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5 lipoxygenase inhibitors

Mosad A Ghareeb, Mansour Sobeh, Samar Rezq, Assem M El-Shazly, Mona F Mahmoud, Michael Wink
Reactive oxygen species (ROS) have been linked to several health conditions, among them inflammation. Natural antioxidants may attenuate this damage. Our study aimed to investigate the chemical composition of a methanol leaf extract from Alpinia zerumbet and its possible antioxidant, anti-inflammatory, anti-nociceptive, and antipyretic effects. Altogether, 37 compounds, representing benzoic and cinnamic acid derivatives and flavonoids (aglycones and glycosides), were characterized. The extract showed substantial in vitro antioxidant effects, and inhibited both cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) in vitro, with a higher selectivity towards COX-2...
December 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Evamarie Hey-Hawkins, Robert Kuhnert, Menyhárt-Botond Sárosi, Sven George, Peter Lönnecke, Bettina Hofmann, Dieter Steinhilber, Sara Steinmann, Regine Schneider-Stock, Blagoje Murganic, Sanja Mijatovic, Danijelа Maksimovic-Ivanic
5-Lipoxygenase converts arachidonic acid to leukotrienes that are involved in inflammation and angiogenesis. The introduction of carboranes can improve the pharmacokinetic behavior of metabolically less stable pharmaceutics. We here report the syntheses of several carborane-based inhibitors of the 5-lipoxygenase pathway. The isosteric replacement of phenyl rings by carboranes leads to improved cytotoxicity for several melanoma and colon cancer cell lines. For the colon cancer cell line HCT-116 the co-inhibition of heat shock protein 90 could be detected...
November 24, 2018: ChemMedChem
Atasi De Chatterjee, Debarshi Roy, Priscilla Guevara, Rituraj Pal, Mahesh Naryan, Sukla Roychowdhury, Siddhartha Das
Background: The migration of tumor cells is critical in spreading cancers through the lymphatic nodes and circulatory systems. Although arachidonic acid (AA) and its soluble metabolites have been shown to induce the migration of breast and colon cancer cells, the mechanism by which it induces such migration has not been fully understood. Objective: The effect of AA on migratory responses of the MDA-MB-231 cell line (a triple-negative breast cancer cell) was examined and compared with MCF-7 (estrogen-receptor positive) breast cancer cells to elucidate the mechanism of AA-induced migration...
2018: Clinical Cancer Drugs
Yesseny Vásquez-Martínez, Claudia Torrent, Giannina Toledo, Francisco Cabezas, Victoria Espinosa, Margarita Montoya-K, Sophia Mejias, Marcelo Cortez-San Martín, Silvia Sepúlveda-Boza, Carolina Mascayano
We investigated twelve benzyl phenyl ketone derivatives which are synthetic precursors of isoflavonoids that are shown be good 5-hLOX inhibitors, especially those that have the catechol group, but these precursors never have been assayed as 5-hLOX inhibitors being a novelty as inhibitors of the enzyme, due to sharing important structural characteristics. Screening assays, half maximal inhibitory concentration (IC50 ) and kinetic assays of all the studied molecules (5 µg/ml in media assay) showed that 1-(2,4-dihydroxy-3-methylphenyl)-2-(3-chlorophenyl)-ethanone (K205; IC50  = 3...
October 27, 2018: Bioorganic Chemistry
Sasikamon Khophai, Malinee Thanee, Anchalee Techasen, Nisana Namwat, Poramate Klanrit, Attapol Titapun, Apiwat Jarearnrat, Prakasit Sa-Ngiamwibool, Watcharin Loilome
Background: Inflammatory lipid mediators play an important role in several cancer types. Leukotrienes (LTs), pro-inflammatory lipid mediators, are involved in chronic inflammation and cancer progression. They are derived from arachidonic acid by 5-lipoxygenase (5-LOX) activity. On the other hand, 15-lipoxygenase (15-LOX-1) converts LTs into lipoxins (LXs), pro-resolving lipid mediators. LXs are involved in the attenuation of inflammation and cancer development. Purpose: We aimed to investigate the lipid mediator pathways, especially the LTs and LXs pathways, by studying 5-LOX and 15-LOX-1 expression in human cholangiocarcinoma (CCA) tissue...
