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Arachidonic Acid Metabolism Zebrafish Eicosanoids A. Nodes Edges 5,6-EET ephx2 5,6-DHET node 8 hpl 16hpl compound cyp2p10 8,9-EET ephx2 8,9-DHET node complex 14,15-EET ephx2 C14775 enrichment score -1 0 1 Linoleic acid metaolism 20-OH-Leukotriene Arachidonic 12(S)-HPETE 5(S)-HETE Leukotriene B4 cyp4f3 B4 acid alox12 gpx1a lta4h pla2g6 Leukotriene alox5a 5-HPETE alox5a A4 ltc4s Leukotriene C4 ggt5a Leukotriene D4 ptgs2a Prostaglandin Phosphatidylcholine G2 Prostaglandin I2 ptgis ptgs2a K17687 Prostaglandin E2 Prostaglandin ptges cyp4f3 20-HETE H2 Thromboxane cbr1 A2 cyp2u1 tbxas1 Prostaglandin F2 cbr1 alpha ptgdsb Prostaglandin D2 K07415 fam213b K17728 K17721 19(S)-HETE K17687 cyp2p10 cyp2u1 K07425 11,12-EET ephx2 11,12-DHET cyp2p10 Mouse B. Eicosanoids 5,6-EET Ephx2 5,6-DHET Nodes Edges rd1/rd1 -/- compound 8,9-EET Ephx2 8,9-DHET node Pde6b Rho Cyp2j6 node 14,15-EET Ephx2 C14775 complex Cyp2c29 16(R)-HETE enrichment score -1 0 1 Alox8 8(S)-HPETE Alox12b 12(R)-HPETE C14781 Arachidonic Cyp2j6 Cyp2j6 C14782 acid Linoleic acid Pla2g5 metaolism 12(S)-HPETE Cyp2j6 C14813 Cyp2j6 C14814 Alox12 15(S)-HPETE Gpx1 15(S)-HETE Phosphatidylcholine Alox15 20-OH-Leukotriene Alox5 5-HPETE Gpx1 5(S)-HETE Leukotriene B4 Cyp4f14 B4 Lta4h Ptgs1 Prostaglandin Leukotriene G2 Alox5 A4 Ltc4s Leukotriene C4 Ggt1 Leukotriene D4 Cyp4a10 Prostaglandin I2 Ptgis Cyp4f14 20-HETE Ptgs1 Prostaglandin E2 Cyp2u1 Prostaglandin Ptges H2 Thromboxane Cbr1 Tbxas1 A2 Cyp2e1 Cbr1 Prostaglandin F2 alpha K17728 Ptgdsb Prostaglandin D2 K17721 Fam213b 19(S)-HETE Cyp4a10 Cyp2j6 Cyp2u1 Cyp4a10 11,12-EET Ephx2 11,12-DHET Cyp2j6 Downloaded from iovs.arvojournals.org on 10/03/2021 Figure S1. Gene expression changes in the Arachidonic Acid Metabolism pathway. A) A sche- matic of the KEGG Arachidonic Acid Metabolism pathway with differential gene expression plotted for genes with FDR ≤ 0.05 in zebrafish Müller glia. |Log2FC ≥ 1| is represented by the maximum and minimum color value according to the color bar. Genes without color (white) either do not have any data, or did not meet the FDR criterion. For each gene, the left half corresponds to expression chang- es at 8 hpl and the right half corresponds to changes at 16 hpl. B) A schematic of the KEGG Arachi- donic Acid Metabolism pathway with differential gene expression plotted for all genes with expression data (no FDR threshold applied) in mouse Müller glia from retinal degeneration models. |Log2FC ≥ 1| is represented by the maximum and minimum color value according to the color bar. Genes without color (white) do not have any data. For each gene, the left half corresponds to expression changes in Pde6brd1/rd1 and the right half corresponds to changes in Rho-/-. Downloaded from iovs.arvojournals.org on 10/03/2021 Circadian Rhythm A. Creb1 Zebrafish 3’,5’-Cyclic AMP Nodes Csnk1e node 8 hpl 16 hpl +p Per node Fbxw11 +u complex Cul1 enrichment score Prkaa1 -1 0 1 +p Edges compound Fbxl3 Cry1 expression Nr1d1 +u repression activation Per Clock Bhlhe40 inhibition Cry1 +p Arntl phophorylation Rora +u Csnk1e ubiquitination B. Creb1 3’,5’-Cyclic AMP Mouse Nodes Csnk1d rd1/rd1 -/- +p node Pde6b Rho Per Btrc +u node complex Skp1a enrichment score Prkab1 -1 0 1 +p Edges compound Fbxl3 Cry1 Nr1d1 +u expression repression Per Clock activation Bhlhe40 Cry1 inhibition Arntl +p phophorylation Csnk1d Rora +u ubiquitination Downloaded from iovs.arvojournals.org on 10/03/2021 Figure S2. Expression changes in the Circadian Rhythm pathway. A) A schematic of the KEGG Circadian Rhythm pathway with differential gene expression plotted for genes with a FDR ≤ 0.05 in zebrafish Müller glia. |Log2FC ≥ 1| is represented by the maximum and minimum color value accord- ing to the color bar. Genes without color (white) either do not have any data, or did not meet the FDR criterion. For each gene, the left half corresponds to gene expression changes at 8 hpl and the right half corresponds to changes at 16 hpl. B) A schematic of the KEGG Circadian Rhythm pathway with differential gene expression plotted for all genes with expression data (no FDR threshold applied) in mouse Müller glia retinal degeneration models. |Log2FC ≥ 1| is represented by the maximum and minimum color value according to the color bar. Genes without color (white) do not have any data. For each gene, the left half corresponds to expression changes in Pde6brd1/rd1 and the right half cor- responds to changes in Rho-/-. Note that the KEGG pathway does not distinguish between Per1 and Per2. In zebrafish, per2 is positively enriched at both 8 and 16 hpl (5.36, 2.29) (Table S2; Suppl. File 1); in the two mouse degeneration models, Per1 (-2,54, -2.26) and Per2 (-1.14, -0.32) are negatively enriched (Suppl. File 1). Downloaded from iovs.arvojournals.org on 10/03/2021 A. D. B. E. C. F. Downloaded from iovs.arvojournals.org on 10/03/2021 Figure S3. Comparative analysis of gene expression in FACS-isolated Müller glia. Histogram plots of the frequency distribution of gene expression levels in FACS-isolated, GFP+ Müller glia as determined by microarray profiling or RNA-seq analysis. Colored vertical lines represent the expression levels of selected, cell-type specific genes in the associated key. A) Data from the present study (RNA-seq). (B,C) Published datasets from zebrafish Müller glia (microarray). Note: the microarray fromAgilent that was used in Ram- achandran et al., (B) did not contain probes for rho, gnat1, or rlbp1a. D,E, F) Published datasets from mouse Müller glia. Information about the published datasets and cell-type specificity of the selected genes can be found in SupplementaryTable S4 and Supplemen- tary Table S5, respectively. Downloaded from iovs.arvojournals.org on 10/03/2021 A. D. G. B. E. H. C. F. I. Downloaded from iovs.arvojournals.org on 10/03/2021 Figure S4. Comparative analysis of gene expression in single mouse Müller glia. A-H) Histogram plots of the frequency distri- bution of gene expression levels determined by microarray profiling from a published dataset of hand-picked, individual Müller glia. Colored vertical lines represent the expression levels of selected, cell-type specific genes in the associated key. A-E) 8 wk wild-type (WT) mouse Müller glia. F-H) P13 WT mouse Müller glia. I) Log2 Rlbp1 expression values plotted (y-axis) vs. log2 Rho expression val- ues (x-axis) for each of the individually, hand-picked WT mouse Müller glia from P13 (blue) or 8wk (red) mice. Information about the published datasets and cell-type specificity of the selected genes can be found in SupplementaryTable S4 and Supplementary Table S5, respectively. Downloaded from iovs.arvojournals.org on 10/03/2021 A. D. B. E. C. F. Downloaded from iovs.arvojournals.org on 10/03/2021 Figure S5. Comparative analysis of gene expression in FACS-isolated mouse rod and cone photoreceptors. A, B, D, E) Histo- gram plots of the frequency distribution of gene expression levels determined by RNA-seq from published datasets of FACS-isolated, GFP+ mouse photoreceptors. Colored vertical lines represent the expression levels of selected, cell-type specific genes in the asso- ciated key. A) Adult, wild-type (WT) rods. B) Adult, WT cones. C) Log2 gene expression levels in rods vs. cones of selected cell-type specific genes, as indicated in the color code in the associated key. D) P28, WT Nrl:GFP mouse rod photoreceptors. E) P28, Nrl-/- ;Nrl:GFP mouse S-cone-like photoreceptors. Note: this mutant retina does not contain rods. F) Log2 gene expression levels in rods vs. S-cone-like photoreceptors of selected cell-type specific genes, as indicated in the color code in the associated key. Information about the published datasets and cell-type specificity of the selected genes can be found in SupplementaryTable S4 and Supplementary Table S5, respectively. Downloaded from iovs.arvojournals.org on 10/03/2021.
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  • Strict Regio-Specificity of Human Epithelial 15-Lipoxygenase-2

