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https://www.readbyqxmd.com/read/29067980/comparative-analysis-of-inflammatory-gene-expression-levels-in-metabolic-syndrome-coronary-artery-disease
#1
Jiny Nair, Vijay V Kakkar, Jayashree Shanker
BACKGROUND & OBJECTIVES: Metabolic syndrome (MetS) increases the likelihood of developing coronary artery disease (CAD), and inflammation is involved in the pathogenesis of both these conditions. The present work was conducted to examine the relative expression of 18 key inflammatory genes associated with MetS and incident CAD in a representative group of patients. METHODS: A total of 178 male patients, including 57 with CAD and 121 without CAD, were enrolled in the study...
June 2017: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/29051536/feasibility-and-physiological-relevance-of-designing-highly-potent-aminopeptidase-sparing-leukotriene-a4-hydrolase-inhibitors
#2
Shin Numao, Franziska Hasler, Claire Laguerre, Honnappa Srinivas, Nathalie Wack, Petra Jäger, Andres Schmid, Arnaud Osmont, Patrik Röthlisberger, Jeremy Houguenade, Christian Bergsdorf, Janet Dawson, Nathalie Carte, Andreas Hofmann, Christian Markert, Liz Hardaker, Andreas Billich, Romain M Wolf, Carlos A Penno, Birgit Bollbuck, Wolfgang Miltz, Till A Röhn
Leukotriene A4 Hydrolase (LTA4H) is a bifunctional zinc metalloenzyme that comprises both epoxide hydrolase and aminopeptidase activity, exerted by two overlapping catalytic sites. The epoxide hydrolase function of the enzyme catalyzes the biosynthesis of the pro-inflammatory lipid mediator leukotriene (LT) B4. Recent literature suggests that the aminopeptidase function of LTA4H is responsible for degradation of the tripeptide Pro-Gly-Pro (PGP) for which neutrophil chemotactic activity has been postulated. It has been speculated that the design of epoxide hydrolase selective LTA4H inhibitors that spare the aminopeptidase pocket may therefore lead to more efficacious anti-inflammatory drugs...
October 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29042030/recent-advances-in-clinical-development-of-leukotriene-b4-pathway-drugs
#3
REVIEW
L Bhatt, K Roinestad, T Van, E B Springman
The LTB4 pathway is an attractive target for therapeutic drug development. Two broad classes of drugs have been pursued: antagonists of the primary LTB4 receptors (BLT1 and BLT2) and inhibitors of LTA4 Hydrolase (LTA4H), the rate limiting enzyme in the production of LTB4. An initial wave of effort culminated in the 1990s. Over the past 15 years, a second wave of more selective drug candidates, including at least 5 BLT antagonists and 6 LTA4H inhibitors, have reached Phase 2 clinical trials. Despite the extensive efforts to discover and develop LTB4 pathway targeting drugs, only one has reached the market to date...
October 2017: Seminars in Immunology
https://www.readbyqxmd.com/read/29042025/biosynthesis-of-leukotriene-b4
#4
REVIEW
Min Wan, Xiao Tang, Alena Stsiapanava, Jesper Z Haeggström
Leukotriene B4 (LTB4) is a lipid mediator derived from arachidonic acid (AA) by the sequential action of 5-lipoxygenase (5-LOX), 5-lipoxygenase-activating protein (FLAP) and LTA4 hydrolase (LTA4H). It was initially recognized for its involvement in the recruitment of neutrophils and is one of the most potent chemotactic agents known to date. A large body of data has indicated that LTB4 plays a significant role in many chronic inflammatory diseases, such as arthritis, chronic obstructive pulmonary disease (COPD), cardiovascular disease, cancer and more recently, metabolic disorder...
October 2017: Seminars in Immunology
https://www.readbyqxmd.com/read/28991413/ligand-based-modeling-for-the-prediction-of-pharmacophore-features-for-multi-targeted-inhibition-of-the-arachidonic-acid-cascade
#5
Nisha Saroj Devi, Rajasekar Shanmugam, Jayanta Ghorai, Meera Ramanan, Pazhamalai Anbarasan, Mukesh Doble
The single-target drugs against the arachidonic acid inflammatory pathway are associated with serious side effects, hence, as a first step towards multi-target drugs, we have studied the pharmacophoric features common to the inhibitors of 5-lipoxygenase-activating protein (FLAP), microsomal prostaglandin E-synthase 1 (mPGES-1) and leukotriene A4 hydrolase (LTA4H). FLAP and mPGES-1 shared subfamily-specific positions (SSPs) and four mPGES-1 inhibitors binding to them mapped onto the pharmacophore derived from FLAP inhibitors (Ph-FLAP)...
