Reduced 15-Lipoxygenase 2 and Lipoxin A4/Leukotriene B4 Ratio in Children with Cystic Fibrosis

Total Page:16

File Type:pdf, Size:1020Kb

Reduced 15-Lipoxygenase 2 and Lipoxin A4/Leukotriene B4 Ratio in Children with Cystic Fibrosis ORIGINAL ARTICLE CYSTIC FIBROSIS Reduced 15-lipoxygenase 2 and lipoxin A4/leukotriene B4 ratio in children with cystic fibrosis Fiona C. Ringholz1, Paul J. Buchanan1, Donna T. Clarke1, Roisin G. Millar1, Michael McDermott2, Barry Linnane1,3,4, Brian J. Harvey5, Paul McNally1,2 and Valerie Urbach1,6 Affiliations: 1National Children’s Research Centre, Crumlin, Dublin, Ireland. 2Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland. 3Midwestern Regional Hospital, Limerick, Ireland. 4Centre for Interventions in Infection, Inflammation and Immunity (4i), Graduate Entry Medical School, University of Limerick, Limerick, Ireland. 5Molecular Medicine Laboratories, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland. 6Institut National de la Sante´ et de la Recherche Me´dicale, U845, Faculte´ de Me´decine Paris Descartes, Paris, France. Correspondence: Valerie Urbach, National Children’s Research Centre, Crumlin, Dublin 12, Ireland. E-mail: [email protected] ABSTRACT Airway disease in cystic fibrosis (CF) is characterised by impaired mucociliary clearance, persistent bacterial infection and neutrophilic inflammation. Lipoxin A4 (LXA4) initiates the active resolution of inflammation and promotes airway surface hydration in CF models. 15-Lipoxygenase (LO) plays a central role in the ‘‘class switch’’ of eicosanoid mediator biosynthesis from leukotrienes to lipoxins, initiating the active resolution of inflammation. We hypothesised that defective eicosanoid mediator class switching contributes to the failure to resolve inflammation in CF lung disease. Using bronchoalveolar lavage (BAL) samples from 46 children with CF and 19 paediatric controls we demonstrate that the ratio of LXA4 to leukotriene B4 (LTB4) is depressed in CF BAL (p,0.01), even in the absence of infection (p,0.001). Furthermore, 15-LO2 transcripts were significantly less abundant in CF BAL samples (p,0.05). In control BAL, there were positive relationships between 15-LO2 transcript abundance and LXA4/LTB4 ratio (p50.01, r50.66) and with percentage macrophage composition of the BAL fluid (p,0.001, r50.82), which were absent in CF. Impoverished 15-LO2 expression and depression of the LXA4/LTB4 ratio are observed in paediatric CF BAL. These observations provide mechanistic insights into the failure to resolve inflammation in the CF lung. @ERSpublications Reduced 15-LO2 expression in the lower airways of children with CF, associated with a depressed LXA4/LTB4 ratio http://ow.ly/tzZWa This article has supplementary material available from erj.ersjournals.com Received: June 21 2013 | Accepted after revision: Feb 03 2014 | First published online: April 2 2014 Support statement: This work was supported by grants from the National Children’s Research Centre, Ireland (E10/08), the Health Research Board of Ireland (1403 HRA_POR/2011/21) and Institut National de la Sante´ et de la Recherche Me´dicale, France. Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com Copyright ßERS 2014 394 Eur Respir J 2014; 44: 394–404 | DOI: 10.1183/09031936.00106013 CYSTIC FIBROSIS | F.C. RINGHOLZ ET AL. Introduction Cystic fibrosis (CF) is caused by mutation of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and characterised by impaired mucociliary clearance, persistent bacterial infection and neutrophil mediated inflammation. Sequential biosynthesis of eicosanoid classes in inflammatory exudates (termed ‘‘class switching’’) directs the temporal progression of acute inflammation from initiation to propagation and finally to active resolution [1]. Prostaglandins initiate the inflammatory response. Leukotrienes follow and are typified by leukotriene B4 (LTB4) which amplifies and propagates inflammation [1]. LTB4 and interleukin (IL)-8 are both potent neutrophil chemoattractants [2, 3] and negatively correlate with pulmonary function in CF [4, 5]. Lipoxin A4 (LXA4) biosynthesis initiates the active resolution phase of inflammation [6], followed by biosynthesis of the resolvins and protectins. LXA4 inhibits neutrophil effector functions [7] and counter-regulates the effector functions of LTB4, most notably inhibiting