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Jérémie A Doiron, Luc M Leblanc, Martin J G Hébert, Natalie A Levesque, Aurélie F Paré, Jacques Jean-François, Marc Cormier, Marc E Surette, Mohamed Touaibia
Leukotrienes (LTs) are a class of lipid mediators implicated in numerous inflammatory disorders. Caffeic acid phenethyl ester (CAPE) possesses potent anti-LTs activity through the inhibition of 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of LTs. In this study, we describe the design and synthesis of CAPE analogs as radical scavengers and 5-LO inhibitors. Caffeic esters bearing propargyl and allyl linkers between the caffeoyl and aryl moieties (4a-i and 5a-i, respectively) were synthesized by Sonogashira and Heck cross coupling reactions to probe the effects of flexibility and aryl substitution on 5-LO inhibition...
September 26, 2016: Chemical Biology & Drug Design
Z I Krutetskaya, L S Milenina, A A Naumova, V G Antonov, A D Nozdrachev
Using Fura-2AM microfluorimetry, we have shown for the first time that 5-lipoxygenase specific inhibitor antiasthmatic agent zileuton significantly inhibits Ca(2+)-responses induced by glutoxim and molixan in macrophages. The results support 5-lipoxygenase involvement in the effect of glutoxim and molixan on intracellular Ca(2+) concentration in macrophages and indicate the inadvisability of a combined use of drugs glutoxim and molixan and antiasthmatic agent zileuton.
July 2016: Doklady. Biochemistry and Biophysics
Hua Yuan, Xuemei Li, Xiuying Zhang, Rui Kang, Daolin Tang
Ferroptosis, a recently identified form of non-apoptotic cell death, is involved in several physiological and pathological processes. Although lipid peroxidation plays a central role in triggering ferroptosis, the essential regulator of lipid metabolism in ferroptosis remains poorly defined. Here, we show that acyl-CoA synthetase long-chain family member 4 (ACSL4) is required for ferroptotic cancer cell death. Compared with ferroptosis-sensitive cells (e.g., HepG2 and HL60), the expression of ACSL4 was remarkably downregulated in ferroptosis-resistant cells (e...
September 23, 2016: Biochemical and Biophysical Research Communications
Tae Young Kim, Joohye Kim, Hea-Young Park Choo, Ho Jeong Kwon
5-Lipoxygenase (5-LOX) is an enzyme that converts arachidonic acid from the cell membrane into leukotriene, a signal lipid mediator. 5-LOX deficiency markedly attenuates the formation of aneurysms in knockout mice. In addition, Zileuton, a clinical drug targeting 5-LOX, is used for treatment of asthma. However, it is unclear whether 5-LOX inhibition results in anti-angiogenic effects for applications in cancer therapy. To explore the roles of 5-LOX in angiogenesis and its potential as a therapeutic target in cancer, the effects of a newly synthesized 5-LOX inhibitor, F3, on in vitro and in vivo angiogenesis were investigated...
September 23, 2016: Biochemical and Biophysical Research Communications
Giovanni Pallio, Alessandra Bitto, Gabriele Pizzino, Federica Galfo, Natasha Irrera, Letteria Minutoli, Vincenzo Arcoraci, Giovanni Squadrito, Antonio Macrì, Francesco Squadrito, Domenica Altavilla
Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) play an important role in inflammatory bowel diseases (IBDs). We investigated the effects of flavocoxid, a dual COX/LOX inhibitor, in experimental colitis induced with either dinitrobenzenesulfonic acid (DNBS) or dextrane sulphate sodium (DSS) In the first model, colitis was induced in rats by a single intra-colonic instillation (25mg in 0.8ml 50% ethanol) of DNBS; after 24h animals were randomized to receive orally twice a day, flavocoxid (10mg/kg), zileuton (50mg/kg), or celecoxib (5mg/kg)...
October 15, 2016: European Journal of Pharmacology
Xian-Kun Tu, Hua-Bin Zhang, Song-Sheng Shi, Ri-Sheng Liang, Chun-Hua Wang, Chun-Mei Chen, Wei-Zhong Yang
Previous studies from our laboratories showed that an anti-inflammatory drug, 5-lipoxygenase inhibitor zileuton, attenuates ischemic brain damage via inhibiting inflammatory reaction. However, it was elusive whether zileuton attenuates inflammatory reaction and ischemic brain damage through the modulation of PI3K/Akt signaling pathway. In the present study, we, for the first time, investigated whether PI3K/Akt pathway was involved in zileuton's anti-inflammatory and neuroprotective properties against brain damage following experimental ischemic stroke...