2018: OncoTargets and Therapy
Marco S Doucet, Jean-Luc Jougleux, Samuel J Poirier, Marc Cormier, Jacob L Leger, Marc E Surette, Nicolas Pichaud, Mohamed Touaibia, Luc H Boudreau
The inflammatory response is necessary for the host's defense against pathogens; however, uncontrolled or unregulated production of eicosanoids has been associated with several types of chronic inflammatory diseases. Thus, it is not surprising that enzymes implicated in the production of eicosanoids have been strategically targeted for potential therapeutic approaches. The 12-hydroxyeicosatetraenoic acid (12(S)-HETE) lipid mediator is among inflammatory molecules that are abundantly produced in various diseases and is primarily biosynthesized via the 12(S)-lipoxygenase (12-LO) pathway...
November 7, 2018: Molecular Pharmacology
Syed Obaidur Rahman, Rakesh Kumar Singh, Salman Hussain, Mohd Akhtar, Abul Kalam Najmi
Cysteinyl leukotrienes (cysLTs) are member of eicosanoid inflammatory lipid mediators family produced by oxidation of arachidonic acid by action of the enzyme 5-lipoxygenase (5-LOX). 5-LOX is activated by enzyme 5-Lipoxygenase-activating protein (FLAP), which further lead to production of cysLTs i.e. leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4). CysLTs then produce their potent inflammatory actions by activating CysLT1 and CysLT2 receptors. Inhibitors of cysLTs are indicated in asthma, allergic rhinitis and other inflammatory disorders...
October 30, 2018: European Journal of Pharmacology
Rajaram Azad, Neela Kishore Babu, Aparna Dutta Gupta, Pallu Reddanna
Premna integrifolia (Agnimantha brihat) is a traditional medicinal plant with a prominent place in Ayurveda, Siddha and Unani systems of medicine. In this study we have evaluated the anti-inflammatory and immunomodulatory properties of the Premna integrifolia root extracts employing cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX) enzyme-based assays, lymphocyte proliferation assay, pro-and anti-inflammatory cytokines measurement. Petroleum ether extract (PEE) of Premna integrifolia showed potent inhibition of COX-2 and 5-LOX with IC50 values of 6...
October 16, 2018: Fitoterapia
T K Shameera Ahamed, Vijisha K Rajan, K Sabira, K Muraleedharan
Developments of novel inhibitors to prevent the function of 5-lipoxygenase (5-LOX) proteins that are responsible for a variety of inflammatory and allergic disease are a major challenge in the scientific community. In this study, robust QSAR classification models for predicting 5-LOX activity were developed using machine learning algorithms. The Support Vector Machines (SVM), Logistic Regression, k-Nearest Neighbour (NN) and Decision Trees were adopted to improve the prediction ability of the classification models...
October 5, 2018: Computational Biology and Chemistry
Tiago Rodrigues, Markus Werner, Jakob Roth, Eduardo H G da Cruz, Marta C Marques, Padma Akkapeddi, Susana A Lobo, Andreas Koeberle, Francisco Corzana, Eufrânio N da Silva Júnior, Oliver Werz, Gonçalo J L Bernardes
Using machine learning, targets were identified for β-lapachone. Resorting to biochemical assays, β-lapachone was validated as a potent, ligand efficient, allosteric and reversible modulator of 5-lipoxygenase (5-LO). Moreover, we provide a rationale for 5-LO modulation and show that inhibition of 5-LO is relevant for the anticancer activity of β-lapachone. This work demonstrates the power of machine intelligence to deconvolute complex phenotypes, as an alternative and/or complement to chemoproteomics and as a viable general approach for systems pharmacology studies...