October 9, 2017: Molecular Informatics
https://www.readbyqxmd.com/read/28839250/pharmacological-profile-and-efficiency-in-vivo-of-diflapolin-the-first-dual-inhibitor-of-5-lipoxygenase-activating-protein-and-soluble-epoxide-hydrolase
#6
Ulrike Garscha, Erik Romp, Simona Pace, Antonietta Rossi, Veronika Temml, Daniela Schuster, Stefanie König, Jana Gerstmeier, Stefanie Liening, Markus Werner, Heiner Atze, Sandra Wittmann, Christina Weinigel, Silke Rummler, Gerhard K Scriba, Lidia Sautebin, Oliver Werz
Arachidonic acid (AA) is metabolized to diverse bioactive lipid mediators. Whereas the 5-lipoxygenase-activating protein (FLAP) facilitates AA conversion by 5-lipoxygenase (5-LOX) to pro-inflammatory leukotrienes (LTs), the soluble epoxide hydrolase (sEH) degrades anti-inflammatory epoxyeicosatrienoic acids (EETs). Accordingly, dual FLAP/sEH inhibition might be advantageous drugs for intervention of inflammation. We present the in vivo pharmacological profile and efficiency of N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N'-(3,4-dichlorophenyl)urea (diflapolin) that dually targets FLAP and sEH...
August 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28827365/capturing-lta4-hydrolase-in-action-insights-to-the-chemistry-and-dynamics-of-chemotactic-ltb4-synthesis
#7
Alena Stsiapanava, Bengt Samuelsson, Jesper Z Haeggström
Human leukotriene (LT) A4 hydrolase/aminopeptidase (LTA4H) is a bifunctional enzyme that converts the highly unstable epoxide intermediate LTA4 into LTB4, a potent leukocyte activating agent, while the aminopeptidase activity cleaves and inactivates the chemotactic tripeptide Pro-Gly-Pro. Here, we describe high-resolution crystal structures of LTA4H complexed with LTA4, providing the structural underpinnings of the enzyme's unique epoxide hydrolase (EH) activity, involving Zn(2+), Y383, E271, D375, and two catalytic waters...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28658259/neutrophil-derived-ltb4-induces-macrophage-aggregation-in-response-to-encapsulated-streptococcus-iniae-infection
#8
William J B Vincent, Elizabeth A Harvie, John-Demian Sauer, Anna Huttenlocher
Immune cells sense and react to a multitude of factors including both host and microbe-derived signals. Understanding how cells translate these cues into particular cellular behaviors is a complex yet critical area of study. We have previously shown that both neutrophils and macrophages are important for controlling the fish pathogen Streptococcus iniae. Here, we report both host and bacterial determinants leading to the formation of organized macrophage aggregates as part of the host inflammatory response in a subset of infected larvae...
2017: PloS One
https://www.readbyqxmd.com/read/28575166/lta4h-regulates-cell-cycle-and-skin-carcinogenesis
#9
Naomi Oi, Hiroyuki Yamamoto, Alyssa Langfald, Ruihua Bai, Mee-Hyun Lee, Ann M Bode, Zigang Dong
Leukotriene A4 hydrolase (LTA4H), a bifunctional zinc metallo-enzyme, is reportedly overexpressed in several human cancers. Our group has focused on LTA4H as a potential target for cancer prevention and/or therapy. In the present study, we report that LTA4H is a key regulator of cell cycle at the G0/G1 phase acting by negatively regulating p27 expression in skin cancer. We found that LTA4H is overexpressed in human skin cancer tissue. Knocking out LTA4H significantly reduced skin cancer development in the 7,12-dimethylbenz(a)anthracene (DMBA)-initiated/12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted two-stage skin cancer mouse model...
