1,460 research outputs found

    Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection

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    Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline–glycine–proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed

    Involvement of leukotriene pathway in the pathogenesis of ischemia-reperfusion injury and septic and non-septic shock.

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    The 5-lipoxygenase (5-LO) pathway is responsible for the production of leukotrienes (LTs), inflammatory lipid mediators which play a role in innate immunity. More recently, a pivotal role of LTs in ischemia-reperfusion and shock injury has been suggested. In fact, these pathological conditions are characterized by a severe neutrophil infiltration that gives rise to tissue injury and 5-LO metabolites control neutrophil recruitment in injured tissue by the modulation of adhesion molecule expression. The aim of this review is to analyze the results reported in the literature on the role of 5-LO pathway, with particular regard to LTs, in these pathological conditions. A better understanding of the mechanisms underlying the role of the 5-LO enzyme and/or its metabolites in the regulation of neutrophil trafficking, might open new perspectives in the therapy of organ dysfunction and/or injury associated with shock and ischemia-reperfusion injury

    Hydroxyurea and zileuton differentially modulate cell proliferation and interleukin-2 secretion by murine spleen cells: Possible implication on the immune function and risk of pain crisis in patients with sickle cell disease

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    Background: Hydroxyurea (HU) reduces major complications associated with sickle cell disease in part because of the induction of fetal hemoglobin. However, because of its antiproliferative property, its long-term use may impair immunity. Zileuton, a derivative of HU, also induces fetal hemoglobin and has antiinflammatory properties, a feature that can reduce the risk of sickling. Our goal was to investigate the capacity of both drugs to modulate the secretion of interleukin-2 (IL-2), a regulatory cytokine for immune responses. Methods: Spleen cells obtained from 11 4-month-old C57BL/6 female mice were incubated without and with 10 µ/mL HU or zileuton, 2.5 µ/mL concanavalin A (ConA), 20 µ/mL phytohemagglutinin (PHA), and 50 ng/mL anti-CD3 antibody for 12-48 h. IL-2 was measured in the supernatant by enzyme-linked immunosorbent assay and cell proliferation byH-thymidine uptake. Results: While HU reduced lymphocyte proliferation in response to mitogens (

    EFFECTS AND UNDERLYING MECHANISM OF 5-LIPOXYGENASE INHIBITOR (ZILEUTON) ON MICE DEPRESSIVE-LIKE BEHAVIOR

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    Objective: Treatment experiment was conducted to investigate the effectiveness and mechanism of the action of zileuton in corticosteroid-induced depressive mice model through neuroinflammation. Methods: The mice were randomly separated into four groups: (Veh+Veh), (Corticosteroid+Veh), (Corticosteroid+ZIL50), and (Corticosteroid+ZIL100). Intraperitoneal injection of corticosterone (CORT) (20 mg/kg for 6 weeks) was used in the mice to induce depression and neuroinflammation diverse from the Veh+Veh group, which was injected only physiological saline. The drug-treated groups (Corticosteroid+ZIL50 and Corticosteroid+ZIL100) were orally administered with the mentioned doses of zileuton. After confirming the effectiveness of zileuton through the behavioral tests, the mechanism of the action of the drug was explored through a set of biochemical assays. Results: Zileuton (50/100 mg/kg) administration improved the performance of the mice in the behavioral experiments (p<0.05 or 0.01). Immunohistochemistry detection of Iba1+ revealed over activation of microglial cells in the corticosteroid-treated mice which was suppressed by the zileuton (50 or 100 mg/kg [p<0.05 or 0.01]). Through Western blotting tests, it had been found that CORT (i.p.) administration led to the increment of the protein 5-Lipoxygenase in the mouse hippocampus associated with neuroinflammation, which was decreased significantly by zileuton (p<0.05 or 0.01). Level of tumor necrosis factor-alpha, interleukin-1 beta, nuclear factor kappa B p65 protein (for neuroinflammation), Bax, and cleaved caspase-3 and TUNEL assay increased, and Bcl-2 expression decreased in the CORT-induced depressive mice. These were significantly reversed by zileuton (50 or 100 mg/kg [p<0.05 or 0.01]). Conclusion: It can be concluded that selective 5-lipoxygenase inhibitor zileuton can efficiently inhibit the depressive-like behavior/activity in CORT-induced depressive mouse model. Moreover, the underlying mechanism may be the inhibition of hippocampal neuroinflammation and apoptosis

