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Reduced Response (reduced + response)
Selected AbstractsEffects of angiotensin II blockade on inflammation-induced alterations of pharmacokinetics and pharmacodynamics of calcium channel blockersBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2008S Hanafy Background and purpose: Inflammation elevates plasma verapamil concentrations but diminishes pharmacological response. Angiotensin II is a pro-inflammatory mediator. We examined the effect of angiotensin II receptor blockade on the pharmacokinetics and pharmacodynamics of verapamil, as well as the binding properties and amounts of its target protein in calcium channels, in a rat model of inflammation. Experimental approach: We used 4 groups of male Sprague,Dawley rats (220,280 g): inflamed-placebo, inflamed-treated, control-placebo and control-treated. Inflammation as pre-adjuvant arthritis was induced by injecting Mycobacterium butyricum on day 0. From day 6 to 12, 30 mg kg,1 oral valsartan or placebo was administered twice daily. On day 12, a single oral dose of 25 mg kg,1 verapamil was administered and prolongation of the PR interval measured and plasma samples collected for verapamil and nor-verapamil analysis. The amounts of the target protein Cav1.2 subunit of L-type calcium channels in heart was measured by Western blotting and ligand binding with 3H-nitrendipine. Key results: Inflammation reduced effects of verapamil, although plasma drug concentrations were increased. This was associated with a reduction in ligand binding capacity and amount of the calcium channel target protein in heart extracts. Valsartan significantly reversed the down-regulating effect of inflammation on verapamil's effects on the PR interval, and the lower level of protein binding and the decreased target protein. Conclusions and implications: Reduced responses to calcium channel blockers in inflammatory conditions appeared to be due to a reduced amount of target protein that was reversed by the angiotensin II antagonist, valsartan. British Journal of Pharmacology (2008) 153, 90,99; doi:10.1038/sj.bjp.0707538; published online 29 October 2007 [source] ,3-Tubulin is induced by estradiol in human breast carcinoma cells through an estrogen-receptor dependent pathwayCYTOSKELETON, Issue 7 2009Jennifer Saussede-Aim Abstract Microtubules are involved in a variety of essential cell functions. Their role during mitosis has made them a target for anti-cancer drugs. However development of resistance has limited their use. It has been established that enhanced ,3-tubulin expression is correlated with reduced response to antimicrotubule agent-based chemotherapy or worse outcome in a variety of tumor settings. However little is known regarding the regulation of ,3-tubulin expression. We investigated the regulatory mechanisms of expression of ,3-tubulin in the MCF-7 cell line, a model of hormone-dependent breast cancer. Exposure of MCF-7 cells to estradiol was found to induce ,3-tubulin mRNA as well as ,3-tubulin protein expression. Conversely, we did not observe induction of ,3-tubulin mRNA by estradiol in MDA-MB-231 cells which are negative for the estrogen receptor (ER). In order to determine whether ,3-tubulin up-regulation is mediated through the ER pathway, MCF-7 cells were exposed to two ER modulators. Exposure to tamoxifen, a selective estrogen receptor modulator, completely abolished the ,3-tubulin mRNA induction due to estradiol in MCF-7 cells. This result was confirmed with fulvestrant, a pure antagonist of ER. These results demonstrate that the effect of estradiol on ,3-tubulin transcription is mediated through an ER dependent pathway. Cell Motil. Cytoskeleton 66:378,388, 2009. © 2009 Wiley-Liss, Inc. [source] Intravenous cocaine induced-activity and behavioural sensitization in norepinephrine-, but not dopamine-transporter knockout miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2002Andy N. Mead Abstract Previously, it was reported that both norepinephrine transporter (NET) and dopamine transporter (DAT) knockout (KO) mice were sensitive to the reinforcing effects of cocaine. However, assessing the locomotor-stimulant effects of cocaine in these subjects has proven difficult due to significant differences in their baseline activity compared to wild-type controls. The present studies were designed to clarify the role of NET and DAT in the stimulant effects of acute and repeated cocaine utilizing these knockout mice, and thereby assess the role of these substrates in the locomotor stimulant effects of cocaine. Mice were habituated to the test environment for sufficient time to ensure equal baselines at the time of cocaine administration. Mice then received cocaine (3,25 mg/kg) intravenously according to a within-session cumulative dose,response design. Cocaine dosing was repeated at 48-h intervals for four sessions to assess behavioural sensitization. NET-KO mice exhibited a reduced response to acute cocaine administration compared to wild-type (WT) controls. However, comparable sensitization developed in NET-KO and WT mice. The DAT-KO and DAT-heterozygote (HT) mice displayed no locomotor activation following either acute or repeated cocaine administration. These data suggest a role for the NET in the acute response to cocaine, but