July 5, 2016: Neurochemical Research
Mong Tieng Ee, Crystal Kantores, Julijana Ivanovska, Mathew J Wong, Amish Jain, Robert P Jankov
Systemically-administered bleomycin causes inflammation, arrested lung growth, and pulmonary hypertension (PHT) in the neonatal rat, similar to human infants with severe bronchopulmonary dysplasia (BPD). Leukotrienes (LTs) are inflammatory lipid mediators produced by multiple cell types in the lung. The major LTs, LTB4 and cysteinyl LTs, are suggested to contribute to BPD, but their specific roles remain largely unexplored in experimental models. We hypothesized that LTs are increased in bleomycin-induced BPD-like injury, and that inhibition of LT production would prevent inflammatory cell influx and thereby ameliorate lung injury...
August 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Rahul Magazine, Hameed Aboobackar Shahul, Bharti Chogtu, Asha Kamath
BACKGROUND: Leukotriene modifiers have an established role in the management of chronic asthma but their role in acute asthma is still under evaluation. OBJECTIVE: To study and compare the effects of oral montelukast with oral zileuton in acute asthma. MATERIALS AND METHODS: This study included 120 asthmatics and was conducted from September 2012 to March 2014. Patients were randomized into three different groups to receive montelukast or zileuton or placebo in addition to standard treatment for asthma exacerbation...
May 2016: Lung India: Official Organ of Indian Chest Society
Baljeet Singh, Puneet Kaur Randhawa, Nirmal Singh, Amteshwar Singh Jaggi
The cardioprotective effects of remote hind limb preconditioning (RIPC) are well established, but its mechanisms still remain to be explored. Therefore, the present study was aimed to explore the possible involvement of 5-lipoxygenase-derived leukotrienes in RIPC. The hind limb was tied by a pressure cuff and was subjected to four episodes of inflation and deflation (5min each) to induce remote hind-limb preconditioning. Thereafter, the hearts were isolated and were subjected to global ischemia (30min) followed by reperfusion (120min) on the Langendorff apparatus...
May 1, 2016: Life Sciences
Naim Morina, Gëzim Boçari, Ali Iljazi, Kadir Hyseini, Gunay Halac
OBJECTIVE: Maximum time of the effect of antileukotriene substances - Zileuton in the treatment of patients with bronchial asthma and increased bronchial reactivity and of the salbutamol as agonist of the beta2 adrenergic receptor studied in this work. METHODS: Parameters of the lung function are determined with Body plethysmography. Raw and ITGV were registered and specific resistance (SRaw) was calculated. Zileuton (Zyflo, tbl. 600 mg), producer Cornerstone Therapeutics, USA was used in the research...
February 2016: Acta Informatica Medica: AIM
Swati Singh, Manika Awasthi, Veda P Pandey, Upendra N Dwivedi
Lipoxygenases (LOXs), key enzymes involved in the biosynthesis of leukotrienes, are well known to participate in the inflammatory and immune responses. With the recent reports of involvement of 5-LOX (one of the isozyme of LOX in human) in cancer, there is a need to find out selective inhibitors of 5-LOX for their therapeutic application. In the present study, plant derived 300 anti-inflammatory and anti-cancerous secondary metabolites (100 each of alkaloids, flavonoids and terpenoids) have been screened for their pharmacokinetic properties and subsequently docked for identification of potent inhibitors of 5-LOX...
March 4, 2016: Journal of Biomolecular Structure & Dynamics
Sebastian Essig, Björn Schmalzbauer, Sebastian Bretzke, Olga Scherer, Andreas Koeberle, Oliver Werz, Rolf Müller, Dirk Menche
Full details on the evaluation and application of an easily feasible and generally useful method for configurational assignments of isolated methyl-bearing stereocenters are reported. The analytical tool relies on a bioinformatic gene cluster analysis and utilizes a predictive enoylreductase alignment, and its feasibility was demonstrated by the full stereochemical determination of the ajudazols, highly potent inhibitors of the mitochondrial respiratory chain. Furthermore, a full account of our strategies and tactics that culminated in the total synthesis of ajudazol B, the most potent and least abundant of these structurally unique class of myxobacterial natural products, is presented...
February 19, 2016: Journal of Organic Chemistry
Y Xie, W Hou, X Song, Y Yu, J Huang, X Sun, R Kang, D Tang
Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e...
March 2016: Cell Death and Differentiation
Varnavas D Mouchlis, Edward A Dennis
Studying phospholipases A2 (PLA2s) is a challenging task since they act on membrane-like aggregated substrates and not on monomeric phospholipids. Multidisciplinary approaches that include hydrogen/deuterium exchange mass spectrometry (DXMS) and computational techniques have been employed with great success in order to address important questions about the mode of interactions of PLA2 enzymes with membranes, phospholipid substrates and inhibitors. Understanding the interactions of PLA2s is crucial since these enzymes are the upstream regulators of the eicosanoid pathway liberating free arachidonic acid (AA) and other polyunsaturated fatty acids (PUFA)...
