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Iranian Journal of Basic Medical... Nov 2017Arachidonic Acid/5-lipoxygenase (AA/5-LOX) pathway connects lipid metabolism and proinflammatory cytokine, which are both related to the development and progression of...
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). Liver function, HE staining, NAFLD activity score (NAS) were used to evaluate NAFLD progression. We detected the lipid metabolism substrates: free fatty acids (FFA) and AA, products: cysteinyl-leukotrienes (CysLTs), and changes in gene and protein level of key enzyme in AA/5-LOX pathway including PLA and 5-LOX. Furthermore, we determined whether NAFLD progression pathway was delayed or reversed when zileuton (1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea) was administrated.
RESULTS
Rat model for progression of NAFLD was well established as analyzed by liver transaminase activities, hematoxylin-eosin (HE) staining and NAS. The concentrations of substrates and products in AA/5-LOX pathway were increased with the progression of NAFLD. mRNA and protein expression of PLA and 5-LOX were all enhanced. Moreover, administration of zileuton inhibited AA/5-LOX pathway and reversed the increased transamine activities and NAS.
CONCLUSION
AA/5-LOX pathway promotes the progression of NAFLD, which can be reversed by zileuton.
PubMed: 29299197
DOI: 10.22038/IJBMS.2017.9482 -
Canadian Respiratory Journal 1999Leukotrienes (LTs), lipid mediators of inflammation, have proved to be important biochemicals involved in the symptoms and physiological changes of asthma. In the past... (Comparative Study)
Comparative Study Review
Leukotrienes (LTs), lipid mediators of inflammation, have proved to be important biochemicals involved in the symptoms and physiological changes of asthma. In the past year and a half, the development of three new drugs that modulate the LT pathway has been completed. The first subclass of these drugs, leukotriene receptor antagonists (LTRA) (zafirlukast and montelukast), blocks the interaction of the cysteinyl form of the LTs with the cell type bearing the receptor. The second subclass, the 5-lipoxygenase (5-LO) inhibitors (zileuton) inhibits the 5-LO enzyme, which prevents the formation of both cysteinyl LTs and LTB4. The LT modulators have shown efficacy in inhibiting the physiological changes occurring after allergen, acetylsalicylic acid and exercise challenge in asthmatics. In addition, they have shown efficacy in improving symptoms, beta-agonist use and forced expiratory volume in 1 s (FEV1) in chronic, 'day-to-day' asthma in patients with mild disease. Comparison studies with low doses of inhaled corticosteroids suggest that LT modulators may have similar effects on symptom scores and beta-agonist use, but have lesser effects on FEV1. Finally, emerging data suggest that these drugs are beneficial in decreasing the dose of inhaled corticosteroids necessary to control more moderate to severe asthma. While long term studies will be helpful in determining the 'disease modifying' effects of these drugs, data suggest that these drugs are useful in the treatment of a broad range of asthmatic patients.
Topics: Acetates; Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Cyclopropanes; Forced Expiratory Volume; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Leukotriene B4; Lipoxygenase Inhibitors; Phenylcarbamates; Quinolines; Receptors, Leukotriene; Sulfides; Sulfonamides; Tosyl Compounds
PubMed: 10322101
DOI: 10.1155/1999/676798 -
The Pharmacogenomics Journal Sep 2018Variable responsiveness to zileuton, a leukotriene antagonist used to treat asthma, may be due in part to genetic variation. While individual SNPs were previously...
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). We identified 1060 QTLs jointly associated with zileuton-related differential LTB production in LCLs and lung function change in patients taking zileuton, of which eight QTLs were also significantly associated with persistent LTB production in LCLs following zileuton treatment (i.e., 'poor' responders). Four nominally significant trans-eQTLs were predicted to regulate three candidate genes (SELL, MTF2, and GAL), the expression of which was significantly reduced in LCLs following zileuton treatment. Gene and pathway enrichment analyses of QTL associations identified multiple genes and pathways, predominantly related to phosphatidyl inositol signaling via PI3K. We validated the PI3K pathway activation status in a subset of LCLs demonstrating variable zileuton-related LTB production, and show that in contrast to LCLs that responded to zileuton, the PI3K pathway was activated in poor responder LCLs. Collectively, these findings demonstrate a role for the PIK3 pathway and its targets as important determinants of differential responsiveness to zileuton.
