673 research outputs found
Structural optimization and biological evaluation of 2-substituted 5-hydroxyindole-3-carboxylates as potent inhibitors of human 5-lipoxygenase.
Pharmacological suppression of leukotriene biosynthesis by inhibitors of 5-lipoxygenase (5-LO) is a strategy to intervene with inflammatory and allergic disorders. We recently presented 2-amino-5-hydroxy-1H-indoles as efficient 5-LO inhibitors in cell-based and cell-free assays. Structural optimization led to novel benzo[g]indole-3-carboxylates exemplified by ethyl 2-(3-chlorobenzyl)-5- hydroxy-1H-benzo[g]indole-3-carboxylate (compound 11a), which inhibits 5-LO activity in human neutrophils and recombinant human 5-LO with IC50 values of 0.23 and 0.086 ÎĽM, respectively. Notably, 11a efficiently blocks 5-LO product formation in human whole blood assays (IC50 = 0.83-1.6 ÎĽM) and significantly prevented leukotriene B4 production in pleural exudates of carrageenan-treated rats, associated with reduced severity of pleurisy. Together, on the basis of their high potency against 5-LO and the marked efficacy in biological systems, these novel and straightforward benzo[g]indole-3-carboxylates may have potential as anti-inflammatory therapeutics
Myrtucommulone from Myrtus communis exhibits potent anti-inflammatory effectiveness in vivo.
Myrtucommulone a nonprenylated acylphloroglucinol contained in the leaves of myrtle (Myrtus communis), has been reported to suppress the biosynthesis of eicosanoids by inhibition of 5-lipoxygenase and cyclooxygenase-1 in vitro and to inhibit the release of elastase and the formation of reactive oxygen species in activated polymorphonuclear leukocytes. Here, in view of the ability of MC to suppress typical proinflammatory cellular responses in vitro, we have investigated the effects of MC in in vivo models of inflammation. MC was administered to mice intraperitoneally, and paw edema and pleurisy were induced by the subplantar and intrapleural injection of carrageenan, respectively. MC (0.5, 1.5, and 4.5 mg/kg i.p.) reduced the development of mouse carrageenan-induced paw edema in a dose-dependent manner. Moreover, MC (4.5 mg/kg i.p. 30 min before and after carrageenan) exerted anti-inflammatory effects in the pleurisy model. In particular, 4 h after carrageenan injection in the pleurisy model, MC reduced: 1) the exudate volume and leukocyte numbers; 2) lung injury (histological analysis) and neutrophil infiltration (myeloperoxidase activity); 3) the lung intercellular adhesion molecule-1 and P-selectin immunohistochemical localization; 4) the cytokine levels (tumor necrosis factor-α and interleukin-1 β in the pleural exudate and their immunohistochemical localization in the lung; 5) the leukotriene B 4, but not prostaglandin E2, levels in the pleural exudates; and 6) lung peroxidation (thiobarbituric acid-reactant substance) and nitrotyrosine and poly (ADP-ribose) immunostaining. In conclusion, our results demonstrate that MC exerts potent anti-inflammatory effects in vivo and offer a novel therapeutic approach for the management of acute inflammation. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
Up-regulation of prostaglandin biosynthesis by leukotriene C4 in elicited mice peritoneal macrophages activated with lipopolysaccharide/interferon-gamma
Leukotrienes (LT) and prostaglandins (PG) are proinflammatory mediators generated by the conversion of arachidonic acid via 5-lipoxygenase (5-LO) and cyclooxygenase (COX) pathways. It has long been proposed that the inhibition of the 5-LO could enhance the COX pathway leading to an increased PG generation. We have found that in in vitro models of inflammation, such as mice-elicited peritoneal macrophages activated with lipopolysaccharide (LPS)/interferon- Îł (IFN-Îł), the deletion of the gene encoding for 5-LO or the enzyme activity inhibition corresponded to a negative modulation of the COX pathway. Moreover, exogenously added LTC4, but not LTD4, LTE 4, and LTB4, was able to increase PG production in stimulated cells from 5-LO wild-type and knockout mice. LTC4 was not able to induce COX-2 expression by itself but rather potentiated the action of LPS/IFN-Îł through the extracellular signal-regulated kinase-1/2 activation, as demonstrated by the use of a specific mitogen-activated protein kinase (MAPK) kinase inhibitor. The LT-induced increase in PG generation, as well as MAPK activation, was dependent by a specific ligand-receptor interaction, as demonstrated by the use of a cys-LT1 receptor antagonist, although also a direct action of the antagonist used, on PG generation, cannot be excluded. Thus, the balance between COX and 5-LO metabolites could be of great importance in controlling macrophage functions and consequently, inflammation and tumor promotion
Propylene glycol-specific dehydrogenases as functional biomarkers for monitoring biodegradation in sites contaminated by de-icing chemicals
The area under study at Gardermoen airport (Oslo, Norway) is a glacial contact formation with sand and gravels dominating near the ground surface. Due to the northern climate, every winter large amounts of de-icing chemicals, i.e. propylene glycol (PG) and potassium formate, are commonly used in the airport for the removal of snow and ice from airplanes and runways, respectively. Even though these contaminants are easily degradable by biotic or abiotic factors, they may still threaten groundwater, due to the system overloading.