July 1, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28419368/leukotriene-a4-hydrolase-genotype-and-hiv-infection-influence-intracerebral-inflammation-and-survival-from-tuberculous-meningitis
#10
RANDOMIZED CONTROLLED TRIAL
Nguyen T T Thuong, Dorothee Heemskerk, Trinh T B Tram, Le T P Thao, Lalita Ramakrishnan, Vu T N Ha, Nguyen D Bang, Tran T H Chau, Nguyen H Lan, Maxine Caws, Sarah J Dunstan, Nguyen V V Chau, Marcel Wolbers, Nguyen T H Mai, Guy E Thwaites
Background: Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM. Methods: We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM...
April 1, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28419367/evaluating-the-impact-of-lta4h-genotype-and-immune-status-on-survival-from-tuberculous-meningitis
#11
Vinicius M Fava, Erwin Schurr
No abstract text is available yet for this article.
April 1, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28419315/clinical-parameters-routine-inflammatory-markers-and-lta4h-genotype-as-predictors-of-mortality-among-608-patients-with-tuberculous-meningitis-in-indonesia
#12
Arjan van Laarhoven, Sofiati Dian, Carolien Ruesen, Ela Hayati, Michelle S M A Damen, Jessi Annisa, Lidya Chaidir, Rovina Ruslami, Tri Hanggono Achmad, Mihai G Netea, Bachti Alisjahbana, Ahmad Rizal Ganiem, Reinout van Crevel
Background: Damaging inflammation is thought to contribute to the high morbidity and mortality of tuberculous meningitis (TBM), but the link between inflammation and outcome remains unclear. Methods: We performed prospective clinical and routine laboratory analyses of a cohort of adult patients with TBM in Indonesia. We also examined the LTA4H promoter polymorphism, which predicted cerebrospinal fluid (CSF) leukocyte count and survival of Vietnamese patients with TBM...
April 1, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28318626/the-leukotriene-b4-leukotriene-b4-receptor-axis%C3%A2-promotes-cisplatin-induced-acute-kidney-injury%C3%A2-by%C3%A2-modulating-neutrophil-recruitment
#13
Bo Deng, Yuli Lin, Shuai Ma, Yin Zheng, Xuguang Yang, Bingji Li, Wenyan Yu, Qingqing Xu, Tingyan Liu, Chuanming Hao, Rui He, Feng Ding
Cisplatin is an effective chemotherapeutic agent and widely used in treatment of various solid organ malignancies, including head and neck, ovarian, and testicular cancers. However, the induction of acute kidney injury (AKI) is one of its main side effects. Leukotriene B4 receptor 1 (BLT1) mediates the majority of physiological effects of leukotriene B4 (LTB4), a potent lipid chemoattractant generated at inflammation sites, but the role of the LTB4-BLT1 axis in cisplatin-induced AKI remains unknown. Here we found upregulated LTB4 synthesis and BLT1 expression in the kidney after cisplatin administration...
July 2017: Kidney International
https://www.readbyqxmd.com/read/28303931/the-development-of-novel-lta4h-modulators-to-selectively-target-ltb4-generation
#14
Caroline M Low, Samia Akthar, Dhiren F Patel, Stephan Löser, Chi-Tung Wong, Patricia L Jackson, J Edwin Blalock, Stephen A Hare, Clare M Lloyd, Robert J Snelgrove
The pro-inflammatory mediator leukotriene B4 (LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A4 hydrolase (LTA4H) catalyses the distal step in LTB4 synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA4H inhibitors entering clinical trials all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA4H in degrading the neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation...
March 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28218840/drug-repurposing-of-histone-deacetylase-inhibitors-that-alleviate-neutrophilic-inflammation-in-acute-lung-injury-and-idiopathic-pulmonary-fibrosis-via-inhibiting-leukotriene-a4-hydrolase-and-blocking-ltb4-biosynthesis
#15
Weiqiang Lu, Xue Yao, Ping Ouyang, Ningning Dong, Dang Wu, Xingwu Jiang, Zengrui Wu, Chen Zhang, Zhongyu Xu, Yun Tang, Shien Zou, Mingyao Liu, Jian Li, Minghua Zeng, Ping Lin, Feixiong Cheng, Jin Huang
Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are both serious public health problems with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. In this study, we identified that two known histone deacetylase (HDAC) inhibitors, suberanilohydroxamic acid (SAHA, 1) and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide (2), are effective inhibitors of Leukotriene A4 hydrolase (LTA4H), a key enzyme in the biosynthesis of leukotriene B4 (LTB4), across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation...