LTB4-induced neutrophil transmigration [8–10]. LXA4 also suppresses production of IL-8 by leukocytes and bronchial epithelial cells [11–13]. Mice treated with analogues of LXA4 and subsequently challenged with Pseudomonas aeruginosa contained the bacterial challenge more effectively [14]. LXA4 augments airway epithelial innate defence by stimulating tight junction formation [15], enhancing calcium-activated chloride secretion [16], and by restoration of airway surface liquid height in CF airway epithelial cells [17]. LXA4 concentration in CF bronchoalveolar lavage (BAL) has been variously reported as significantly suppressed or not significantly different from controls [14, 18]. LXA4 is biosynthesised in the respiratory tract by transcellular cooperation of neutrophils [19], eosinophils [20], alveolar macrophages [21] or airway epithelial cells [22], each expressing different lipoxygenase (LO) enzymes (fig. 1)[2, 23]. Upregulation of 15-LO activity favours LXA4 biosynthesis at the expense of leukotriene biosynthesis [1, 24]. This occurs both as a result of 15-LO product, 15-hydroxyeicosatetraenoic acid (HETE), competing for catalytic sites at the 5-LO enzyme and thereby reducing the formation of 5(S) HETE, and by competition for the common biosynthetic intermediate leukotriene A4 [1, 22–24]. We hypothesised that ‘‘eicosanoid mediator class switching’’ is defective in CF and may play a mechanistic role in the failure to resolve inflammation in CF lung disease. We measured eicosanoids associated with the ‘‘class switch’’ [1] from propagation (leukotrienes) to resolution of inflammation (lipoxins), and the relative expression of mRNA transcripts for eicosanoid synthetic enzymes (5-LO, 12-LO and 15-LO1/2 and leukotriene A4 hydrolase (LTA4H)) in BAL from children with CF and compared this with paediatric a) Neutrophil AA 5-LO LTA4H LTA4 5-LO FIGURE 1 An illustration of lipoxin A4 (LXA4) biosynthesis pathways involving transcellular cooperation in LTB4 LXA4 the airways. a) The neutrophil donates the leukotriene A4 (LTA4) intermediate 15S H(p)ETE formed by the action of 5-lipoxygenase b) (LO) on arachidonic acid (AA) to the acceptor airway epithelial cell or alveolar macrophage, whereby 15-LO1/2 (15- 15-LO1/2 15-LO1/2 LO isoform 1 or 2) catalyses LXA4 formation. Leukotriene B4 (LTB4)is also generated from the LTA4 inter- AA mediate by the action of leukotriene A4 hydrolase (LTA4H). b) Airway epithelial Airway cell or alveolar macrophage 15-LO1/2 epithelial cell activity catalyses the conversion of AA OR Macrophage to 15(S)-hydroperoxyeicosatetraenoic acid 15(S) H(p)ETE, which is donated to the acceptor neutrophil and converted to LXA4 by 5-LO catalysis. DOI: 10.1183/09031936.00106013 395 CYSTIC FIBROSIS | F.C. RINGHOLZ ET AL. controls. In addition, we conducted subgroup analysis based on the presence or absence of microbial pathogens (.104 CFU?mL-1) detected in the BAL fluid. Methods Study population Children with CF were recruited through SHIELD CF (Study of Host Immunity and Early Lung Disease in Children with CF), a longitudinal study established around the preschool surveillance bronchoscopy programmes at Our Lady’s Children Hospital, Crumlin (OLCHC), the National Children’s Hospital, Tallaght and University Hospital Limerick, Limerick, Ireland. Children without CF undergoing bronchoscopy for clinical reasons were recruited as paediatric controls (see the online supplementary material for indications and treatment characteristics). Assessments were undertaken when the children were in a stable clinical condition. Children were excluded from the analysis if they were taking leukotriene receptor antagonists or treatment doses of antibiotics in the 2 weeks prior to bronchoscopy. Ethical approval for this study was granted by the research ethics committee at each hospital and written informed consent was obtained from the parents of all participating subjects. Bronchoscopy, BAL collection and processing to obtain a supernatant and cell pellet were performed as previously described (online supplementary material) [25]. Measurements An aliquot of BAL was sent to the microbiology lab at OLCHC where testing, including conventional bacterial and viral studies, was performed according to Clinical Pathology Accreditation guidelines (online supplementary material). Samples were considered to have