Topics: Asthma; Cell Line; Humans; Hydroxyurea; Leukotrienes; Phosphatidylinositol 3-Kinases; Polymorphism, Single Nucleotide; Quantitative Trait Loci; RNA, Messenger; Signal Transduction
PubMed: 29298996
DOI: 10.1038/s41397-017-0006-0 -
The American Journal of Managed Care Apr 1997This 6-month, randomized, multicenter study was designed to determine whether patients who had been treated with the leukotriene pathway inhibitor zileuton 600 mg four... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Randomized trial of zileuton in patients with moderate asthma: effect of reduced dosing frequency and amounts on pulmonary function and asthma symptoms. Zileuton Study Group.
This 6-month, randomized, multicenter study was designed to determine whether patients who had been treated with the leukotriene pathway inhibitor zileuton 600 mg four times daily (QID) for 2 months could be maintained at the same level of pulmonary function, symptom control, and beta-agonist use with less frequent dosing--first 600 or 800 mg three times daily (TID) and then twice daily (BID). A total of 278 patients with chronic asthma, ages 16 to 70, participated at 25 US centers. All had a 1-second forced expiratory volume (FEV1) of 35%-75%, reversible airway disease, and a nonsmoking history of 1 year. An 8-week open-label period (zileuton 600 mg QID) was followed by a 16-week double-blind period, in which patients who responded to the QID treatment were randomized to receive zileuton 600 or 800 mg TID for 8 weeks and then rerandomized to receive zileuton 600 or 800 mg BID for another 8 weeks. Primary outcomes were FEV1 and asthma symptom scores; secondary outcomes were peak expiratory flow rate, beta-agonist use, and asthma exacerbations requiring steroid rescue. Patients who showed improvements in lung function when treated with zileuton 600 mg QID demonstrated minimal decreases in FEV1 and comparable peak expiratory flow rates, symptom control, beta-agonist use, and systemic corticosteroid rescue when being treated with lower doses and/or less frequent doses of zileuton. Patients who demonstrate improved asthma control with zileuton 600 mg QID may be able to reduce their daily dosage and/or frequency while still maintaining the same level of symptom control.
Topics: Adolescent; Adult; Aged; Asthma; Double-Blind Method; Drug Administration Schedule; Humans; Hydroxyurea; Lipoxygenase Inhibitors; Managed Care Programs; Middle Aged; Respiratory Function Tests; Respiratory System Agents; United States
PubMed: 10169531
DOI: No ID Found -
Neurobiology of Aging Nov 2014The enzyme 5-lipoxygenase (5LO) is upregulated in Alzheimer's disease (AD), and its pharmacologic blockade with zileuton slows down the development of the AD-like...
The enzyme 5-lipoxygenase (5LO) is upregulated in Alzheimer's disease (AD), and its pharmacologic blockade with zileuton slows down the development of the AD-like phenotype in young AD mice. However, its efficacy after the AD pathology is established is unknown. To this end, starting at 12 months of age triple transgenic mice (3xTg) received zileuton, a selective 5LO inhibitor, or placebo for 3 months, and then the effect of this treatment on behavior, amyloid, and tau pathology assessed. Although mice on placebo showed worsening of their memory, treated mice performed even better than at baseline. Compared with placebo, treated mice had significantly less Aβ deposits and tau phosphorylation secondary to reduced γ-secretase and CDK-5 activation, respectively. Our data provide novel insights into the disease-modifying action of pharmacologically inhibiting 5LO as a viable AD therapeutic approach. They represent the successful completion of preclinical studies for the development of this class of drug as clinically applicable therapy for the disease.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloidogenic Proteins; Animals; Arachidonate 5-Lipoxygenase; Cyclin-Dependent Kinase 5; Hydroxyurea; Lipoxygenase Inhibitors; Memory; Mice, Transgenic; Molecular Targeted Therapy; Phosphorylation; Protein Aggregates; Protein Aggregation, Pathological; Up-Regulation; tau Proteins
PubMed: 24973121
DOI: 10.1016/j.neurobiolaging.2014.05.016 -
Metabolites Jul 2021Recently, manipulations with reactive astrocytes have been viewed as a new therapeutic approach that will enable the development of treatments for acute brain injuries...
