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LTA4H

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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
#1
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
#2
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...
August 21, 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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
https://www.readbyqxmd.com/read/27761137/selection-of-reliable-reference-genes-for-gene-expression-analysis-under-abiotic-stresses-in-the-desert-biomass-willow-salix-psammophila
#16
Jianbo Li, Huixia Jia, Xiaojiao Han, Jin Zhang, Pei Sun, Mengzhu Lu, Jianjun Hu
Salix psammophila is a desert shrub willow that has extraordinary adaptation to abiotic stresses and plays an important role in maintaining local ecosystems. Moreover, S. psammophila is regarded as a promising biomass feedstock because of its high biomass yields and short rotation coppice cycle. However, few suitable reference genes (RGs) for quantitative real-time polymerase chain reaction (qRT-PCR) constrain the study on normalization of gene expression in S. psammophila until now. Here, we investigated the expression stabilities of 14 candidate RGs across tissue types and under four abiotic stress treatments, including heat, cold, salt, and drought treatments...
2016: Frontiers in Plant Science
https://www.readbyqxmd.com/read/27730172/genetic-regulation-of-expression-of-leukotriene-a4-hydrolase
#17
Tomasz Szul, Peter Castaldi, Michael H Cho, J Edwin Blalock, Amit Gaggar
In chronic inflammatory lung disorders such as chronic obstructive pulmonary disease (COPD), the concurrent organ-specific and systemic inflammatory responses lead to airway remodelling and vascular dysfunction. Although a major common risk factor for COPD, cigarette smoke alone cannot explain the progression of this disease; there is increasing evidence that genetic predisposition also plays a role in COPD susceptibility and progression. A key enzyme in chronic lung inflammation is leukotriene A4 hydrolase (LTA4H)...
January 2016: ERJ Open Research
https://www.readbyqxmd.com/read/27651294/thermodynamic-properties-of-leukotriene-a4-hydrolase-inhibitors
#18
Sandra K Wittmann, Lena Kalinowsky, Jan S Kramer, René Bloecher, Stefan Knapp, Dieter Steinhilber, Denys Pogoryelov, Ewgenij Proschak, Jan Heering
The leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme, containing a peptidase and a hydrolase activity both activities having opposing functions regulating inflammatory response. The hydrolase activity is responsible for the conversion of leukotriene A4 to pro-inflammatory leukotriene B4, and hence, selective inhibitors of the hydrolase activity are of high pharmacological interest. Here we present the thermodynamic characterization of structurally distinct inhibitors of the LTA4H that occupy different regions of the binding site using different biophysical methods...
November 1, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27643598/role-of-lta4h-polymorphism-in-tuberculosis-associated-immune-reconstitution-inflammatory-syndrome-occurrence-and-clinical-severity-in-patients-infected-with-hiv
#19
Gopalan Narendran, Dhanasekaran Kavitha, Ramesh Karunaianantham, Leonardo Gil-Santana, Jilson L Almeida-Junior, Sirasanambatti Devarajulu Reddy, Marimuthu Makesh Kumar, Haribabu Hemalatha, Nagesh Nalini Jayanthi, Narayanan Ravichandran, Raja Krishnaraja, Angamuthu Prabhakar, Tamizhselvan Manoharan, Lokeswaran Nithyananthan, Gunasundari Arjunan, Mohan Natrajan, Soumya Swaminathan, Bruno B Andrade
BACKGROUND: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an inflammatory phenomenon complicating HIV management in coincidental tuberculosis (TB) infection, upon immune reconstitution driven by antiretroviral therapy (ART). Leukotriene A4 hydroxylase (LTA4H), an enzyme which converts LTA4 to LTB4, regulates the balance between the anti-inflammatory lipoxins and pro-inflammatory LTB4, with direct implications in TB-driven inflammation. In humans, a single nucleotide polymorphism (SNP) in the LTA4H promoter which regulates its transcriptional activity (rs17525495) has been identified and described to impact clinical severity of TB presentation and response to corticosteroid therapy...
2016: PloS One
https://www.readbyqxmd.com/read/27379098/aerobic-exercise-reduces-asthma-phenotype-by-modulation-of-the-leukotriene-pathway
#20
Ricardo Wesley Alberca-Custódio, Flávia Regina Greiffo, BreAnne MacKenzie, Manoel Carneiro Oliveira-Junior, Adilson Santos Andrade-Sousa, Gustavo Silveira Graudenz, Angela Batista Gomes Santos, Nilsa Regina Damaceno-Rodrigues, Hugo Caire Castro-Faria-Neto, Fernanda Magalhaes Arantes-Costa, Milton De Arruda Martins, Asghar Abbasi, Chin Jia Lin, Marco Idzko, Ana Paula Ligeiro Oliveira, Hinnak Northoff, Rodolfo Paula Vieira
INTRODUCTION: Leukotrienes (LTs) play a central role in asthma. Low- to moderate-intensity aerobic exercise (AE) reduces asthmatic inflammation in clinical studies and in experimental models. This study investigated whether AE attenuates LT pathway activation in an ovalbumin (OVA) model of asthma. METHODS: Sixty-four male, BALB/c mice were distributed into Control, Exercise (Exe), OVA, and OVA + Exe groups. Treadmill training was performed at moderate intensity, 5×/week, 1 h/session for 4 weeks...
2016: Frontiers in Immunology
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