 10 and 46 for bone marrow, 27 and 31 for appendix, 40 and 45 for spleen, 42 and 46 for Peyer's patches, 96 and 0.3 for thymus and 70 and 16 for peripheral lymph nodes. The percentage of "null" cells in lymphocyte populations derived from bone marrow and appendix is rather high. The final percentages of T and B cells in rabbit PBL depend to a significant extent on the method of isolation, especially isolation by Ficoll-Hypaque centrifugation results in a depletion of T cells. Moreover, a rather impure lymphoid cell suspension is obtained. In double incubation experiments, T cells (as defined by T cell antigen(s) or rosette formation) and B cells (Fab-bearing cells) were entirely different subpopulations. Allotypes of the a locus could not be detected on the surface of T cells. The results are discussed with respect to genetic coding of antigen receptors on B and T cells.

Animals↗
PubMed1980

Fc receptors on rabbit lymphocytes. Existence of receptors for IgG antibody complexed with antigen; conditions for its detection.

The presence of Fc receptors (FcR) on rabbit peripheral blood leukocytes is demonstrated using rosette formation with an ox erythrocyte-antibody (EoxA) complex. The receptor is specific for the Fc fragment of IgG (neither IgM nor F (ab')2 anti-Eox mediates rosette formation) that is antigen-bound (aggregated rabbit IgG inhibits the rosette formation only transiently). The receptor is species-specific: guinea pig IgG/Eox, goat IgG/Eox and sheep IgG/Eox complexes do not show rosette formation, and goat IgG aggregates do not inhibit rosette formation. The origin of the target erythrocytes is of importance. Sheep erythrocytes are not useful, and within Eox large differences between donors were found. Rosette formation was only inhibited by pretreatment of the rosette-forming cells with homologous immune complexes, whereas the size of the antigen greatly influenced the degree of inhibition. The rabbit FcR is pronase-resistant, unlike the human and murine RcR. The interaction of IgG and the FcR is not inhibited by isolated C gamma 3 domains. Further evidence for the requirement of the whole Fc region was obtained in experiments where inhibition of the rosette formation was observed using antisera directed to the C gamma 3 and the C gamma 2 domain, respectively. Anti-Fab antiserum did not inhibit rosette formation. Results are discussed in relation to the mechanism of allotypic suppression.

Animals↗
PubMed1980

Fc receptors on rabbit lymphocytes. Identification and organ distribution of rosette-forming cells; cocapping with surface immunoglobulin.

Fc receptor (FcR)-bearing cells were demonstrated using ox erythrocytes coated with homologous IgG-type antibodies (EA gamma) in rabbit peripheral blood leukocytes (PBL) and in various lymphoid organs. Discrimination of the rosette-forming cells (RFC) is carried out after prior ingestion of tetramethylrhodamine isothiocyanate-labeled latex particles and in transmission electron microscopic studies. Most of the nonlymphoid cells (5-10%) in PBL and spleen cell suspensions expose FcR. These nonlymphoid cells are almost absent in other lymphoid organs, except in bone marrow. The average percentage of cells rosetting with IgG-sensitized erythrocytes (EA gamma RFC) in lymphoid cell preparations of the various tissues was as follows: PBL 25%, bone marrow 65%, appendix 37%, spleen 40%, Peyer's patches 44%, thymus 2% and peripheral lymph node 27%. The nature of FcR-bearing PBL was further studied using F (ab')2 anti-IgM, anti-IgA or anti-T cell conjugates. About half of the population of B cells, bearing IgM or IgA express FcR. Moreover, about 80% of the RFC are found within the B cell population. Only a few T cells were found rosetting with EA gamma suggesting that most of the non-B lymphoid RFC are "null" cells. In different lymphoid organs, the percentages of EA gamma RFC and B cells are comparable but not identical A greater part of the EA gamma RFC also expresses the receptor for the third component of complement. After capping of membrane IgM determinants, FcR is located in the same cap on the majority (60%) of the FcR-positive IgM-capped cells.

