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Mohamed K S El-Nagar, Hajjaj H M Abdu-Allah, Ola I A Salem, Abdel-Hamid N Kafafy, Hanan S M Farghaly
Three new series of 5-aminosalicylic acid derivatives; series I (14, 16-18), series II (19-30) and series III (31-41) were synthesized as potential dual COX-2/5-LOX inhibitors. Their chemical structures were confirmed using spectroscopic tools including IR,1 H NMR,13 C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity for all target compounds was evaluated in vivo using carrageenan-induced paw edema. Compound 36 showed the highest anti-inflammatory activity (114.12%) relative to reference drug indomethacin at 4 h interval...
March 6, 2018: Bioorganic Chemistry
Juliana Pavan Zuliani, José María Gutiérrez, Catarina Teixeira
Phagocytosis, a process involved in host defense, requires coordination of a variety of signaling reactions. MT-II, a catalytically-inactive Lys49-PLA2 ¸ and MT-III, an active Asp49-PLA2 isolated from Bothrops asper snake venom, activate phagocytosis in macrophages. In this study the signal pathways mediating zymosan phagocytosis, focusing in lipidic second messengers, were investigated. Macrophages collected from male Swiss mouse peritoneum were obtained 96 h after i.p. injection of thioglycollate. Phagocytosis was evaluated with non-opsonized zymosan in the presence or absence of specific inhibitors...
February 28, 2018: International Journal of Biological Macromolecules
Glaucia Souza-Almeida, Heloisa D'Avila, Patricia E Almeida, Tatiana Luna-Gomes, Sally Liechocki, Barbara Walzog, Ingrid Hepper, Hugo Caire Castro-Faria-Neto, Patricia T Bozza, Christianne Bandeira-Melo, Clarissa M Maya-Monteiro
Leptin directly activates macrophages and lymphocytes, but the role of leptin in neutrophil activation and migration is still controversial. Here, we investigate the in vivo mechanisms of neutrophil migration induced by leptin. The intraperitoneal injection of leptin (1 mg/kg) induces a time- and concentration-dependent neutrophil influx. We did not observe the enhancement of lipid bodies/droplets in neutrophils, after leptin treatment, as we had observed previously in peritoneal macrophages. The participation of leukotriene B4 (LTB4 ) in neutrophil recruitment triggered by leptin was investigated using different strategies...
2018: Frontiers in Immunology
Dan Liao, Bo Qian, Yefei Zhang, Kai Wu, Min Xu
Pancreatic glandular necrosis is rapid inflammation of the pancreas and contributes to severe acute pancreatitis in humans. The pathogenesis of pancreatic tissue inflammation during acute pancreatitis is still largely unknown. Recent studies suggest that 5-lipoxygenase (5-LOX) is an essential mediator in modulating cell death pathways in human diseases. In this study, we aimed to evaluate the effects of a 5-LOX inhibitor, zileuton, on tissue apoptosis and neutrophils activation in pancreatic tissues during acute necrotizing pancreatitis (ANP) in a rat model...
February 5, 2018: Biochemical and Biophysical Research Communications
Delphine L Chen, Howard J Huang, Derek E Byers, Adrian Shifren, Bryan Belikoff, Jacquelyn T Engle, Elizabeth Arentson, Debra Kemp, Sharon Phillips, David E Scherrer, Hideji Fujiwara, Katherine J Spayd, Frank J Brooks, Richard A Pierce, Mario Castro, Warren Isakow
BACKGROUND: Anti-inflammatory drug development efforts for lung disease have been hampered in part by the lack of noninvasive inflammation biomarkers and the limited ability of animal models to predict efficacy in humans. We used 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in a human model of lung inflammation to assess whether pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, and zileuton, a 5-lipoxygenase inhibitor, reduce lung inflammation...
2018: PloS One
Phoebe F Lamie, John N Philoppes, Lucie Rárová
A new series of 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives 4a-l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, 1 H NMR, DEPT-Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)-1, COX-2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX-2 rather than COX-1, and the IC50 values (0...
February 5, 2018: Archiv der Pharmazie
Mai M Helmy, Amel A Hashim, Samar M Mouneir
OBJECTIVE: The current study investigated for the first time the possible beneficial effect of zileuton, a selective 5-lipoxygenase inhibitor (5-LOX), against cisplatin-induced acute renal failure. METHODOLOGY: Male Sprague-Dawley rats (180-200 g) were administered cisplatin once (5 mg/kg, i.p.) alone or combined with oral zileuton (10 mg/kg, given twice; 1 hour before and 12 hours after cisplatin). RESULTS: Compared with control rats, acute cisplatin administration caused significant increases of BUN (33...