    PROTECTIVE EFFECT OF ZILEUTON AND MK-866 AGAINST HEPATIC DAMAGE INDUCED BY DOXORUBICIN

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    Objective: The present study was designed to investigate the protective effect of Zileuton and MK-886 against hepatic damage induced by doxorubicin. Methods: A total of 30 healthy adult male albino rats were randomized and rats were divided into five groups, six animals in each: Control negative group, Vehicle group: Rats were given ethanol i.p., Dx group: Doxorubicin (15 mg/kg), Mk group: Mk-886-treated rats given 0.6 mg/kg of Mk-886 i.p, and Z group: Zileuton-treated rats given zileuton 10 mg/kg i.p. Biochemical tests of the serum for ASAT and ALAT level were estimated. Serum glutathione (GSH) concentrations (μg/ml) were determined using GSH ELISA Kit, while serum malondialdehyde (MDA) concentrations (ng/ml) were determined using MDA ELISA Kit. Livers were removed from each rat and fixed in 10% neutral-buffered formalin and embedded in paraffin for histopathological studies. Results: MK- and zileuton-treated groups showed higher GSH levels and lower MDA levels as compared with Dx-treated group. MK-886 associated with significant p<0.05 decreased the liver enzymes in comparison with doxorubicin-treated rats. Zileuton showed insignificant (p>0.05) changes. The liver tissues that treated with Dx only showed several histopathological changes such as moderate sinusoidal dilation, vacuolation, mild-to-moderate hepatocyte necrosis/degeneration and inflammatory cell infiltration, and severe congestion. Liver tissues that treated by zileuton with Dx showed sinusoidal dilation, vacuolation, mild congestion, and inflammatory cell infiltration, while those treated with Mk-886 plus Dx showed nearly normal liver pathophysiology. Conclusion: It has been concluded that Zileuton and MK-886 have protective effects against hepatic damage induced by doxorubicin

    The Possible Protective Effects of Zileuton against Pulmonary Fibrosis Induced by Amiodarone in Male Rats

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    Introduction Pulmonary fibrosis is characterized by cellular alteration of the alveolar region with lung inflammation. Leukotrienes play an important role in the progression of the disease. This study was designed to investigate the possible protective effect of zileuton against amiodarone-induced pulmonary fibrosis in male rats. Materials and methods Pulmonary fibrosis was induced by administering amiodarone (100 mg/kg intraperitoneally i.p) and concomitantly treated with zileuton (30 mg/kg intraperitoneally i.p) for 15 days in wistar albino male rats. Biochemical parameters include TNF-?, IL-1?, 5-lipoxygenase; MDA and GSH in lung tissue were estimated, as well as lung histological studies. Results In rats treated with amiodarone, levels of TNF-?, IL-1?, 5-lipoxygenase and MDA were significantly elevated (p<0.05) with reduction in GSH level when compared with those treated with saline only. Meanwhile; administration of zileuton in group 3 was concerned with significant (p<0.05) improvement in the biochemical parameters when compared with group 1 and 2.  Furthermore, zileuton histologically reduced the number of inflammatory cells and ameliorate the destruction of lung architecture and pulmonary fibrosis induced by amiodarone. Conclusion Zileuton ameliorate pulmonary fibrosis induced by amiodarone in male rats, by inhibiting 5-lipoxygenase activity and reducing leukotrienes synthesis. Keywords: Zileuton, pulmonary fibrosis, amiodarone, rats

    Structural optimization and biological evaluation of 2-substituted 5-hydroxyindole-3-carboxylates as potent inhibitors of human 5-lipoxygenase.

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    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 μM, respectively. Notably, 11a efficiently blocks 5-LO product formation in human whole blood assays (IC50 = 0.83-1.6 μM) 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

    Zileuton™ loaded in polymer micelles effectively reduce breast cancer circulating tumor cells and intratumoral cancer stem cells

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    Tumor recurrence, metastatic spread and progressive gain of chemo-resistance of advanced cancers are sustained by the presence of cancer stem cells (CSCs) within the tumor. Targeted therapies with the aim to eradicate these cells are thus highly regarded. However, often the use of new anti-cancer therapies is hampered by pharmacokinetic demands. Drug delivery through nanoparticles has great potential to increase efficacy and reduce toxicity and adverse effects. However, its production has to be based on intelligent design. Likewise, we developed polymeric nanoparticles loaded with Zileuton™, a potent inhibitor of cancer stem cells (CSCs), which was chosen based on high throughput screening. Its great potential for CSCs treatment was subsequently demonstrated in in vitro and in in vivo CSC fluorescent models. Encapsulated Zileuton™ reduces amount of CSCs within the tumor and effectively blocks the circulating tumor cells (CTCs) in the blood stream and metastatic spread
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