no involvement in sensitization to cocaine. In contrast, DAT appears to be necessary for both the acute locomotor response to cocaine and the subsequent development of sensitization. In addition to existing data concerning the reinforcing effects of cocaine in DAT-KO mice, these data suggest a dissociation between the reinforcing and locomotor stimulant effects of cocaine. [source] In vivo potentiation of human oestrogen receptor , by Cdk7-mediated phosphorylationGENES TO CELLS, Issue 10 2004Saya Ito Phosphorylation of the Ser118 residue in the N-terminal A/B domain of the human oestrogen receptor , (hER,) by mitogen-activated protein kinase (MAPK), stimulated via growth factor signalling pathways, is known to potentiate ER, ligand-induced transactivation function. Besides MAPK, cyclin dependent kinase 7 (Cdk7) in the TFIIH complex has also been found to potentiate hER, transactivation in vitro through Ser118 phosphorylation. To investigate an impact of Cdk7 on hER, transactivation in vivo, we assessed activity of hER, in a wild-type and cdk7 inactive mutant Drosophila that ectopically expressed hER, in the eye disc. Ectopic expression of the wild-type or mutant receptors, together with a green fluorescent protein (GFP) reporter gene, allowed us to demonstrate that hER, expressed in the fly tissues was transcriptionally functional and adequately responded to hER, ligands in the patterns similar to those observed in mammalian cells. Replacement of Ser118 with alanine in hER, (S118A mutant) significantly reduced the ligand-induced hER, transactivation function. Importantly, while in cdk7 inactive mutant Drosophila the wild-type hER, exhibited reduced response to the ligand; levels of transactivation by the hER, S118A mutant were not affected in these inactive cdk7 mutant flies. Furthermore, phosphorylation of hER, at Ser118 has been observed in vitro by both human and Drosophila Cdk7. Our findings demonstrate that Cdk7 is involved in regulation of the ligand-induced transactivation function of hER,in vivo via Ser118 phosphorylation. [source] Ageing and the neutrophil: no appetite for killing?IMMUNOLOGY, Issue 4 2000S. Butcher Summary In the armoury of the immune system developed to combat the various micro-organisms that could invade the host, the neutrophil forms the first line of defence against rapidly dividing bacteria and fungi. However, as humans age they become more susceptible to infection with these microbes and this has been ascribed to a decline in immune status, termed immune senescence. Here we summarize the literature specifically concerning the attenuation of neutrophil function with age and the possible mechanisms underlying their reduced response to infectious agents. [source] A quantitative study of epidermal Langerhans cells in cutaneous leishmaniasis caused by Leishmania tropicaINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 11 2004Simin Meymandi MD Objective, The purpose of this study was to characterize the number and distribution of epidermal Langerhans cells in different clinical forms of dry-type cutaneous leishmaniasis (CL). Methods, Sixteen cases of dry-type cutaneous leishmaniasis caused by Leishmania tropica were studied. These cases were classified clinically as five cases of acute leishmaniasis with indurated papules, nodules and plaques with central crust formation and duration < 2 years, six cases of lupoid leishmaniasis with characteristic papules around previous scars of cutaneous leishmaniasis with duration > 2 years, and five cases of chronic nonlupoid type with nonhealing lesions of duration > 2 years. Paraffin-embedded blocks were stained with hematoxylin and eosin (H&E) and stained immunohistochemically for CD1a. Results, The number of Langerhans cells per millimeter length of epidermis was increased in acute cases compared to chronic and lupoid cases. Conclusions, Lesions of acute leishmaniasis contain the greatest amounts of antigen for presentation, so Langerhans cells increase in number and in trafficking to present antigens derived from Leishman bodies to the cellular immune system. In chronic leishmaniasis, the Langerhans cell population is reduced, perhaps because of exhaustion of the source of Langerhans cells, or because of reduced response to modified antigen. [source] Subjective Response to Alcohol: A Critical Review of the LiteratureALCOHOLISM, Issue 3 2010Meghan E. Morean Background:, Subjective response to alcohol (SR), which reflects individual differences in sensitivity to the pharmacological effects of alcohol, may be an important endophenotype in understanding genetic influences on drinking behavior and alcohol use disorders (AUDs). SR predicts alcohol use and problems and has been found to differ by a range of established risk factors for the development of AUDs (e.g., family history of alcoholism). The exact pattern of SR associated with increased risk for alcohol problems, however, remains unclear. The Low Level of Response Model (LLR) suggests that high-risk individuals experience decreased sensitivity to the full range of alcohol effects, while the Differentiator Model (DM) asserts that high risks status is associated with increased sensitivity to alcohol's positive effects but decreased sensitivity to negative effects. Aims:, The current paper (1) reviews