January 17, 2018: Prostaglandins & Other Lipid Mediators
Kuifen Ma, Yihe Chen, Xingguang Liang, Jing Miao, Qingwei Zhao
Objectives: Arachidonic Acid/5-lipoxygenase (AA/5-LOX) pathway connects lipid metabolism and proinflammatory cytokine, which are both related to the development and progression of nonalcoholic fatty liver disease (NAFLD). Therefore, the present study was designed to investigate the role of AA/5-LOX pathway in progression of NAFLD, and the effect of zileuton, an inhibitor of 5-LOX, in this model. Materials and Methods: Animal model for progression of NAFLD was established via feeding high saturated fat diet (HFD)...
November 2017: Iranian Journal of Basic Medical Sciences
Amber Dahlin, Weiliang Qiu, Augusto A Litonjua, John J Lima, Mayumi Tamari, Michiaki Kubo, Charles G Irvin, Stephen P Peters, Ann C Wu, Scott T Weiss, Kelan G Tantisira
Variable responsiveness to zileuton, a leukotriene antagonist used to treat asthma, may be due in part to genetic variation. While individual SNPs were previously associated with zileuton-related lung function changes, specific quantitative trait loci (QTLs) and biological pathways that may contribute have not been identified. In this study, we investigated the hypothesis that genetic variation within biological pathways is associated with zileuton response. We performed an integrative QTL mapping and pathway enrichment study to investigate data from a GWAS of zileuton response, in addition to mRNA expression profiles and leukotriene production data from lymphoblastoid cell lines (LCLs) (derived from asthmatics) that were treated with zileuton or ethanol (control)...
January 3, 2018: Pharmacogenomics Journal
Seon Min Woo, Kyoung-Jin Min, Seung Un Seo, Shin Kim, Jong-Wook Park, Dae Kyu Song, Hyun-Shik Lee, Sang Hyun Kim, Taeg Kyu Kwon
Cathepsin G is a serine protease secreted from activated neutrophils, it has important roles in inflammation and immune response. Moreover, cathepsin G promotes tumor cell-cell adhesion and migration in cancer cells. In this study, we investigated whether inhibition of cathepsin G could sensitize TRAIL-mediated apoptosis in cancer cells. An inhibitor of cathepsin G [Cathepsin G inhibitor I (Cat GI); CAS 429676-93-7] markedly induced TRAIL-mediated apoptosis in human renal carcinoma (Caki, ACHN, and A498), lung cancer (A549) and cervical cancer (Hela) cells...
December 5, 2017: Oncotarget
Ghandoura Moussa, Rana Alaaeddine, Lynn M Alaeddine, Rasha Nassra, Ahmed S F Belal, Azza Ismail, Ahmed F El-Yazbi, Yasser S Abdel-Ghany, Aly Hazzaa
Click chemistry was used to synthesize a new series of thioquinazolinone molecules equipped with propargyl moiety,1,2,3-triazolyl and isoxazolyl rings. Our design was based on merging pharmacophores previously reported to exhibit COX-2 inhibitory activities to a thioquinazolinone-privileged scaffold. The synthesized compounds were subjected to in vitro cyclooxygenase COX-1/COX-2 and 15-LOX inhibition assays. Compounds 2c, 3b, 3h, 3j, and 3k showed COX-2 inhibition with IC50 (μM) 0.18, 0.19, 0.11, 0.16 and 0...
December 18, 2017: European Journal of Medicinal Chemistry
Daniel A Yanes, Joy L Mosser-Goldfarb
The role of leukotrienes and prostaglandins in development of atopy has been prototypically established in studies of asthma pathogenesis. Likewise, both in vitro and in vivo studies of atopic dermatitis have demonstrated that these molecules maintain important pathophysiologic roles. Thus, it follows that targeted therapies against these molecules may be promising in management of atopic dermatitis. Montelukast has had questionable efficacy in patients with atopic dermatitis, while small pilots using zileuton did have some clinically significant improvement...
December 14, 2017: Journal of the American Academy of Dermatology
Dan-Dan Li, Hang Xie, Yi-Feng Du, Yan Long, Miranda N Reed, Mei Hu, Vishnu Suppiramaniam, Hao Hong, Su-Su Tang
BACKGROUND: Recent studies demonstrated beneficial effects of zileuton, a 5-lipoxygenase (5LO) inhibitor, on some brain diseases in animal models, but the role of zileuton in the depression remains unknown. METHODS: We investigated the effects of zileuton on depressive behaviors using tail suspension test (TST), forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice injected with lipopolysaccharide (LPS). The 5LO level, activation of microglia, NF-κB p65, TNF-α, IL-1β, brain-derived neurotrophic factor (BDNF), and c-AMP response element-binding protein (CREB) were determined in the mouse hippocampus...