March 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28074614/mutation-analysis-and-gene-expression-profiling-of-ocular-melanomas-in-cats
#16
J G Rushton, R Ertl, D Klein, B Nell
Feline ocular melanomas show a high malignant behaviour, but adjunctive therapies are non-existent. The aim of this pilot study was to determine, whether feline ocular melanomas harbour mutations comparable to mutations in human melanomas and to evaluate the gene expression status of genes known to be involved in initiation and progression of human melanomas. Mutation hotspot regions of several genes of feline ocular melanomas were analysed by DNA sequencing and RNA expression levels of the respective genes and others were evaluated by quantitative real-time polymerase chain reaction (RT-qPCR)...
January 11, 2017: Veterinary and Comparative Oncology
https://www.readbyqxmd.com/read/28065501/synthesis-docking-cytotoxicity-and-lta4h-inhibitory-activity-of-new-gingerol-derivatives-as-potential-colorectal-cancer-therapy
#17
Mai H El-Naggar, Amira Mira, Fatma M Abdel Bar, Kuniyoshi Shimizu, Mohamed M Amer, Farid A Badria
Leukotriene A4 hydrolase (LTA4H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene which may play an important role in chronic inflammation associated carcinogenesis. [6]-gingerol, the major bioactive compound of Zingiber officinale, is a potential inhibitor of LTA4H, a highly expressed enzyme in colorectal carcinoma. Eighteen compounds; seven of natural origin (including [4]-, [6]-, [8]-, and [10]-gingerol), five new and six known semi-synthesized [6]-gingerol derivatives were examined using docking, in vitro cytotoxicity against human colon cancer cells (HCT-116) and LTA4H aminopeptidase and epoxide hydrolase inhibitory studies...
February 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27990118/cysteinyl-leukotrienes-pathway-genes-atopic-asthma-and-drug-response-from-population-isolates-to-large-genome-wide-association-studies
#18
REVIEW
Miles D Thompson, Valerie Capra, Mark T Clunes, G E Rovati, Jana Stankova, Mary C Maj, David L Duffy
Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27914004/hybrid-receptor-bound-mm-gbsa-per-residue-energy-based-pharmacophore-modelling-enhanced-approach-for-identification-of-selective-lta4h-inhibitors-as-potential-anti-inflammatory-drugs
#19
Patrick Appiah-Kubi, Mahmoud Soliman
Leukotriene A4 hydrolase has been identified as an enzyme with dual anti- and pro-inflammatory role, thus, the conversion of leukotriene to leukotriene B4 in the initiation stage of inflammation and the removal of the chemotactic Pro-Gly-Pro tripeptide. These findings make leukotriene A4 hydrolase an attractive drug target: suggesting an innovative approach towards the identification and design of novel class of compounds that can selectively inhibit leukotriene B4 synthesis while sparing the aminopeptidase activity...
March 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/27856749/in-vivo-amelioration-of-endogenous-antitumor-autoantibodies-via-low-dose-p4n-through-the-lta4h-activin-a-baff-pathway
#20
Yu-Ling Lin, Nu-Man Tsai, Cheng-Hao Hsieh, Shu-Yi Ho, Jung Chang, Hsin-Yi Wu, Ming-Hua Hsu, Chia-Ching Chang, Kuang-Wen Liao, Tiffany L B Jackson, David E Mold, Ru Chih C Huang
Cancer progression is associated with the development of antitumor autoantibodies in patients' sera. Although passive treatment with antitumor antibodies has exhibited remarkable therapeutic efficacy, inhibitory effects on tumor progression by endogenous antitumor autoantibodies (EAAs) have been limited. In this study, we show that P4N, a derivative of the plant lignan nordihydroguaiaretic acid (NDGA), enhanced the production of EAAs and inhibited tumor growth at low noncytotoxic concentrations via its immunoregulatory activity...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
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