positive microbial culture if one or more pathogen was detected on viral studies or cultured at a concentration of .104 CFU?mL-1. LXA4 and LTB4 concentrations were measured by ELISA (Oxford Biomedical Research, Rochester Hills, MI, USA and Cayman Chemical, Ann Arbor, MI, USA) (for specificities of antisera see online supplementary table E1). IL-8 was measured by ELISA using mouse anti-IL8 capture antibody and biotinylated goat anti- IL8 detection antibody (R&D Systems, Abingdon, UK). Neutrophil elastase (NE) activity was measured as described previously (online supplementary material) [25]. Total and differential cell counts were obtained by the trypan blue exclusion method and light microscopy (for further detail see the online supplementary material). Total RNA was extracted from the BAL cell pellets using RNAqueous kit (Ambion Inc., Austin, TX, USA). RNA was reverse transcribed using a High Capacity cDNA Reverse Transcription kit (Applied Biosystems, Dun Laoghaire, Ireland).
Recommended publications
  • Epigenetic Regulations of Ahr in the Aspect of Immunomodulation
    International Journal of Molecular Sciences Review Epigenetic Regulations of AhR in the Aspect of Immunomodulation Anna Wajda 1,* , Joanna Łapczuk-Roma ´nska 2 and Agnieszka Paradowska-Gorycka 1 1 Department of Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; [email protected] 2 Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland; [email protected] * Correspondence: [email protected] Received: 31 July 2020; Accepted: 28 August 2020; Published: 3 September 2020 Abstract: Environmental factors contribute to autoimmune disease manifestation, and as regarded today, AhR has become an important factor in studies of immunomodulation. Besides immunological aspects, AhR also plays a role in pharmacological, toxicological and many other physiological processes such as adaptive metabolism. In recent years, epigenetic mechanisms have provided new insight into gene regulation and reveal a new contribution to autoimmune disease pathogenesis. DNA methylation, histone modifications, chromatin alterations, microRNA and consequently non-genetic changes in phenotypes connect with environmental factors. Increasing data reveals AhR cross-roads with the most significant in immunology pathways. Although study on epigenetic modulations in autoimmune diseases is still not well understood, therefore future research will help us understand their pathophysiology and help to find new therapeutic strategies. Present literature review
    [Show full text]
  • Environmental Pollution 275 (2021) 116665
    Environmental Pollution 275 (2021) 116665 Contents lists available at ScienceDirect Environmental Pollution journal homepage: www.elsevier.com/locate/envpol Metabolomics reveals the reproductive abnormality in female zebrafish exposed to environmentally relevant levels of climbazole* Ting Zou a, 1, Yan-Qiu Liang b, 1, Xiaoliang Liao a, Xiao-Fan Chen a, Tao Wang c, * Yuanyuan Song c, Zhi-Cheng Lin a, Zenghua Qi a, Zhi-Feng Chen a, d, , Zongwei Cai a, c a Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, School of Environmental Science and Engineering, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou, 510006, China b Faculty of Chemistry and Environmental Science, Guangdong Ocean University, Zhanjiang, 524088, China c State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong Special Administrative Region, China d Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety, South China Normal University, Guangzhou, 510006, China article info abstract Article history: Climbazole (CBZ) ubiquitously detected in the aquatic environment may disrupt fish reproductive Received 15 November 2020 function. Thus far, the previous study has focused on its transcriptional impact of steroidogenesis-related Received in revised form genes on zebrafish, but the underlying toxic mechanism still needs further investigation at the metabolic 10 January 2021 level. In this study, adult zebrafish were chronically exposed to CBZ at concentrations of 0.1 (corre- Accepted 2 February 2021 sponding to the real concentration in surface water), 10, and 1000 mg/L and evaluated for reproductive Available online 5 February 2021 function by egg production, with subsequent ovarian tissue samples taken for histology, metabolomics, and other biochemical analysis.