Animals↗
PubMed1984

Cellular expression of idiotopes defined by monoclonal antibodies.

Monoclonal anti-idiotype (Id) antibodies with specificities for determinants related to the antigen-binding sites of 3 BALB/c myeloma proteins, MOPC-460, HOPC-8 and J558, were used to study Id expression on murine lymphocytes. The monoclonal antibodies were shown to react only with Id structures associated with immunoglobulin on B cells. None of these 3 Id nor a VH Id, detected by a monoclonal antibody made against HOPC-8 heavy chain, were found on T cells. These Id were detected on splenic B cells in neonatal mice; the frequencies in normal, nude and germ-free mice were similar: MOPC-460 Id+: 1.05 +/- 1.7/10(4) spleen cells, HOPC-8 Id+: 1.45 +/- 1.2/10(4) and J558: 0.35 +/- 0.6/10(4). Almost all Id+ cells bore surface IgM, a few expressed surface IgG. MOPC-460 Id+ IgG+ cells were mainly gamma 2a+ or gamma 2b+, whereas J558 and HOPC-8 Id+ IgG+ cells were gamma 3+.

Aging↗
PubMed2005

Immunoregulatory effects of adenosine 5'-triphosphate on cytokine release from stimulated whole blood.

In vitro studies suggest that extracellular nucleotides and nucleosides may be important regulators of inflammatory and immune responses. Most studies with adenosine 5'-triphosphate (ATP) have been performed in cell lines, which are remote from the human situation. The purpose of the present study was to determine the effects of ATP on TNF-alpha, IL-6 and IL-10 release in stimulated whole blood. Blood samples were drawn from healthy volunteers and incubated with ATP and lipopolysaccharide (LPS) + phytohemagglutinin (PHA) for 24 h. Contrary to expectations, ATP at 100 microM and 300 microM induced a reduction in TNF-alpha secretion by 32+/-8% (mean +/- SEM) and 65+/-4%, respectively. Furthermore, these ATP concentrations induced an increase in IL-10 secretion by 48+/-5% and 62+/-7% in whole blood. The ATP analogue adenosine 5'-O-(3-thiotriphosphate) (ATP-gamma-S) and adenosine 5'-diphosphate (ADP) also inhibited TNF-alpha release, but only ADP showed a stimulatory effect on IL-10. Co-treatment with adenosine deaminase did not reverse the ATP effect on TNF-alpha and IL-10. These results show, for the first time, that ATP inhibits the inflammatory response in stimulated whole blood as indicated by inhibition of TNF-alpha and stimulation of IL-10 release and that this effect is predominantly mediated by ATP and not by adenosine.

Adenosine Triphosphate↗
PubMed2003

Dorsal hippocampus and classical fear conditioning to tone and context in rats: effects of local NMDA-receptor blockade and stimulation.

Consistent with the importance of the hippocampus in learning more complex stimulus relations, but not in simple associative learning, the dorsal hippocampus has commonly been implicated in classical fear conditioning to context, but not to discrete stimuli, such as a tone. In particular, a specific and central role in contextual fear conditioning has been attributed to mechanisms mediated by dorsal hippocampal N-methyl-D-aspartate (NMDA)-type glutamate receptors. The present study characterized the effects of blockade or tonic stimulation of dorsal hippocampal NMDA receptors by bilateral local infusion of the noncompetitive NMDA receptor antagonist MK-801 (dizocilpine maleate; 6.25 microg/side) or of NMDA (0.7 microg/side), respectively, on classical fear conditioning to tone and context in Wistar rats. Freezing was used to measure conditioned fear. Regardless of whether conditioning was conducted with tone-shock pairings or unsignaled footshocks (background or foreground contextual conditioning), both NMDA and MK-801 infusion before conditioning resulted in reduced freezing during subsequent exposure to the conditioning context. Freezing during subsequent tone presentation in a new context, normally resulting from conditioning with tone-shock pairings, was not impaired by MK-801 but was strongly reduced by NMDA infusion before conditioning; this freezing was also reduced by NMDA infusion before tone presentation (in an experiment involving NMDA infusions before conditioning and subsequent tone presentation to assess the role of state-dependent learning). It was assessed whether unspecific infusion effects (altered sensorimotor functions, state dependency) or infusion-induced dorsal hippocampal damage contributed to the observed reductions in conditioned freezing. Our data suggest that formation of fear conditioning to context, but not tone, requires NMDA receptor-mediated mechanisms in the dorsal hippocampus. As indicated by the effects of NMDA, some dorsal hippocampal processes may also contribute to fear conditioning to tone. The role of the dorsal hippocampus and local NMDA receptor-mediated processes in fear conditioning to tone and context is discussed in comparison with ventral hippocampal processes.

