| 1. |
- Alenmyr, Lisa, et al.
(författare)
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Effect of Mucosal TRPV1 Inhibition in Allergic Rhinitis.
- 2012
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 110, s. 264-268
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Tidskriftsartikel (refereegranskat)abstract
- Transient receptor potential vanilloid-1 (TRPV1) has been implicated as a mediator of itch in allergic rhinitis. To address this possibility, we synthesized a TRPV1 blocker (SB-705498) for nasal administration in patients with seasonal allergic rhinitis. The pharmacological activity of SB-705498 was confirmed on human TRPV1-expressing HEK293 cells, using fluorometric calcium imaging, and in patients with allergic rhinitis subjected to nasal capsaicin challenges. The effect of SB-705498 was studied in patients with seasonal allergic rhinitis subjected to daily allergen challenges for seven days, using a double-blind, placebo-controlled, randomized and cross-over design. SB-705498 was delivered by nasal lavage 10 min. before each allergen challenge. Primary end-point was total nasal symptom score on days 5 to 7. Nasal peak inspiratory flow and eosinophil cationic protein content in nasal lavages were also monitored. Daily topical applications of SB-705498 at a concentration that inhibited capsaicin-induced nasal symptoms had no effect on total symptom score, nasal peak inspiratory flow and eosinophil cationic protein levels in allergen-challenged patients with seasonal allergic rhinitis. The individual symptom nasal itch or sneezes was also not affected. These findings may indicate that TRPV1 is not a key mediator of the symptoms in allergic rhinitis. However, additional studies, using drug formulations with a prolonged duration of action, should be conducted before TRPV1 is ruled out as a drug target in allergic rhinitis.
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| 2. |
- Buhl, Mads, et al.
(författare)
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Circulating Free Fatty Acids do not Contribute to the Acute Systemic Inflammatory Response. An Experimental Study in Porcine Endotoxaemia
- 2009
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 105:5, s. 319-326
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Tidskriftsartikel (refereegranskat)abstract
- Intensive insulin therapy, aiming for strict normoglycaemia, is associated with increased survival in critically ill patients. Insulin therapy concomitantly reduces plasma-free fatty acids. Recent studies indicate that free fatty acids mediate inflammation. In addition to plasma glucose and free fatty acid-lowering effects, insulin also has anti-inflammatory properties. This study was designed to study the pro-inflammatory effects of two free fatty acid concentrations during acute endotoxaemia and controlled comparable levels of plasma glucose and insulin. Twenty pigs were anaesthetized and mechanically ventilated. Pigs were randomized to two different, constant Intralipid (R) infusion rates, throughout observation. All pigs were administered continuous intravenous infusion of endotoxin and subjected to controlled levels of p-glucose (4.5 mmol/l) and insulin by use of a hyperinsulinaemic euglycaemic clamp. Changes in circulating tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, leucocytes, insulin, glucose, free fatty acids, triglycerides, albumin, blood gases, temperature, and, haemodynamic function were monitored. Immediately following killing, biopsies were taken from heart and kidney. Biopsies were analysed for protein content of TNF-alpha, IL-6, IL-8 and IL-10. Sustained elevated and significantly different plasma levels of free fatty acids were demonstrated between groups (mean free fatty acid concentrations, 1.62 mM versus 0.58 mM, p < 0.0002). Endotoxaemia induced a steep increase in plasma TNF-alpha, IL-6 and leucocytes, however, without differences between the low- and high-free fatty acid groups. Cytokine content in heart and kidney tissue was not modified by free fatty acids. Compared with the response obtained at lower free fatty acid levels, high free fatty acid levels did not exacerbate the inflammatory response to acute endotoxaemia. Our results do not support the role of free fatty acids as a significant pro-inflammatory mediator.
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| 3. |
- Canaparo, Roberto, et al.
(författare)
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Expression of cytochromes P450 3A and P-glycoprotein in human large intestine in paired tumour and normal samples
- 2007
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 100:4, s. 240-248
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Tidskriftsartikel (refereegranskat)abstract
- Our objective was to investigate the expression of different cytochromes P450 3A (CYP3A4, CYP3A5, and CYP3A7) and P-glycoprotein (ABCBI) genes along the human large intestine in paired tumour and normal samples. Real-time reverse transcriptase-polymerase chain reaction was used to measure CYP3A4-, CYP3A5-, CYP3A7- and ABCB1-specific mRNA expression, and Western blot analysis was used to measure membrane protein levels of CYP3A4/7, CYP3A5 and P-glycoprotein. Levels of mRNA and membrane protein fractions in the large intestine were compared with those of normal human liver. The mRNA expressions of CYP3A4, CYP3A5, CYP3A7 and ABCB1 in the large intestine were found to be highly variable, but overall the levels were significantly lower than those measured in liver (P < 0.0001, P < 0.00 1, P < 0.0001 and P < 0.01, respectively). At the membrane protein level, CYP3A4/7 was detected in all large intestine samples examined and the levels were substantially higher than those of the liver (P < 0.01). Although expression of CYP3A5 was detected in all large intestine samples, in most the levels were too low to allow quantification. P-glycoprotein was readily detected at levels slightly higher than those of liver (P < 0.05). Comparison between paired samples of normal and tumour in large intestine showed no significant differences in either the mRNA or membrane protein levels of these genes. In conclusion, this work suggests a potential role of the large intestine in the absorption and metabolism of xenobiotics and nutrients and no difference in the CYP3A and P-glycoprotein membrane protein fractions and mRNA expression between normal and tumour tissues.