    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.
  • Montelukast, a Leukotriene Receptor Antagonist, for the Treatment of Persistent Asthma in Children Aged 2 to 5 Years

    Montelukast, a Leukotriene Receptor Antagonist, for the Treatment of Persistent Asthma in Children Aged 2 to 5 Years

    Montelukast, a Leukotriene Receptor Antagonist, for the Treatment of Persistent Asthma in Children Aged 2 to 5 Years Barbara Knorr, MD*; Luis M. Franchi, MD‡; Hans Bisgaard, MD§; Jan Hendrik Vermeulen, MDʈ; Peter LeSouef, MD¶; Nancy Santanello, MD, MS*; Theresa M. Michele, MD*; Theodore F. Reiss, MD*; Ha H. Nguyen, PhD*; and Donna L. Bratton, MD# ABSTRACT. Background. The greatest prevalence of baseline period. Patients had a history of physician-di- asthma is in preschool children; however, the clinical agnosed asthma requiring use of ␤-agonist and a pre- utility of asthma therapy for this age group is limited by defined level of daytime asthma symptoms. Caregivers a narrow therapeutic index, long-term tolerability, and answered questions twice daily on a validated, asthma- frequency and/or difficulty of administration. Inhaled specific diary card and, at specified times during the corticosteroids and inhaled cromolyn are the most com- study, completed a validated asthma-specific quality-of- monly prescribed controller therapies for young children life questionnaire. Physicians and caregivers completed a with persistent asthma, although very young patients global evaluation of asthma control at the end of the may have difficulty using inhalers, and dose delivery can study. be variable. Moreover, reduced compliance with inhaled Efficacy end points included: daytime and overnight therapy relative to orally administered therapy has been asthma symptoms, daily use of ␤-agonist, days without reported. One potential advantage of montelukast is the asthma, frequency of asthma attacks, number of patients ease of administering a once-daily chewable tablet; ad- discontinued because of asthma, need for rescue medica- ditionally, no tachyphylaxis or change in the safety pro- tion, physician and caregiver global evaluations of file has been evidenced after up to 140 and 80 weeks of change, asthma-specific caregiver quality of life, and pe- montelukast therapy in adults and pediatric patients ripheral blood eosinophil counts.