    [Show full text]
  • Interactions Between the Parasite Philasterides Dicentrarchi and the Immune System of the Turbot Scophthalmus Maximus.A Transcriptomic Analysis
    biology Article Interactions between the Parasite Philasterides dicentrarchi and the Immune System of the Turbot Scophthalmus maximus.A Transcriptomic Analysis Alejandra Valle 1 , José Manuel Leiro 2 , Patricia Pereiro 3 , Antonio Figueras 3 , Beatriz Novoa 3, Ron P. H. Dirks 4 and Jesús Lamas 1,* 1 Department of Fundamental Biology, Institute of Aquaculture, Campus Vida, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; [email protected] 2 Department of Microbiology and Parasitology, Laboratory of Parasitology, Institute of Research on Chemical and Biological Analysis, Campus Vida, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; [email protected] 3 Institute of Marine Research, Consejo Superior de Investigaciones Científicas-CSIC, 36208 Vigo, Spain; [email protected] (P.P.); antoniofi[email protected] (A.F.); [email protected] (B.N.) 4 Future Genomics Technologies, Leiden BioScience Park, 2333 BE Leiden, The Netherlands; [email protected] * Correspondence: [email protected]; Tel.: +34-88-181-6951; Fax: +34-88-159-6904 Received: 4 September 2020; Accepted: 14 October 2020; Published: 15 October 2020 Simple Summary: Philasterides dicentrarchi is a free-living ciliate that causes high mortality in marine cultured fish, particularly flatfish, and in fish kept in aquaria. At present, there is still no clear picture of what makes this ciliate a fish pathogen and what makes fish resistant to this ciliate. In the present study, we used transcriptomic techniques to evaluate the interactions between P. dicentrarchi and turbot leucocytes during the early stages of infection. The findings enabled us to identify some parasite genes/proteins that may be involved in virulence and host resistance, some of which may be good candidates for inclusion in fish vaccines.
    [Show full text]
  • Role of Arachidonic Acid and Its Metabolites in the Biological and Clinical Manifestations of Idiopathic Nephrotic Syndrome
    International Journal of Molecular Sciences Review Role of Arachidonic Acid and Its Metabolites in the Biological and Clinical Manifestations of Idiopathic Nephrotic Syndrome Stefano Turolo 1,* , Alberto Edefonti 1 , Alessandra Mazzocchi 2, Marie Louise Syren 2, William Morello 1, Carlo Agostoni 2,3 and Giovanni Montini 1,2 1 Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Pediatric Nephrology, Dialysis and Transplant Unit, Via della Commenda 9, 20122 Milan, Italy; [email protected] (A.E.); [email protected] (W.M.); [email protected] (G.M.) 2 Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy; [email protected] (A.M.); [email protected] (M.L.S.); [email protected] (C.A.) 3 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pediatric Intermediate Care Unit, 20122 Milan, Italy * Correspondence: [email protected] Abstract: Studies concerning the role of arachidonic acid (AA) and its metabolites in kidney disease are scarce, and this applies in particular to idiopathic nephrotic syndrome (INS). INS is one of the most frequent glomerular diseases in childhood; it is characterized by T-lymphocyte dysfunction, alterations of pro- and anti-coagulant factor levels, and increased platelet count and aggregation, leading to thrombophilia. AA and its metabolites are involved in several biological processes. Herein, Citation: Turolo, S.; Edefonti, A.; we describe the main fields where they may play a significant role, particularly as it pertains to their Mazzocchi, A.; Syren, M.L.; effects on the kidney and the mechanisms underlying INS. AA and its metabolites influence cell Morello, W.; Agostoni, C.; Montini, G.