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| 7. |
- Xie, Yan-hua, et al.
(författare)
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Up-Regulation of G-Protein-Coupled Receptors for Endothelin and Thromboxane by Lipid-Soluble Smoke Particles in Renal Artery of Rat
- 2010
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 107:4, s. 803-812
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Tidskriftsartikel (refereegranskat)abstract
- Up-regulation of G-protein-coupled receptors (GPCR) plays key roles in renal hypertension and cardiovascular disease pathogenesis. The present study was designed to examine if lipid-soluble cigarette smoking particles (DSP), nicotine and endotoxin (LPS), induce GPCR up-regulation for thromboxane A(2) (TP), endothelin type A (ETA) and type B (ETB) receptors in renal artery, and if intracellular signal mechanisms are involved. Renal artery segments of rats were exposed to DSP, nicotine or LPS, in organ culture for up to 24 hr. The GPCR-mediated contractions were recorded by using a myograph system. Expression of the GPCR was examined by real-time PCR and immunohistochemistry at mRNA and protein levels. Sarafatoxin 6c (S6c, selective ETB receptor agonist), endothelin-1 (ET-1, non-selective ETA and ETB receptor agonist) and 9,11-Dideoxy-9a,11a-methanoepoxy prostaglandin F-2a (U46619, a TP receptor agonist) induced contractions were significantly increased after the arterial segments exposed to DSP in a concentration-dependent (0.1-0.4 mu l/ml) manner, and S6c also induced a time-dependent contraction, compared to control (dimethyl sulfoxide). This was in parallel with enhanced mRNA expression for ETB receptor but not ETA and TP receptors, while increased protein expression for ETA, ETB and TP receptors was seen. The specific nuclear factor-kappa B (NF-kappa B) signal pathway inhibitor BMS345541 was applied to link DSP effects to the GPCR up-regulation. It totally abolished ETB receptor up-regulation, but not ETA and TP receptor up-regulations. Our results suggest that DSP transcriptionally up-regulated ETB receptor expression in rat renal artery via NF-kappa B signal pathways, whereas up-regulation of ETA and TP receptor-mediated contraction may involve post-transcriptional mechanisms.
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| 8. |
- Zhang, W, et al.
(författare)
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Down-regulation of alpha-adrenoceptor expression by lipid-soluble smoke particles through transcriptional factor nuclear factor-kappaB pathway.
- 2007
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 101:6, s. 401-406
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Tidskriftsartikel (refereegranskat)abstract
- Smoking is a strong risk factor for cardiovascular disease that is a leading cause of death and disability in Western countries. The present study was designed to investigate the effect of lipid-soluble smoke particles (DSP) on alpha-adrenoceptor expression in organ culture of rat mesenteric arteries and human epiploon arteries. Myograph and real-time reverse transcription-polymerase chain reaction were employed to assess vascular smooth muscle contractibility and the receptor mRNA expression in the smooth muscle cells. Organ culture of the arterial segments in the presence of DSP (0.2 microl/ml) resulted in a significantly decreased contractile response to norepinephrine, compared to control (i.e. in the presence of dimethyl sulfoxide) (P < 0.05). This was in parallel with a down-regulation of alpha(1A)-adrenoceptor mRNA expression in the smooth muscle, while alpha(2)-adrenoceptor mRNA expression remained unchanged. General transcription inhibitor actinomycin D (10(-5.4 )M), but not the translational inhibitor cycloheximide (10(-5 )M), significantly abolished the DSP-induced depressed contraction to norepinephrine. IMD-0354 (10(-7.5 )M), a specific nuclear factor-kappaB (NF-kappaB) pathway inhibitor, markedly reversed the DSP-induced down-regulation of alpha(1A)-adrenoceptor expression in the smooth muscle at both functional and mRNA levels. Thus, we have demonstrated that smoking-induced down-regulation of alpha(1A)-adrenoceptor expression was via the transcriptional factor NF-kappaB pathway.
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| 9. |
- Grandjean, Philippe, et al.
(författare)
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The faroes statement : human health effects of developmental exposure to chemicals in our environment.
- 2008
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 102:2, s. 73-5
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Tidskriftsartikel (refereegranskat)abstract
- The periods of embryonic, foetal and infant developmentare remarkably susceptible to environmental hazards. Toxicexposures to chemical pollutants during these windows ofincreased susceptibility can cause disease and disability ininfants, children and across the entire span of human life.Among the effects of toxic exposures recognized in the pasthave been spontaneous abortion, congenital malformations,lowered birthweight and other adverse effects. These outcomesmay be readily apparent. However, even subtle changes causedby chemical exposures during early development may leadto important functional deficits and increased risks ofdisease later in life. The timing of exposure during early lifehas therefore become a crucial factor to be considered intoxicological assessments.During 20–24 May 2007, researchers in the fields of environmentalhealth, environmental chemistry, developmentalbiology, toxicology, epidemiology, nutrition and paediatricsgathered at the International Conference on Fetal Programmingand Developmental Toxicity, in Tórshavn, FaroeIslands. The conference goal was to highlight new insightsinto the effects of prenatal and early postnatal exposure tochemical agents, and their sustained effects on the individualthroughout the lifespan. The conference brought togetherresearchers to focus on human data and the translationof laboratory results to elucidate the environmental risks tohuman health.
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