The present study, performed within the FPVII European research project: “SoilCAM - Soil Contamination: Advanced integrated characterisation and time-lapse Monitoring”, deals with the physic-chemical and microbiological characterization of the site and the development of suitable methods for monitoring PG biodegradation on site under reclamation. For this purpose, functional biomarkers were selected to evaluate their potential use in Real Time quantitative PCR (q-PCR) experiments directly on soil DNA. The soils are highly leached, with low biological and biochemical activities. Therefore, pollutant transfer to the groundwater occurs quickly and is virtually unhindered. Bacterial strains isolated from the soil were able to degrade PG in aerobic conditions at 4, 15 and 30 °C. The PG-degrading population was mainly composed by different species of Pseudomonas, as shown by denaturing gradient gel electrophoresis (DGGE) analysis on soil DNA. Gene probes for PG-specific alcohol dehydrogenase (ADH-IIG) detected the presence of such genes in the isolates. The deduced amino acid sequence of representative strains presented over 92% identities with PG-specific dehydrogenase-related proteins. ADH-IIG detected in soil DNA indicated that PG-degrading strains were present along the soil profile from 0 to 100 cm.
The application of q-PCR analysis on DNA from soil mesocosm experiments will confirm the suitability of ADH-IIG as biomarker for monitoring PG biodegradation in soil systems
Enhanced third harmonic generation from the epsilon-near-zero modes of ultrathin films
We experimentally demonstrate efficient third harmonic generation from an
indium tin oxide (ITO) nanofilm (lambda/42 thick) on a glass substrate for a
pump wavelength of 1.4 um. A conversion efficiency of 3.3x10^-6 is achieved by
exploiting the field enhancement properties of the epsilon-near-zero (ENZ) mode
with an enhancement factor of 200. This nanoscale frequency conversion method
is applicable to other plasmonic materials and reststrahlen materials in
proximity of the longitudinal optical phonon frequencies.Comment: 13 pages, 5 figure
PROTECTIVE EFFECTS OF ANTHOCYANINS FROM BLACKBERRY IN A RAT MODEL OF ACUTE LUNG INFLAMMATION.
Anthocyanins are a group of naturally occuring phenolic compounds related to the coloring of plants, flowers and fruits. These pigments are important as quality indicators, as chemotaxonomic markers and for their antioxidant activities. Here, we have investigated the therapeutic efficacy of anthocyanins contained in blackberry extract (cyanidin-3-O-glucoside represents about 80% of the total anthocyanin contents) in an experimental model of lung inflammation induced by carrageenan in rats. Injection of carrageenan into the pleural cavity elicited an acute inflammatory response characterized by fluid accumulation which contained a large number of neutrophils as well as an infiltration of polymorphonuclear leukocytes in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx) and prostaglandin E2 (PGE2). All parameters of inflammation were attenuated in a dose-dependent manner by anthocyanins (10, 30 mg kg-1 30 min before carrageenan). Furthermore, carrageenan induced an upregulation of the adhesion molecule ICAM-1, nitrotyrosine and poly (ADP-ribose) synthetase (PARS) as determined by immunohistochemical analysis of lung tissues. The degree of staining was lowered by anthocyanins treatment. Thus, the anthocyanins contained in the blackberry extract exert multiple protective effects in carrageenan-induced pleurisy
ROLE OF 5-LIPOXYGENASE IN THE MULTIPLE ORGAN FAILURE INDUCED BY ZYMOSAN.
Objective: This study investigated the role of 5-lipoxygenase in the pathogenesis of multiple organ failure (MOF) induced by zymosan. Design: Male mice with a targeted disruption of the 5-lipoxygenase gene (5-LOKO) and littermate wild-type (WT) controls (5-LOWT) were used to evaluate the role of 5-lipoxygenase (5-LO) in the pathogenesis of MOF. Setting: University research laboratory. Interventions and measurements: MOF was induced by peritoneal injection of zymosan (500 mg/kg i.p. as a suspension in saline) in 5-LOWT and in 5-LOKO mice. MOF was assessed 18 h after administration of zymosan and monitored for 12 days (for loss of body weight and mortality). Results: A severe inflammatory process induced by zymosan administration in WT mice coincided with the damage of lung and small intestine, as assessed by histological examination. Myeloperoxidase activity indicative of neutrophil infiltration and lipid peroxidation were significantly increased in zymosan-treated WT mice. Zymosan in the WT mice also induced a significant increase in the plasma level of nitrite/nitrate. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to ICAM-1 and P-selectin in the lung and intestine of zymosan-treated WT mice. In contrast, the degree of (a) peritoneal inflammation and tissue injury, (b) upregulation/expression of P-selectin and ICAM-1, and (c) neutrophil infiltration were markedly reduced in intestine and lung tissue obtained from zymosan-treated 5-LO deficient mice. Zymosan-treated 5-LOKO showed also a significantly decreased mortality. Conclusions: These findings clearly demonstrate that 5-LO exerts a role in zymosan-induced nonseptic shock
Vitamin K deficiency bleeding leading to a diagnosis of Crohn’s Disease
We report the case of a 45 year old man who came to Emergency Room of Polyclinic for sudden onset of localized ecchymosis and widespread hematomas. He was subjected to blood count and first level investigations to assess coagulation. Based on the results, second level investigations were performed. Endoscopy of the gastrointestinal tract with histological examination revealed a diagnosis of Crohn's disease. Vitamin K deficiency causes the formation of vitamin K-dependent clotting factors that cannot perform their pro-coagulant action. Consequently, patients present with hemorrhagic manifestations. Clinical and laboratory features observed in this patient show that the deficiency of vitamin K-dependent coagulation factors may reveal a complex clinical condition such as an inflammatory bowel disease
Changes in Microbial Plankton Assemblages Induced by Mesoscale Oceanographic Features in the Northern Gulf of Mexico
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