    [Show full text]
  • The Role of Ferroptosis in Breast Cancer Patients: a Comprehensive Analysis Zeng-Hong Wu1,2, Yun Tang3,Hongyu1 and Hua-Dong Li4
    Wu et al. Cell Death Discovery (2021) 7:93 https://doi.org/10.1038/s41420-021-00473-5 Cell Death Discovery ARTICLE Open Access The role of ferroptosis in breast cancer patients: a comprehensive analysis Zeng-Hong Wu1,2, Yun Tang3,HongYu1 and Hua-Dong Li4 Abstract Breast cancer (BC) affects the breast tissue and is the second most common cause of mortalities among women. Ferroptosis is an iron-dependent cell death mode that is characterized by intracellular accumulation of reactive oxygenspecies(ROS).Weconstructed a prognostic multigene signature based on ferroptosis-associated differentially expressed genes (DEGs). Moreover, we comprehensively analyzed the role of ferroptosis-associated miRNAs, lncRNAs, and immune responses. A total of 259 ferroptosis-related genes wereextracted.KEGGfunction analysis of these genes revealed that they were mainly enriched in the HIF-1 signaling pathway, NOD-like receptor signaling pathway, central carbon metabolism in cancer, and PPAR signaling pathway. Fifteen differentially expressed genes (ALOX15, ALOX15B, ANO6, BRD4, CISD1, DRD5, FLT3, G6PD, IFNG, NGB, NOS2, PROM2, SLC1A4, SLC38A1,andTP63) were selected as independent prognostic factors for BC patients. Moreover, T cell functions, including the CCR score, immune checkpoint, cytolytic activity, HLA, inflammation promotion, para-inflammation, T cell co-stimulation, T cell co-inhibition, and type II INF responses were significantly different between the low- risk and high-risk groups of the TCGA cohort. Immune checkpoints between the two groups revealed that the expressions of PDCD-1 (PD-1), CTLA4, LAG3, TNFSF4/14, TNFRSF4/8/9/14/18/25,andIDO1/2 among others were significantly different. A total of 1185 ferroptosis-related lncRNAs and 219 ferroptosis-related miRNAs were also included in this study.
    [Show full text]
  • Quantitative Proteomics Analysis of Young and Elderly Skin with DIA Mass Spectrometry Reveals New Skin Aging-Related Proteins
    www.aging-us.com AGING 2020, Vol. 12, No. 13 Research Paper Quantitative proteomics analysis of young and elderly skin with DIA mass spectrometry reveals new skin aging-related proteins Jing Ma1,2, Mengting Liu1,2, Yaochi Wang1,2, Cong Xin1,2, Hui Zhang1,2, Shirui Chen1,2, Xiaodong Zheng1,2, Xuejun Zhang1,2, Fengli Xiao1,2,3, Sen Yang1,2 1Department of Dermatology of First Affiliated Hospital, and Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China 2Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, Anhui, China 3The Center for Scientific Research of Anhui Medical University, Hefei, Anhui, China Correspondence to: Fengli Xiao, Sen Yang; email: [email protected], [email protected] Keywords: aging, epidermal proteins, skin rejuvenation and aging, proteome, mass spectrometer Received: February 25, 2020 Accepted: May 27, 2020 Published: June 29, 2020 Copyright: Ma et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Skin aging is a specific manifestation of the physiological aging process that occurs in virtually all organisms. In this study, we used data independent acquisition mass spectrometry to perform a comparative analysis of protein expression in volar forearm skin samples from of 20 healthy young and elderly Chinese individuals. Our quantitative proteomic analysis identified a total of 95 differentially expressed proteins (DEPs) in aged skin compared to young skin. Enrichment analyses of these DEPs (57 upregulated and 38 downregulated proteins) based on the GO, KEGG, and KOG databases revealed functional clusters associated with immunity and inflammation, oxidative stress, biosynthesis and metabolism, proteases, cell proliferation, cell differentiation, and apoptosis.