May 2016: Advances in Biological Regulation
Marthe-Sandrine Eiymo Mwa Mpollo, Eric B Brandt, Shiva Kumar Shanmukhappa, Paritha I Arumugam, Swati Tiwari, Anastacia Loberg, Devin Pillis, Tilat Rizvi, Mark Lindsey, Bart Jonck, Peter Carmeliet, Vijay K Kalra, Timothy D Le Cras, Nancy Ratner, Marsha Wills-Karp, Gurjit K Khurana Hershey, Punam Malik
Airway hyperresponsiveness (AHR) affects 55%-77% of children with sickle cell disease (SCD) and occurs even in the absence of asthma. While asthma increases SCD morbidity and mortality, the mechanisms underlying the high AHR prevalence in a hemoglobinopathy remain unknown. We hypothesized that placenta growth factor (PlGF), an erythroblast-secreted factor that is elevated in SCD, mediates AHR. In allergen-exposed mice, loss of Plgf dampened AHR, reduced inflammation and eosinophilia, and decreased expression of the Th2 cytokine IL-13 and the leukotriene-synthesizing enzymes 5-lipoxygenase and leukotriene-C4-synthase...
February 2016: Journal of Clinical Investigation
O O Vinogradova, P I Yanchuk, O M Pasichnichenko
Effects of picotamide and zileuton on tonic contractile activity of the rat portal vein preparations, induced by acetylcholine (2.10(-5) mol/1) and phenylephrine (5.10(-7) mol/1) were investigated. Conversion of arachidonic acid products (prostaglandins, leukotrienes) synthesized by endothelial cells, plays an important role in the local regulation of vascular tone. The compounds formed in a cascade of enzymatic transformations can modulate the effect of other vasoactive factors. Picotamide (6,5.10(-5) mol/1) - thromboxane receptor and thromboxane -synthase blocker - depress acetylcholine-induction tonic contraction of isolated segments of portal vein with intact endothelium by 29% and norepinephrine-induction reduction of 45% relative to the control values...
2015: Fiziolohichnyĭ Zhurnal
Solo Kuvibidila, Rajasekharan P Warrier, Johnson Haynes, Surendra B Baliga
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...
2015: Ochsner Journal
Cemal Cingi, Nuray Bayar Muluk, Kagan Ipci, Ethem Şahin
Leukotrienes (LTs) are a family of inflammatory mediators including LTA4, LTB4, LTC4, LTD4, and LTE4. By competitive binding to the cysteinyl LT1 (CysLT1) receptor, LT receptor antagonist drugs, such as montelukast, zafirlukast, and pranlukast, block the effects of CysLTs, improving the symptoms of some chronic respiratory diseases, particularly bronchial asthma and allergic rhinitis. We reviewed the efficacy of antileukotrienes in upper airway inflammatory diseases. An update on the use of antileukotrienes in upper airway diseases in children and adults is presented with a detailed literature survey...
November 2015: Current Allergy and Asthma Reports
Bruno Costa Silva, Aline Silva de Miranda, Flavia Guimaraes Rodrigues, Ana Leticia Malheiros Silveira, Gustavo Henrique de Souza Resende, Marcio Flavio Dutra Moraes, Antonio Carlos Pinheiro de Oliveira, Patricia Martins Parreiras, Luciola da Silva Barcelos, Mauro Martins Teixeira, Fabiana Simao Machado, Antonio Lucio Teixeira, Milene Alvarenga Rachid
Stroke is one of the most frequent causes of death and disability worldwide causing a major clinical and socioeconomic impact. Although the pathophysiology of brain ischemia and reperfusion is complex, the inflammatory process plays an important role in pathogenesis, contributing to the expansion of brain injury. The 5-lipoxygenase (5-LOX) is a key enzyme in the biosynthesis of the leukotrienes and has been implicated and in the central nervous system (CNS) disorders such as Alzheimer's disease and acute ischemic stroke...
2015: Current Neurovascular Research
Yang Liu, Wei Wang, Yuyao Li, Yunqi Xiao, Jian Cheng, Jia Jia
5-Lipoxygenase (5-LOX) inhibitors have been shown to be protective in several neurodegenerative disease models; however, the underlying mechanisms remain unclear. We investigated whether 5-LOX inhibitor zileuton conferred direct neuroprotection against glutamate oxidative toxicity by inhibiting ferroptosis, a newly identified iron-dependent programmed cell death. Treatment of HT22 mouse neuronal cell line with glutamate resulted in significant cell death, which was inhibited by zileuton in a dose-dependent manner...
2015: Biological & Pharmaceutical Bulletin
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