February 2018: Journal of Affective Disorders
Ferdinando Bruno, Giuseppe Spaziano, Angela Liparulo, Fiorentina Roviezzo, Seyed Mohammed Nabavi, Antoni Sureda, Rosanna Filosa, Bruno D'Agostino
The products of 5-lipoxygenase are synthesized and released in the airway when an asthmatic reaction occurs. 5-lipoxygenase via arachidonic acid metabolism produces leukotrienes that mediate bronchoconstriction and inflammatory modifications essential in the pathophysiology of asthma. Until to now, only one approved 5-LO inhibitor, zileuton, can be found as a potential therapy for asthma. With the increasing number of indications for anti-leukotriene (anti-LT) drugs, the development of 5-LO inhibitor agents becomes increasingly important...
October 10, 2017: European Journal of Medicinal Chemistry
Sharon W Y Law, Angel Y S Wong, Shweta Anand, Ian C K Wong, Esther W Chan
INTRODUCTION: Leukotriene-modifying agents (LTMAs) including montelukast, zafirlukast, and zileuton are approved by the US Food and Drug Administration (FDA) for the treatment of asthma and allergic rhinitis. Various neuropsychiatric events (NEs) have been reported; however, the evidence of the association is conflicting. This systematic review investigates the association between NEs and LTMAs by assessing the relevant published literature. METHODS: PubMed, EMBASE, MEDLINE, and Cochrane Library were searched using keywords...
October 26, 2017: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
Yuechun Wang, Prativa Sherchan, Lei Huang, Onat Akyol, Devin W McBride, John H Zhang
BACKGROUND: Intra-operative bleeding, post-operative brain edema and neuroinflammation are major complications in patients with surgical brain injury (SBI). Phospholipase A2 (PLA2) is the upstream enzyme which initiates the PLA2, 5-lipoxygenase (5-LOX) and leukotriene B4 (LTB4) inflammatory pathway. We hypothesized PLA2preconditioning (PPC) prior to SBI can activate endogenous anti-inflammatory responses to protect against SBI. This study evaluated if PPC can ameliorate neurosurgical complications and elucidated PPC-mediated possible protective mechanisms in a rat SBI model...
February 2018: Experimental Neurology
Barbara Maximino Rezende, Rayssa Maciel Athayde, William Antônio Gonçalves, Carolina Braga Resende, Priscila Teles de Tolêdo Bernardes, Denise Alves Perez, Lísia Esper, Alesandra Côrte Reis, Milene Alvarenga Rachid, Marina Gomes Miranda E Castor, Thiago Mattar Cunha, Fabiana Simão Machado, Mauro Martins Teixeira, Vanessa Pinho
Leukotriene B4 (LTB4 ), a proinflammatory mediator produced by the enzyme 5-lipoxygenase (5-LO), is associated with the development of many inflammatory diseases. In this study, we evaluated the participation of the 5-LO/LTB4 axis in graft-versus-host disease (GVHD) pathogenesis by transplanting 5-LO-deficient leukocytes and investigated the effect of pharmacologic 5-LO inhibition by zileuton and LTB4 inhibition by CP-105,696. Mice that received allogeneic transplant showed an increase in nuclear 5-LO expression in splenocytes, indicating enzyme activation after GVHD...
November 6, 2017: Journal of Experimental Medicine
Mohamed A Abdelgawad, Madlen B Labib, Mahmoud Abdel-Latif
A new series of pyrazole-hydrazone derivatives 4a-i were designed and synthesized, their chemical structures were confirmed by IR, (1)H NMR, (13)C NMR, MS spectral data and elemental analysis. IC50 values for all prepared compounds to inhibit COX-1, COX-2 and 5-LOX enzymes were determined in vitro. Compounds 4a (IC50=0.67μM) and 4b (IC50=0.58μM) showed better COX-2 inhibitory activity than celecoxib (IC50=0.87μM) with selectivity index (SI=8.41, 10.55 in sequent) relative to celecoxib (SI=8.85). Also, compound 4a and 4b exhibited superior inhibitory activity against 5-LOX (IC50=1...
October 2017: Bioorganic Chemistry
Dominik Saul, Milena Ninkovic, Marina Komrakova, Lorenz Wolff, Turab Gasimov, Björn Menger, Daniel Bernd Hoffmann, Veit Rohde, Stephan Sehmisch
Estrogen deficiency and aging are associated with osteoporosis, impaired bone healing and lower cognitive performance. Close functional and physical connections occur between bone and the central nervous system. An anti-inflammatory drug, zileuton, is known to have a positive effect on bone and ischemic brain. We studied the effect of zileuton on bone, its healing and on the genes for bone-brain cross-talks. Three-month-old Sprague-Dawley rats were ovariectomized or left untreated. After 8 weeks, bilateral metaphyseal tibia osteotomy with plate osteosynthesis was performed in all rats...
August 31, 2017: Journal of Applied Physiology
Fa-Qian Shen, Zhong-Chang Wang, Song-Yu Wu, Shen-Zhen Ren, Ruo-Jun Man, Bao-Zhong Wang, Hai-Liang Zhu
In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC50 =0...
August 15, 2017: Bioorganic & Medicinal Chemistry Letters
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