    [Show full text]
  • Lipoxin A4: a Novel Anti-Inflammatory Molecule? Thorax: First Published As 10.1136/Thx.50.2.111 on 1 February 1995
    Thorax 1995;50:111-112 illl Lipoxin A4: a novel anti-inflammatory molecule? Thorax: first published as 10.1136/thx.50.2.111 on 1 February 1995. Downloaded from Arachidonic acid is metabolised by the cyclooxygenase contractions.22 These studies support the view that LXA4 pathway to the prostaglandins and thromboxane A2 or via may act as a partial agonist at the same or similar site as one of the lipoxygenase pathways.' Three major lip- the sulphidopeptide leukotrienes. oxygenase pathways have been identified in mammalian The fact that 1 5-lipoxygenase is abundant in lung tissue tissue - namely, the 5-, 12-, and 15-lipoxygenases.2A The and that LXA4 has been recovered in the bronchoalveolar 5-lipoxygenase pathway metabolises arachidonic acid lavage fluid ofpatients with asthma and other lung diseases through two intermediates, 5-hydroperoxyeicosatetranoic suggests that LXA4 may be a potential mediator or mod- acid (5-HPETE) and leukotriene A4 (LTA4), to LTB4 and ulator of inflammation in the lung. In a recent study eight the sulphidopeptide leukotrienes LTC4, LTD4, and LTE4.5 subjects underwent inhalation challenge with LXA4,23 but The sulphidopeptide leukotrienes are potent spasmogens6 no effect was seen on specific conductance, rate of airflow for non-vascular smooth muscle and may play a part in at 25% vital capacity (V25), blood pressure, pulse, or the pathogenesis of bronchial asthma.7`10 asthmatic symptoms. There was, however, a significant The interactions between 5-lipoxygenase and 15-lip- shift of the specific conductance and V25 dose-response oxygenase on arachidonic acid metabolism have recently curve to the right after inhalation challenge with LTC4 been studied and a new series of biologically active me- combined with LXA4 compared with that after inhalation tabolites described." 12 These molecules have been termed challenge with LTC4 alone.
    [Show full text]
  • (ALOX15B) (NM 001039130) Human Tagged ORF Clone Product Data
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for RC214018 15 Lipoxygenase 2 (ALOX15B) (NM_001039130) Human Tagged ORF Clone Product data: Product Type: Expression Plasmids Product Name: 15 Lipoxygenase 2 (ALOX15B) (NM_001039130) Human Tagged ORF Clone Tag: Myc-DDK Symbol: ALOX15B Synonyms: 15-LOX-2 Vector: pCMV6-Entry (PS100001) E. coli Selection: Kanamycin (25 ug/mL) Cell Selection: Neomycin This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 5 15 Lipoxygenase 2 (ALOX15B) (NM_001039130) Human Tagged ORF Clone – RC214018 ORF Nucleotide >RC214018 representing NM_001039130 Sequence: Red=Cloning site Blue=ORF Green=Tags(s) TTTTGTAATACGACTCACTATAGGGCGGCCGGGAATTCGTCGACTGGATCCGGTACCGAGGAGATCTGCC GCCGCGATCGCC ATGGCCGAGTTCAGGGTCAGGGTGTCCACCGGAGAAGCCTTCGGGGCTGGCACATGGGACAAAGTGTCTG TCAGCATCGTGGGGACCCGGGGAGAGAGCCCCCCACTGCCCCTGGACAATCTCGGCAAGGAGTTCACTGC GGGCGCTGAGGAGGACTTCCAGGTGACGCTCCCGGAGGACGTAGGCCGAGTGCTGCTGCTGCGCGTGCAC AAGGCGCCCCCAGTGCTGCCCCTGCTGGGGCCCCTGGCCCCGGATGCCTGGTTCTGCCGCTGGTTCCAGC TGACACCGCCGCGGGGCGGCCACCTCCTCTTCCCCTGCTACCAGTGGCTGGAGGGGGCGGGGACCCTGGT GCTGCAGGAGGGTACAGCCAAGGTGTCCTGGGCAGACCACCACCCTGTGCTCCAGCAACAGCGCCAGGAG GAGCTTCAGGCCCGGCAGGAGATGTACCAGTGGAAGGCTTACAACCCAGGTTGGCCTCACTGCCTGGATG AAAAGACAGTGGAAGACTTGGAGCTCAATATCAAATACTCCACAGCCAAGAATGCCAACTTTTATCTACA