Recently, manipulations with reactive astrocytes have been viewed as a new therapeutic approach that will enable the development of treatments for acute brain injuries and neurodegenerative diseases. Astrocytes can release several substances, which may exert neurotoxic or neuroprotective effects, but the nature of these substances is still largely unknown. In the present work, we tested the hypothesis that these effects may be attributed to oxylipins, which are synthesized from n-3 or n-6 polyunsaturated fatty acids (PUFAs). We used astrocyte-enriched cultures and found that: (1) lipid fractions secreted by lipopolysaccharide (LPS)-stimulated rat primary astrocyte-enriched cultures-possessed neurotoxic activity in rat primary neuronal cultures; (2) both of the tested oxylipin synthesis inhibitors, ML355 and Zileuton, reduce the LPS-stimulated release of interleukin 6 (IL-6) by astrocyte cultures, but only ML355 can change lipid fractions from neurotoxic to non-toxic; and (3) oxylipin profiles, measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) from neurotoxic and non-toxic lipid fractions, reveal a group of n-3 docosahexaenoic acid derivatives, hydroxydocosahexaenoic acids (HdoHEs)-4-HdoHE, 8-HdoHE, and 17-HdoHE, which may reflect the neuroprotective features of lipid fractions. Regulating the composition of astrocyte oxylipin profiles may be suggested as an approach for regulation of neurotoxicity in inflammatory processes.
PubMed: 34436439
DOI: 10.3390/metabo11080498 -
Prostaglandins, Leukotrienes, and... Oct 2020
Topics: Acetates; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Betacoronavirus; COVID-19; Coronavirus Infections; Cyclopropanes; Cytokine Release Syndrome; Humans; Hydroxyurea; Immunologic Factors; Indoles; Leukotrienes; Pandemics; Phenylcarbamates; Pneumonia, Viral; Quinolines; SARS-CoV-2; Severity of Illness Index; Sulfides; Sulfonamides; Tosyl Compounds
PubMed: 32977289
DOI: 10.1016/j.plefa.2020.102174 -
Basic & Clinical Pharmacology &... Jan 20145-Lipoxygenase (5-LO) is an important enzyme of the arachidonic acid cascade and catalyses with the help of FLAP, the 5-LO-activating protein, the formation of bioactive... (Review)
Review
5-Lipoxygenase (5-LO) is an important enzyme of the arachidonic acid cascade and catalyses with the help of FLAP, the 5-LO-activating protein, the formation of bioactive leukotrienes (LTs). LTs are inflammatory mediators playing a pathophysiological role in different diseases such as asthma, allergic rhinitis as well as cardiovascular diseases and certain types of cancer. Up to now, only one 5-LO inhibitor is on the market, zileuton for the treatment of asthma. With the rising number of indications for anti-LT therapy, 5-LO inhibitor drug development becomes more and more important. This MiniReview gives an update on 5-LO inhibitors currently under clinical development. Furthermore, the recent advances in the search for novel 5-lipoxygenase inhibitors with a focus on computational methods are summarized. Currently, licofelone is the compound with the highest clinical development status (completed phase III trials). 5-LO inhibitor screening programmes based on computational methods could deliver several promising drug-like new molecules. These activities can be expected to be driven by the newly resolved structure of human 5-LO in the future, enabling structure-based drug design. For the prospective drugs in late-stage clinical development, the future will show their clinical safety and efficacy in the particular diseases.
Topics: Arachidonate 5-Lipoxygenase; Arachidonic Acid; Computational Biology; Drug Design; Humans; Leukotrienes; Lipoxygenase Inhibitors; Pyrroles; Rhinitis, Allergic; Rhinitis, Allergic, Perennial
PubMed: 23953428
DOI: 10.1111/bcpt.12114 -
Pharmacological Reports : PR 2012Oxidative stress is a component of many pathological conditions including neurodegenerative diseases and inflammation. An important source of reactive oxygen species...
BACKGROUND
Oxidative stress is a component of many pathological conditions including neurodegenerative diseases and inflammation. An important source of reactive oxygen species (ROS) are lipoxygenases (LOX) - enzymes responsible for the metabolism of arachidonic acid and other polyunsaturated fatty acids. LOX inhibitors have a protective effect in inflammatory diseases and in neurodegenerative disorders because of their anti-inflammatory activity. However, the molecular mechanism of the protective action of LOX inhibitors has not yet been fully elucidated.