September 14, 2018: Chemical Science
Sabrin R M Ibrahim, Gamal A Mohamed, Rwaida A Al Haidari, Amal A El-Kholy, Mohamed F Zayed, Maan T Khayat
A new peroxy fatty acid, tagetnoic acid (5) [4-((3S,6S)-6-((3E,8E)-octadeca-3,8-dien-1-yl)-3,6-dihydro-1,2-dioxin-3-yl)butanoic acid] and four known metabolites: ecliptal (5-formyl-α-terthiophene) (1), 5-(4-hydroxybut-1-ynyl)-2,2'-bithiophene (2), 22,23-dihydrospinasterone (3), and stigmasterol (4) were separated from the n-hexane fraction of the aerial parts of Tagetes minuta L. (Asteraceae). Their chemical structures were verified using IR, UV, 2D and 1D NMR, and HRMS. Compounds 3-5 displayed potent lipoxygenase inhibitory potential with IC50 s 2...
October 8, 2018: Natural Product Research
Saravanan S Karuppagounder, Lauren Alin, Yingxin Chen, David Brand, Megan W Bourassa, Kristen Dietrich, Cassandra M Wilkinson, Colby A Nadeau, Amit Kumar, Steve Perry, John T Pinto, Victor Darley-Usmar, Stephanie Sanchez, Ginger L Milne, Domenico Pratico, Theodore R Holman, S Thomas Carmichael, Giovanni Coppola, Frederick Colbourne, Rajiv R Ratan
OBJECTIVES: N-acetylcysteine (NAC) is a clinically approved thiol-containing redox modulatory compound currently in trials for many neurological and psychiatric disorders. Although generically labeled as an "antioxidant", poor understanding of its site(s) of action is a barrier to its use in neurological practice. Here, we examined the efficacy and mechanism of action of NAC in rodent models of hemorrhagic stroke. METHODS: Hemin was used to model ferroptosis and hemorrhagic stroke in cultured neurons...
October 7, 2018: Annals of Neurology
Zhan Li, Yue Gao, Cheng Lin, Ronghui Pan, Wenguang Ma, Yunye Zheng, Yajing Guan, Jin Hu
The preservation of seed viability and quality in storage is an important trait both for commercial and germplasm usage. To better explore potential mechanisms of tobacco seed deterioration, seed packed in cloth bag (C) and vacuum bag (V) were stored under room temperature (RT) and low temperature (LT, 18°C), and sampled periodically for laboratory testing. Seed stored in low temperature with vacuum bag (LT/V) owned the highest seed vigour after 25 months of storage and in room temperature with cloth bag (RT/C) lost seed vigour and germination ability after 20-month storage...
2018: Conservation Physiology
Yanzhuo Liu, Honglin Tang, Xiaoxiao Liu, Honglei Chen, Na Feng, Jing Zhang, Chenlong Wang, Miao Qiu, Jing Yang, Xiaoyang Zhou
Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and cytochrome P450 (CYP) 4A-mediated arachidonic acid (AA) metabolism play an essential role in human inflammatory disorders. Blocking COX-2 pathway would shunt AA metabolism to the other pathway, thereby decreasing the efficacy and exacerbating adverse effects. Here we demonstrated that reprogramming COX-2, 5-LOX, and CYP4A-mediated AA metabolism in macrophages by salidroside (Sal) ameliorates monosodium urate (MSU) crystal-induced inflammation. Compared with COX-2 inhibitor celecoxib, Sal (80 mg/kg) presented a superior anti-arthritic profile in MSU crystal-treated rats, accompanied with the decreased expression of COX-2, 5-LOX, and CYP4A and production of prostaglandin E2 (PGE2 ), leukotriene B4 (LTB4 ), and 20-hydroxyeicosatetraenoic acid (20-HETE) in the synovial fluid macrophages...
September 28, 2018: Journal of Leukocyte Biology
Silke Brand, Sayantani Roy, Peter Schröder, Bernd Rathmer, Jessica Roos, Shobhna Kapoor, Sumersing Patil, Claudia Pommerenke, Thorsten Maier, Petra Janning, Sonja Eberth, Dieter Steinhilber, Dennis Schade, Gisbert Schneider, Kamal Kumar, Slava Ziegler, Herbert Waldmann
Identification and validation of the targets of bioactive small molecules identified in cell-based screening is challenging and often meets with failure, calling for the development of new methodology. We demonstrate that a combination of chemical proteomics with in silico target prediction employing the SPiDER method may provide efficient guidance for target candidate selection and prioritization for experimental in-depth evaluation. We identify 5-lipoxygenase (5-LO) as the target of the Wnt pathway inhibitor Lipoxygenin...