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Electronic Supplementary Material (ESI) for Metallomics
    Electronic Supplementary Material (ESI) for Metallomics. This journal is © The Royal Society of Chemistry 2018 Uniprot Entry name Gene names Protein names Predicted Pattern Number of Iron role EC number Subcellular Membrane Involvement in disease Gene ontology (biological process) Id iron ions location associated 1 P46952 3HAO_HUMAN HAAO 3-hydroxyanthranilate 3,4- H47-E53-H91 1 Fe cation Catalytic 1.13.11.6 Cytoplasm No NAD biosynthetic process [GO:0009435]; neuron cellular homeostasis dioxygenase (EC 1.13.11.6) (3- [GO:0070050]; quinolinate biosynthetic process [GO:0019805]; response to hydroxyanthranilate oxygenase) cadmium ion [GO:0046686]; response to zinc ion [GO:0010043]; tryptophan (3-HAO) (3-hydroxyanthranilic catabolic process [GO:0006569] acid dioxygenase) (HAD) 2 O00767 ACOD_HUMAN SCD Acyl-CoA desaturase (EC H120-H125-H157-H161; 2 Fe cations Catalytic 1.14.19.1 Endoplasmic Yes long-chain fatty-acyl-CoA biosynthetic process [GO:0035338]; unsaturated fatty 1.14.19.1) (Delta(9)-desaturase) H160-H269-H298-H302 reticulum acid biosynthetic process [GO:0006636] (Delta-9 desaturase) (Fatty acid desaturase) (Stearoyl-CoA desaturase) (hSCD1) 3 Q6ZNF0 ACP7_HUMAN ACP7 PAPL PAPL1 Acid phosphatase type 7 (EC D141-D170-Y173-H335 1 Fe cation Catalytic 3.1.3.2 Extracellular No 3.1.3.2) (Purple acid space phosphatase long form) 4 Q96SZ5 AEDO_HUMAN ADO C10orf22 2-aminoethanethiol dioxygenase H112-H114-H193 1 Fe cation Catalytic 1.13.11.19 Unknown No oxidation-reduction process [GO:0055114]; sulfur amino acid catabolic process (EC 1.13.11.19) (Cysteamine
    [Show full text]
  • Strict Regio-Specificity of Human Epithelial 15-Lipoxygenase-2
    Strict Regio-specificity of Human Epithelial 15-Lipoxygenase-2 Delineates its Transcellular Synthesis Potential Abigail R. Green, Shannon Barbour, Thomas Horn, Jose Carlos, Jevgenij A. Raskatov, Theodore R. Holman* Department Chemistry and Biochemistry, University of California Santa Cruz, 1156 High Street, Santa Cruz CA 95064, USA *Corresponding author: Tel: 831-459-5884. Email: [email protected] FUNDING: This work was supported by the NIH NS081180 and GM56062. Abbreviations: LOX, lipoxygenase; h15-LOX-2, human epithelial 15-lipoxygenase-2; h15-LOX-1, human reticulocyte 15-lipoxygenase-1; sLO-1, soybean lipoxygenase-1; 5-LOX, leukocyte 5-lipoxygenase; 12-LOX, human platelet 12-lipoxygenase; GP, glutathione peroxidase; AA, arachidonic acid; HETE, hydoxy-eicosatetraenoic acid; HPETE, hydroperoxy-eicosatetraenoic acid; diHETEs, dihydroxy-eicosatetraenoic acids; 5-HETE, 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid; 