two prominent models of subjective response, (2) reviews extant laboratory-based research on subjective response, (3) highlights remaining gaps in our understanding and assessment of subjective response, and (4) encourages collaborative efforts to address these methodological and conceptual concerns. Methods:, This paper reviews studies which employed placebo-controlled and non-placebo-controlled alcohol challenge paradigms to assess a range of alcohol effects including impairment, stimulation, and sedation. Results:, The research literature provides at least partial support for both the LLR and DM models. High-risk individuals have been shown to have a reduced response to alcohol with respect to sedative or impairing effects, particularly on the descending limb of the blood alcohol curve (BAC). There is also evidence that ascending limb stimulant effects are more pronounced or operate differently for high-risk individuals. Discussion:, Despite commendable advances in SR research, important questions remain unanswered. Inconsistent results across studies may be attributable to a combination of an inadequate understanding of the underlying construct and methodological differences across studies (e.g., number and timing of assessments across the BAC, inclusion of a placebo condition). With respect to the underlying construct, existing measures fail to adequately distinguish between cognitive/behavioral impairment and sedation, aspects of which may be perceived positively (e.g., anxiolysis) due to their ability to act as negative reinforcers. Conclusions:, Addressing the concerns raised by the current review will be integral to making meaningful scientific progress in the field of subjective response. [source] Attenuated prefrontal activation during a verbal fluency task in remitted major depressionPSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 3 2009Go Okada md The aim of the present study was to investigate whether a functional abnormality in the left prefrontal cortex observed in patients with major depression performing a verbal fluency task is present after remission of depression. Functional magnetic resonance imaging was used to study changes in cerebral blood oxygenation in eight remitted patients with major depression and 10 healthy control subjects during a verbal fluency task. Compared to the control subjects, the patients had a reduced response in the left prefrontal cortex (middle frontal gyrus, Brodmann area 10). These findings suggest the presence of dysfunction in the left prefrontal cortex during remission in major depression. [source] The vascular effects of different arginase inhibitors in rat isolated aorta and mesenteric arteriesBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009NN Huynh Background and purpose:, Arginase and nitric oxide (NO) synthase share the common substrate L-arginine, and arginase inhibition is proposed to increase NO production by increasing intracellular levels of L-arginine. Many different inhibitors are used, and here we have examined the effects of these inhibitors on vascular tissue. Experimental approach:, Each arginase inhibitor was assessed by its effects on isolated rings of aorta and mesenteric arteries from rats by: (i) their ability to preserve the tolerance to repeated applications of the endothelium-dependent agonist acetylcholine (ACh); and (ii) their direct vasorelaxant effect. Key results:, In both vessel types, tolerance (defined as a reduced response upon second application) to ACh was reversed with addition of L-arginine, (S)-(2-boronethyl)-L-cysteine HCl (BEC) or NG -Hydroxy-L-arginine (L-NOHA). On the other hand, N, -hydroxy-nor-L-arginine (nor-NOHA) significantly augmented the response to ACh, an effect that was partially reversed with L-arginine. No effect on tolerance to ACh was observed with L-valine, nor-valine or D,L, ,-difluoromethylornithine (DFMO). BEC, L-NOHA and nor-NOHA elicited endothelium-independent vasorelaxation in both endothelium intact and denuded aorta while L-valine, DFMO and nor-valine did not. Conclusions and implications:, BEC and L-NOHA, but not nor-NOHA, L-valine, DFMO or nor-valine, significantly reversed tolerance to ACh possibly conserving L-arginine levels and therefore increasing NO bioavailability. However, both BEC and L-NOHA caused endothelium-independent vasorelaxation in rat aorta, suggesting that these inhibitors have a role beyond arginase inhibition alone. Our data thus questions the interpretation of many studies using these antagonists as specific arginase inhibitors in the vasculature, without verification with other methods. [source] Glucocorticoid sensitivity of lipopolysaccharide-stimulated chronic obstructive pulmonary disease alveolar macrophagesCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 1 2009J. Armstrong Summary It has been reported that alveolar macrophages from patients with chronic obstructive pulmonary disease (COPD) display glucocorticoid (Gc) resistance. The Gc sensitivity of inflammatory mediators released by COPD macrophages may vary. The objective of this study was to identify Gc-insensitive inflammatory mediators produced by lipopolysaccharide (LPS)-stimulated alveolar macrophages from COPD patients. LPS-stimulated alveolar macrophages from 15 COPD patients, nine smokers (S) and nine healthy non-smokers (HNS) were stimulated with LPS with or without dexamethasone (100 and 1000 nM). Luminex and enzyme-linked immunosorbent assay were used to measure 23 inflammatory mediators. After LPS stimulation there were lower levels of inflammatory mediators in COPD patients and S compared to HNS. There was no difference between groups for the effects of dexamethasone at either concentration (P > 0·05 for all comparisons). Tumour necrosis factor (TNF)-,, interleukin (IL)-6 and growth-related oncogene (GRO)-, displayed the greatest sensitivity to dexamethasone in COPD patients, while IL-8, granulocyte,macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) were the least sensitive. COPD macrophages have a reduced response to LPS. Gc sensitivity was similar in COPD macrophages compared to controls. We identify some Gc-insensitive cytokines, including GM-CSF, G-CSF and IL-8, that may be involved in the progression of airway inflammation in COPD patients. [source] Multiple functions of human T cells generated by experimental malaria challengeEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2009Stephen M. Todryk Abstract Protective immunity generated following malaria infection may be comprised of Ab or T cells against malaria Ag of different stages; however, the short-lived immunity that is observed suggests deficiency in immune memory or regulatory activity. In this study, cellular immune responses were investigated in individuals receiving Plasmodium falciparum sporozoite challenge by the natural (mosquito bite) route as part of a malaria vaccine efficacy trial. Parasitemia, monitored by blood film microscopy and PCR, was subsequently cleared with drugs. All individuals demonstrated stable IFN-,, IL-2 and IL-4 ex vivo ELISPOT effector responses against P. falciparum -infected RBC (iRBC) Ag, 28 and 90,days after challenge. However, infected RBC-specific central memory responses, as measured by IFN-, cultured ELISPOT, were low and unstable over time, despite CD4+ T cells being highly proliferative by CFSE dilution, and showed an inverse relationship to parasite density. In support of the observation of poor memory, co-culture experiments showed reduced responses to common recall Ag, indicating malaria-specific regulatory activity. This activity could not be accounted for by the expression of IL-10, TGF-,, FOXP3 or CTLA-4, but proliferating T cells expressed high levels of CD95, indicating a pro-apoptotic phenotype. Lastly, there was an inverse relationship between FOXP3 expression, when measured 10 days after challenge, and ex vivo IFN-, measured more than 100 days later. This study shows that malaria infection elicits specific Th1 and Th2 effector cells, but concomitant weak central memory and regulatory activity, which may help to explain the short-lived immunity observed. [source] Assessing forest growth across southwestern Oregon under a range of current and future global change scenarios using a process model, 3-PGGLOBAL CHANGE BIOLOGY, Issue 1 2001N. C. Coops Summary With improvements in mapping regional distributions of vegetation using satellite-derived information, there is an increasing interest in the assessment of current limitations on forest growth and in making projections of how productivity may be altered in response to changing climatic conditions and management policies. We utilised a simplified physiologically based process model (3-PG) across a 54 000 km2 mountainous region of southwestern Oregon, USA, to evaluate the degree to which maximum periodic mean annual increment (PAI) of forests could be predicted at a set of 448 forest inventory plots. The survey data were pooled into six broad forest types (coastal rain forest, interior coast range forest, mixed conifer, dry-site Douglas-fir, subalpine forest, and pine forest) and compared to the 3-PG predictions at a spatial resolution of 1 km2. We found good agreement (r2 = 0.84) between mean PAI values of forest productivity for the six forest types with those obtained from field surveys. With confidence at this broader level of integration, we then ran model simulations to evaluate the constraints imposed by (i) soil fertility under current climatic conditions, (ii) the effect of doubling monthly precipitation across the region, and (iii) a widely used climatic change scenario that involves modifications in monthly mean temperatures and precipitation, as well as a doubling in atmospheric CO2 concentrations. These analyses showed that optimum soil fertility would more than double growth, with the greatest response in the subalpine type and the least increase in the coastal rain forests. Doubling the precipitation increased productivity in the pine type (> 50%) with reduced responses elsewhere. The climate change scenario with doubled atmospheric CO2 increased growth by 50% on average across all forest types, primarily as a result of a projected 33% increase in photosynthetic capacity. This modelling exercise indicates that, at a regional scale, a general relationship exists between simulated maximum leaf area index and maximum aboveground growth, supporting the contention that satellite-derived estimates of leaf area index may be good measures of the potential productivity of temperate evergreen forests. [source] | |||||||||||||