September 20, 2018: Cell Chemical Biology
Helmut Pein, Alexia Ville, Simona Pace, Veronika Temml, Ulrike Garscha, Martin Raasch, Khaled Alsabil, Guillaume Viault, Chau-Phi Dinh, David Guilet, Fabiana Troisi, Konstantin Neukirch, Stefanie König, Rosella Bilancia, Birgit Waltenberger, Hermann Stuppner, Maria Wallert, Stefan Lorkowski, Christina Weinigel, Silke Rummler, Marc Birringer, Fiorentina Roviezzo, Lidia Sautebin, Jean-Jacques Helesbeux, Denis Séraphin, Alexander S Mosig, Daniela Schuster, Antonietta Rossi, Pascal Richomme, Oliver Werz, Andreas Koeberle
Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13'-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8-49 nM) that inhibit 5-lipoxygenase in human leukocytes...
September 20, 2018: Nature Communications
Seung E Baek, So Y Park, Sun S Bae, Koanhoi Kim, Won S Lee, Chi D Kim
Given the importance of high-mobility group box 1 (HMGB1) and 5-lipoxygenase (5-LO) signaling in vascular inflammation, we investigated the role of leukotriene signaling in monocytes on monocyte-to-macrophage differentiation (MMD) induced by HMGB1, and on vascular inflammation and subsequent intimal hyperplasia in a mouse model of wire-injured femoral artery. In cultured primary bone marrow-derived cells (BMDCs) stimulated with HMGB1, the number of cells with macrophage-like morphology was markedly increased in association with an increased expression of CD11b/Mac-1, which were attenuated in cells pre-treated with Zileuton, a 5-LO inhibitor as well as in 5-LO-deficient BMDCs...
2018: Frontiers in Immunology
Shweta Sinha, Mukesh Doble, S L Manju
Human 5-Lipoxygenase (5-LOX) is a key enzyme targeted for asthma and inflammation. Zileuton, the only drug against 5-LOX, was withdrawn from the market due to several problems. In the present study, the performance of rationally designed conjugates of thiazole (2) and thiourea (3) scaffolds from our previously reported 2-amino-4-aryl thiazole (1) is reported. They are synthesized (total 31 derivatives), characterized, and tested against the 5-LOX enzyme in vitro and the mode of action of the most active ones are determined...
October 5, 2018: European Journal of Medicinal Chemistry
Hamid Sadeghian, Seyed Mohammad Seyedi, Zeinab Jafari
Objectives: 15-Lipoxygenases are one of the iron-containing proteins capable of performing peroxidation of unsaturated fatty acids in animals and plants. The critical role of enzymes in the formation of inflammations, sensitivities, and some cancers has been demonstrated in mammals. The importance of enzymes has led to the development of mechanistic studies, product analysis, and synthesis of inhibitors. Materials and Methods: The inhibitory activity of all synthetic compounds against SLO (soybean 15-lipoxygenase: L1; EC 1,13,11,12) was determined using the peroxide formation method...
July 2018: Iranian Journal of Basic Medical Sciences
Hou-Chuan Lai, Chueng-He Lu, Chih-Shung Wong, Bo-Feng Lin, Shun-Ming Chan, Chan-Yang Kuo, Zhi-Fu Wu
BACKGROUND: Modulating the inflammatory response to nerve injury may provide therapeutic opportunities by aborting the neurobiological alterations that support the development of persistent pain. Baicalein, a 12-lipoxygenase inhibitor, has anti-inflammation properties. It also demonstrates anti-inflammatory functions by inhibiting lipopolysaccharide-induced barrier disruption, expression of cell adhesion molecules, and adhesion and migration of leukocytes. The aim of the present study was to assess the possibility of early treatment of neuropathic pain via the systemic injection of baicalein in rats with left partial sciatic nerve transection (PST)...
November 2018: Journal of the Chinese Medical Association: JCMA
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