Acoustic Stimulation↗
PubMed2006

4-HPR modulates gene expression in ovarian cells.

Ovarian cancer has a high rate of recurrence and subsequent mortality following chemotherapy despite intense efforts to improve treatment outcomes. Recent trials have suggested that retinoids, especially 4-(N-hydroxyphenyl) retinamide (4-HPR), play an important role as a chemopreventive agent and are currently being used in clinical trials for ovarian cancer chemoprevention as well as treatment. This study examines the mechanism of its activity in premalignant and cancer cells. We investigated the modulation of gene expression by 4-HPR in immortalized ovarian surface epithelial (IOSE) cells and ovarian cancer (OVCA433) cells with DNA microarray. Real time RT-PCR and western blotting were used to confirm the microarray results and metabolic changes were examined with optical fluorescence spectroscopy. 4-HPR resulted in an up-regulation of expression of proapoptotic genes and mitochondrial uncoupling protein in OVCA433 cells and modulation of the RXR receptors in IOSE cells, and down-regulation of mutant BRCA genes in both IOSE and OVCA433 cells. 4-HPR had a larger effect on the redox in the 433 cells compared to IOSE. These findings suggest that 4-HPR acts through different mechanisms in premalignant ovarian surface cells and cancer cells, with a preventive effect in premalignant cells and a treatment effect in cancer cells.

Anticarcinogenic Agents↗
PubMed1983

Expression of major histocompatibility antigens and nature of inflammatory cellular infiltrate in ovarian neoplasms.

Expression of histocompatibility antigens and the intensity of inflammatory cellular infiltrate were evaluated in frozen tissue sections from 70 human ovarian tumors and six normal ovaries using monoclonal antibodies and an avidin-biotin immunoperoxidase technique. In the normal human ovary, surface epithelial cells, mature granulosa cells and lutein cells reacted with anti-HLA-A,B,C (HLA) and beta2-microglobulin antibodies but not with anti-Ia (Ia-like, HLA-DR). Stromal cells and granulosa cells of the primordial follicles did not react with any of the antibodies. Among the neoplasms examined, all benign epithelial tumors, 86% of borderline an 81% of malignant epithelial tumors reacted with anti-HLA and/or beta2-microglobulin antibodies. HLA-negative epithelial tumors were of serous or endometrioid types. Although Ia was not found in normal ovarian surface epithelium, the antigen could be detected in 44% of benign, and 43% of borderline and malignant epithelial ovarian tumors. Mononuclear cellular infiltrate was generally scarce in ovarian tumors and consisted mainly of T cells. Malignant epithelial tumors contained significantly more T cells than did benign tumors. More T cells were observed in HLA-positive ovarian tumors than in HLA-negative neoplasms, but the difference did not achieve statistical significance. No correlation could be found between Ia expression and the intensity of T-cell infiltrate. Significantly more T8 and Leu-3a-positive cells were found in the tumor stroma than amongst neoplastic cells. HNK-I-positive natural killer cells, OK-MI-positive macrophages and BI-positive B lymphocytes were rarely encountered either in the tumor stroma or between adjacent tumor cells.

Antibodies, Monoclonal↗