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Dual Mechanism (dual + mechanism)
Selected AbstractsDual Mechanism of Intercellular Communication in HOBIT Osteoblastic Cells: A Role for Gap-Junctional HemichannelsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2001Milena Romanello Abstract Intercellular communication allows tissue coordination of cell metabolism and sensitivity to extracellular stimuli. Paracrine stimulation and cell-to-cell coupling through gap junctions induce the formation of complex cellular networks, which favors the intercellular exchange of nutrients and second messengers. Intercellular Ca2+ signaling was investigated in human osteoblast-like initial transfectant (HOBIT) cells, a human osteoblastic cell line in which cells retain most of the osteoblastic differentiation markers. HOBIT cells express connexin43 (Cx43) clustered at the cell-to-cell boundary and display functional intercellular coupling as assessed by the intercellular transfer of Lucifer yellow. Mechanical stimulation of a single cell induced a wave of increased Ca2+ that was radially propagated to surrounding cells. Treatment of cells with thapsigargin blocked mechanically induced signal propagation. Intercellular Ca2+ spreading and dye transfer were inhibited by 18,-glycyrrhetinic acid (18-GA), showing the involvement of gap junctions in signal propagation. Pretreatment of cells with suramin or with apyrase decreased the extent of wave propagation, suggesting that ATP-mediated paracrine stimulation contribute to cell-to-cell signaling. The functional expression of gap-junctional hemichannels was evidenced in experiments of Mn2+ quenching, extracellular dye uptake, and intracellular Ca2+ release, activated by uptake of inositol 1,4,5-trisphosphate (InsP3) from the external medium. Gap-junctional hemichannels were activated by low extracellular Ca2+ concentrations and inhibited by 18-GA. A role for Cx hemichannels in adenosine triphosphate (ATP) release and paracrine stimulation is suggested. [source] Dual mechanisms governing muscle cell death in tadpole tail during amphibian metamorphosisDEVELOPMENTAL DYNAMICS, Issue 2 2003Keisuke Nakajima Abstract The tadpole tail, which is twice as long as the body, is induced to resorb completely by thyroid hormone within several days during the anuran metamorphosis. To investigate the underlying mechanism, we undertook two approaches. First, we examined the effect of dominant-negative thyroid hormone receptor (DNTR) on muscle cell death in vitro. The overexpression of DNTR suppressed the death of a tail-derived myoblastic cell line induced by thyroid hormone. Second, tadpole tails were injected with a reporter gene and the DNTR expression construct, and the reporter gene expression in muscle cells was followed during the spontaneous metamorphosis. DNTR overexpression inhibited a decrease of the reporter gene expression that began at stage 57 in the control tadpoles but only delayed massive muscle cell death at stage 63 when tails shrink very rapidly. Some remained even a few weeks after the metamorphosis, although most DNTR-overexpressing cells died by the end of the metamorphosis. These results led us to propose that thyroid hormone induces the suicide of muscle cells (the cell-autonomous death) in the tail between stage 57 and 62 and that both the murder and suicide mechanisms execute muscle cell death in stage 62,64 to remove muscle promptly and completely. Developmental Dynamics 227:246,255, 2003. © 2003 Wiley-Liss, Inc. [source] Bimatoprost, a novel efficacious ocular hypotensive drug now recognized as a member of a new class of agents called prostamidesDRUG DEVELOPMENT RESEARCH, Issue 4 2007Robert M. Burk Pursuit of a new FP-agonist prodrug led to the identification of an interesting series of neutral C1-substituted prostaglandin F2, analogues. Although these initial analogues were devoid of any inherent pharmacological activity at the FP-receptor, two compounds AGN-190910 and AGN-191129, were found to have pronounced effects in lowering intraocular pressure (IOP) in normotensive dogs and monkeys. The cat iris sphincter assay was quickly developed as a primary screen for these analogues, leading to rapid identification of AGN-192024 (17-phenyl PGF2, ethyl amide, bimatoprost). While bimatoprost is structurally similar to naturally occurring mammalian hormones of the prostanoid family, surprisingly it demonstrates no significant activity at any of the known prostanoid receptors. Furthermore, results of considerable additional pharmacological studies provide evidence that it may indeed act through a unique receptor yet to be identified. The effect of Bimatoprost on lowering IOP has also been found to be unique in comparison to prostanoids. Bimatoprost reduces human IOP by increasing aqueous humor outflow through a dual mechanism of action where it improves both pressure-dependent and pressure-independent outflow pathways. First introduced to the market in 2002, bimatoprost is currently the most potent single therapy available for control of ocular hypertension. Drug Dev Res 68:147,155, 2007. ©2007 Wiley-Liss, Inc. [source] Oxidation of substituted benzaldehydes by quinolinium chlorochromate: A structure and solvent dependent kinetic studyINTERNATIONAL JOURNAL OF CHEMICAL KINETICS, Issue 4 2003G. Fatima Jeyanthi The kinetics of oxidation of several para-substituted benzaldehydes by quinolinium chlorochromate was studied under pseudo-first-order conditions in different (hydrogen bond donor and hydrogen bond acceptor) neat organic solvents. The operation of nonspecific and specific solvent,solvent,solute interactions was explored by correlating the rate data with solvent parameters through correlation analysis. Both electron-releasing and electron-withdrawing substituents enhanced the rate and the Hammett plot showed a break in the reactivity order indicating applicability of dual mechanism. An explanation in conformity with structure and solvent effects on reactivity has been proposed. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 154,158, 2003 [source] Galantamine: a randomized, double-blind, dose comparison in patients with Alzheimer's disease,INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 9 2001D. Wilkinson Abstract Objectives To investigate whether Galantamine significantly improves the core symptoms of Alzheimer's disease (AD). Background Galantamine is a reversible, competitive, selective inhibitor of acetylcholinesterase (AChE) that also allosterically modulates nicotinic acetylcholine receptors. This dual mechanism of action provided the rationale for a phase II trial of galantamine in AD. Method A multicentre, randomized, parallel, double-blind, placebo-controlled trial was carried out to evaluate the efficacy and tolerability of galantamine 18, 24 and 36,mg/day administered for 3 months in 285 patients with mild-to-moderate probable AD. The primary outcome measure was the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog); secondary outcome measures were the Clinical Global Impression of Change (CGIC) and the Progressive Deterioration Scale (PDS). Results Patients treated with galantamine 24,mg/day had a significantly better outcome than placebo on ADAS-cog; the treatment difference was 3 points on the intention-to-treat (ITT) analysis ( p,=,0.01) and 4.2 points on per protocol analysis ( p,=,0.001). Per protocol analysis showed that galantamine had a significantly better outcome than placebo on PDS ( 24-mg/day dose, p,<,0.05) and CGIC (36-mg/day dose, p,<,0.05). Galantamine was well tolerated at the lower doses of 18 and 24,mg/day where it produced mild, transient effects typical of cholinomimetic agents. Conclusion This study shows that, relative to placebo, galantamine significantly improves the core symptoms of Alzheimer's disease. Copyright © 2001 John Wiley & Sons, Ltd. [source] Effects of levosimendan on indocyanine green plasma disappearance rate and the gastric mucosal,arterial pCO2 gradient in abdominal aortic aneurysm surgeryACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 6 2008H. LEPPIKANGAS Background: Levosimendan has a dual mechanism of action: it improves myocardial contractility and causes vasodilatation without increasing myocardial oxygen demand. In a laboratory setting, it selectively increases gastric mucosal oxygenation in particular and splanchnic perfusion in general. The aim of our study was to describe the effects of levosimendan on systemic and splanchnic circulation during and after abdominal aortic surgery. Methods: Twenty abdominal aortic aneurysm surgery patients were randomized to receive either levosimendan (n=10) or placebo (n=10) in a double-blinded manner. Both the mode of anaesthesia and the surgical procedures were performed according to the local guidelines. Automatic gas tonometry was used to measure the gastric mucosal partial pressure of carbon dioxide. Systemic indocyanine green clearance plasma disappearance rate (ICG-PDR) was used to estimate the total splanchnic blood flow. Results: The immediate post-operative recovery was uneventful in the two groups with a comparable, overnight length of stay in the intensive care unit. Cumulative doses of additional vasoactive drugs were comparable between the groups, with a tendency towards a higher cumulative dose of noradrenaline in the levosimendan group. After aortic clamping, the cardiac index was higher [4(3.8,4.7) l/min/m2 vs. 2.6(2.3,3.6) l/min/m2; P<0.05] and the gastric mucosal,arterial pCO2 gradient was lower in levosimendan-treated patients [0.9(0.6,1.2) kPa vs. 1.7(1.2,2.1) kPa; (P<0.05)]. However, the total splanchnic blood flow, estimated by ICG-PDR, was comparable [29(21,29)% vs. 20(19,25)%; NS]. Organ dysfunction scores (sequential organ dysfunction assessment) were similar between the groups on the fifth post-operative day. Conclusion: Levosimendan favours gastric perfusion but appears not to have a major effect on total splanchnic perfusion in patients undergoing an elective aortic aneurysm operation. [source] The combination of the antitumoural pyridyl cyanoguanidine CHS 828 and etoposide in vitro,from cytotoxic synergy to complete inhibition of apoptosisBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2002P Martinsson The present study was aimed at elucidating the apoptosis inhibitory properties of the cyanoguanidine CHS 828. CHS 828 exhibits impressive cytotoxic activity in vitro and in vivo. Apoptosis is not its main mode of cytotoxic effect, and we have previously proposed a dual mechanism, where CHS 828 inhibits its own cell death pathways. Etoposide on the other hand, is a well-established anticancer agent with documented effect in a number of malignancies, induces apoptosis through extensively studied caspase dependent pathways. Here we studied the combined effect of the two drugs in the human lymphoma cell line U-937 GTB. Cytotoxicity was evaluated as total viability measured by the fluorometric microculture cytotoxicity assay (FMCA). Caspase activity was assessed by colorimetric detection of specific cleavage products for caspases 3, 8 and 9, respectively. Morphology was evaluated in May-Grünwald/Giemsa stained preparations. Interaction analysis based on FMCA results of simple combination exposure revealed impressive synergistic effect on cell kill. Detailed investigations of the kinetics involved showed that short pre-exposure (0,12 h) to CHS 828 enhanced caspase activation by etoposide, while longer pre-exposure (18,48 h) inhibited both caspase activation and apoptotic morphology otherwise induced by etoposide. The present results support the theory that CHS 828 block specific cell death pathways. The synergistic results are promising for future combination trials in animals, however, different dosing schedules should be considered, in order to investigate whether the above findings translate into the in vivo setting. British Journal of Pharmacology (2002) 137, 568,573. doi:10.1038/sj.bjp.0704888 [source] | ||||||||||