METHODS
The aim of this study was to compare the antioxidative potential of widely used LOX inhibitors: BWB70C, AA-861, zileuton, baicalein and NDGA. The antioxidative properties were evaluated in cell-free systems. We measured the effect of the tested compounds on iron/ascorbate-induced lipid peroxidation and on carbonyl group formation in the rat brain homogenate. Direct free radical scavenging was analyzed by using DPPH assay.
RESULTS
Our data showed that the inhibitor of all LOXs, i.e., NDGA, 5-LOX inhibitor BWB70C and the inhibitor of 12/15-LOX, baicalein, significantly decreased the level of lipid and protein oxidation. The free radical scavenging activity of these inhibitors was comparable to known ROS scavengers, i.e., resveratrol and trolox. Zileuton (the inhibitor of 5-LOX) slightly prevented lipid and protein oxidation, it also scavenged the DPPH radical. AA-861 (the inhibitor of 5 and 12/15-LOX) slightly protected lipids against Fe/asc-evoked lipid peroxidation at high concentrations, but had no effect on carbonyl group formation and DPPH scavenging.
CONCLUSIONS
Our results indicate that some LOX inhibitors demonstrate potent anti-oxidative, free radical scavenging properties. AA-861, whose antioxidative potential is very weak, may be a specific tool to be used in experimental and perhaps even clinical applications.
Topics: Animals; Antioxidants; Benzoquinones; Flavanones; Lipoxygenase Inhibitors; Male; Masoprocol; Rats; Rats, Wistar
PubMed: 23238474
DOI: 10.1016/s1734-1140(12)70914-3 -
Journal of Translational Medicine Dec 2023Intrahepatic cholangiocarcinoma (ICC) is poorly treated due to the presence of an inhibitory immune microenvironment. Tumor-associated macrophages (TAM) are an important...
BACKGROUND
Intrahepatic cholangiocarcinoma (ICC) is poorly treated due to the presence of an inhibitory immune microenvironment. Tumor-associated macrophages (TAM) are an important component of TME. ALOX5 is an important lipid metabolism enzyme in cancer progression, but the mechanism by which it regulates TAM to promote ICC progression is unknown. The aim of this study was to investigate the potential mechanism of TAM regulation by ALOX5 and the translational effect of targeting ALOX5.
METHODS
In this study, we investigated the association between the spatial localization of epithelial cells and TAMs by combining scRNA-seq analysis with multiplex immunofluorescence analysis. Through bulk sequencing analysis and spatial analysis, lipid metabolism genes closely related to TAM infiltration were screened. In vitro co-culture model was constructed to verify that ALOX5 and its downstream metabolite LTB4 promote M2 macrophage migration. Bulk sequencing after co-culture combined with single-cell analysis was performed to identify key pathways for up-regulation of M2 macrophage migration. Finally, the effect of CSF1R inhibitor (PLX3397) combined with ALOX5 inhibitor (Zileuton) in vivo was investigated by by xenograft tumor formation experiment in nude mice.
RESULTS
ALOX5 in ICC cells was a key lipid metabolism gene affecting the infiltration of M2 macrophages in TME. Mechanically, LTB4, a metabolite downstream of ALOX5, recruited M2 macrophages to migrate around tumor cells by binding to BLT1/BLT2 and activating the PI3K pathway, which ultimately lead to the promotion of ICC progression. Targeting CSF1R in combination with ALOX5 inhibitor effectively reduced tumor volume and M2 macrophage infiltration abundance.
CONCLUSION
In ICC, LTB4, a metabolite secreted by ALOX5 of epithelial cells, binded to BLT1/BLT2 on TAM surface to activate PI3K pathway and promote TAM migration, thus promoting ICC progression. Targeting CSF1R in combination with ALOX5 inhibitor for ICC is a promising combination therapy modality.
Topics: Animals; Mice; Humans; Phosphatidylinositol 3-Kinases; Tumor-Associated Macrophages; Mice, Nude; Leukotriene B4; Cholangiocarcinoma; Tumor Microenvironment; Cell Line, Tumor; Arachidonate 5-Lipoxygenase
PubMed: 38124204
DOI: 10.1186/s12967-023-04804-1