5-HPETE, 5-hydro peroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid; 12-HPETE, 12-hydroperoxy-5Z,8Z,10E, 14Z-eicosatetraenoic acid; 15-HPETE, 15-hydroperoxy-5Z,8Z,10Z,13E- eicosatetraenoic acid; 5,15-HETE, 5S,15S-dihydroxy-6E,8Z,10Z,13E-eicosatetraenoic acid; 5,15-diHPETE, 5,15-dihydroperoxy-6E,8Z,10Z,13E-eicosatetraenoic acid; 5,6- diHETE, 5S,6R-dihydroxy-7E,9E,11Z,14Z-eicosatetraenoic acid; LTA4, 5S-trans-5,6- oxido-7E,9E,11Z,14Z-eicosatetraenoic acid; LTB4, 5S,12R-dihydroxy-6Z,8E,10E,14Z- eicosatetraenoic acid; LipoxinA4 (LxA4), 5S,6R,15S-trihydroxy-7E,9E,11Z,13E- eicosatetraenoic acid; LipoxinB4 (LxB4), 5S,14R,15S-trihydroxy-6E,8Z,10E,12E- eicosatetraenoic acid. Abstract Lipoxins are an important class of lipid mediators that induce the resolution of inflammation, and arise from transcellular exchange of arachidonic acid (AA)- derived lipoxygenase products.
    [Show full text]
  • Phospholipase A2 Regulates Eicosanoid Class Switching During Inflammasome Activation
    Phospholipase A2 regulates eicosanoid class switching during inflammasome activation Paul C. Norrisa, David Gosselinb, Donna Reichartb, Christopher K. Glassb, and Edward A. Dennisa,1 Departments of aChemistry/Biochemistry and Pharmacology, and bCellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093 Edited by Michael A. Marletta, The Scripps Research Institute, La Jolla, CA, and approved July 30, 2014 (received for review March 13, 2014) Initiation and resolution of inflammation are considered to be to initiate pathogenic killing, subsequent “class switching” to lipoxin tightly connected processes. Lipoxins (LX) are proresolution lipid (LX) formation by “reprogrammed” neutrophils inhibits additional mediators that inhibit phlogistic neutrophil recruitment and pro- neutrophil recruitment during self-resolving inflammatory resolu- mote wound-healing macrophage recruitment in humans via tion (9). The direct link between inflammatory commitment and potent and specific signaling through the LXA4 receptor (ALX). resolution mediated by eicosanoid signaling in macrophages One model of lipoxin biosynthesis involves sequential metabolism remains unclear from short-term vs. long-term priming, but the of arachidonic acid by two cell types expressing a combined trans- complete temporal changes and important interconnections cellular metabolon. It is currently unclear how lipoxins are effi- within the entire eicosadome are now demonstrated. ciently formed from precursors or if they are directly generated after receptor-mediated inflammatory commitment. Here, we pro- Results vide evidence for a pathway by which lipoxins are generated in We first primed immortalized macrophage-like cells (RAW264.7) macrophages as a consequence of sequential activation of toll-like with the TLR4 agonist Kdo2 lipid A (KLA) for various times and receptor 4 (TLR4), a receptor for endotoxin, and P2X7, a purinergic examined the effects on subsequent purinergic stimulated COX receptor for extracellular ATP.
    [Show full text]