Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease
Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity...
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| Veröffentlicht in: | PloS one 2019-04, Vol.14 (4), p.e0215033-e0215033 |
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| creator | Reisdorf, William C Xie, Qing Zeng, Xin Xie, Wensheng Rajpal, Neetu Hoang, Bao Burgert, Mark E Kumar, Vinod Hurle, Mark R Rajpal, Deepak K O'Donnell, Sarah MacDonald, Thomas T Vossenkämper, Anna Wang, Lin Reilly, Mike Votta, Bart J Sanchez, Yolanda Agarwal, Pankaj |
| description | Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature. To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Follow-up immunohistochemistry analysis verified the presence of EPHX2 protein in infiltrated immune cells from Crohn's patient tissue biopsies. We further demonstrated that GSK2256294, a clinical EPHX2i, reduced the production of IL2, IL12p70, IL10 and TNFα in both ulcerative colitis and Crohn's disease patient-derived explant cultures. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1β in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD. |
| doi_str_mv | 10.1371/journal.pone.0215033 |
| format | Article |
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EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature. To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Follow-up immunohistochemistry analysis verified the presence of EPHX2 protein in infiltrated immune cells from Crohn's patient tissue biopsies. We further demonstrated that GSK2256294, a clinical EPHX2i, reduced the production of IL2, IL12p70, IL10 and TNFα in both ulcerative colitis and Crohn's disease patient-derived explant cultures. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1β in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0215033</identifier><identifier>PMID: 31002701</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Animals ; Anti-inflammatory agents ; Arachidonic acid ; Biology ; Biomarkers ; Care and treatment ; Colitis ; Colitis - chemically induced ; Colitis - drug therapy ; Colitis - metabolism ; Colitis - pathology ; Colon ; Crohn's Disease ; Crohns disease ; Cyclohexylamines - pharmacology ; Cyclosporin A ; Cyclosporins ; Cytochrome ; Cytochrome P450 ; Cytochromes P450 ; Cytokines ; Cytokines - metabolism ; Dextran Sulfate - toxicity ; Disease Models, Animal ; Disease susceptibility ; Drug Evaluation, Preclinical - methods ; EDTA ; Epoxide hydrolase ; Epoxide Hydrolases - antagonists & inhibitors ; Fatty acids ; Female ; Gastroenterology ; Gastrointestinal diseases ; Gene expression ; Gene regulation ; Genes ; Genetic regulation ; Humans ; Hydrolases ; Immune system ; Immunohistochemistry ; Inflammation ; Inflammatory bowel disease ; Inflammatory bowel diseases ; Inflammatory Bowel Diseases - drug therapy ; Inflammatory Bowel Diseases - metabolism ; Inflammatory Bowel Diseases - pathology ; Inhibition ; Interleukin 1 ; Interleukin 10 ; Interleukin 2 ; Interleukin 4 ; Intestine ; Laboratory rats ; Lipid metabolism ; Lipids ; Medical research ; Medical treatment ; Mice ; Mice, Inbred C57BL ; Novels ; Patients ; Pattern recognition ; Proteins ; Rodents ; Staphylococcal enterotoxin H ; Triazines - pharmacology ; Tumor necrosis factor-TNF ; Tumor necrosis factor-α ; Ulcerative colitis ; Ulcers ; Unsaturated fatty acids ; γ-Interferon</subject><ispartof>PloS one, 2019-04, Vol.14 (4), p.e0215033-e0215033</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>2019 Reisdorf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 Reisdorf et al 2019 Reisdorf et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-cfa7158829873ea2ed43a6e3096fda5fb5bb20c47fe0b9c319e9ddbbf92d75243</citedby><cites>FETCH-LOGICAL-c758t-cfa7158829873ea2ed43a6e3096fda5fb5bb20c47fe0b9c319e9ddbbf92d75243</cites><orcidid>0000-0001-9411-0179</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474586/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474586/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31002701$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Reisdorf, William C</creatorcontrib><creatorcontrib>Xie, Qing</creatorcontrib><creatorcontrib>Zeng, Xin</creatorcontrib><creatorcontrib>Xie, Wensheng</creatorcontrib><creatorcontrib>Rajpal, Neetu</creatorcontrib><creatorcontrib>Hoang, Bao</creatorcontrib><creatorcontrib>Burgert, Mark E</creatorcontrib><creatorcontrib>Kumar, Vinod</creatorcontrib><creatorcontrib>Hurle, Mark R</creatorcontrib><creatorcontrib>Rajpal, Deepak K</creatorcontrib><creatorcontrib>O'Donnell, Sarah</creatorcontrib><creatorcontrib>MacDonald, Thomas T</creatorcontrib><creatorcontrib>Vossenkämper, Anna</creatorcontrib><creatorcontrib>Wang, Lin</creatorcontrib><creatorcontrib>Reilly, Mike</creatorcontrib><creatorcontrib>Votta, Bart J</creatorcontrib><creatorcontrib>Sanchez, Yolanda</creatorcontrib><creatorcontrib>Agarwal, Pankaj</creatorcontrib><title>Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature. To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Follow-up immunohistochemistry analysis verified the presence of EPHX2 protein in infiltrated immune cells from Crohn's patient tissue biopsies. We further demonstrated that GSK2256294, a clinical EPHX2i, reduced the production of IL2, IL12p70, IL10 and TNFα in both ulcerative colitis and Crohn's disease patient-derived explant cultures. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1β in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD.</description><subject>Acids</subject><subject>Animals</subject><subject>Anti-inflammatory agents</subject><subject>Arachidonic acid</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Care and treatment</subject><subject>Colitis</subject><subject>Colitis - chemically induced</subject><subject>Colitis - drug therapy</subject><subject>Colitis - metabolism</subject><subject>Colitis - pathology</subject><subject>Colon</subject><subject>Crohn's Disease</subject><subject>Crohns disease</subject><subject>Cyclohexylamines - pharmacology</subject><subject>Cyclosporin A</subject><subject>Cyclosporins</subject><subject>Cytochrome</subject><subject>Cytochrome P450</subject><subject>Cytochromes P450</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Dextran Sulfate - toxicity</subject><subject>Disease Models, Animal</subject><subject>Disease susceptibility</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>EDTA</subject><subject>Epoxide hydrolase</subject><subject>Epoxide Hydrolases - antagonists & inhibitors</subject><subject>Fatty acids</subject><subject>Female</subject><subject>Gastroenterology</subject><subject>Gastrointestinal diseases</subject><subject>Gene expression</subject><subject>Gene regulation</subject><subject>Genes</subject><subject>Genetic regulation</subject><subject>Humans</subject><subject>Hydrolases</subject><subject>Immune system</subject><subject>Immunohistochemistry</subject><subject>Inflammation</subject><subject>Inflammatory bowel disease</subject><subject>Inflammatory bowel diseases</subject><subject>Inflammatory Bowel Diseases - drug therapy</subject><subject>Inflammatory Bowel Diseases - metabolism</subject><subject>Inflammatory Bowel Diseases - pathology</subject><subject>Inhibition</subject><subject>Interleukin 1</subject><subject>Interleukin 10</subject><subject>Interleukin 2</subject><subject>Interleukin 4</subject><subject>Intestine</subject><subject>Laboratory rats</subject><subject>Lipid metabolism</subject><subject>Lipids</subject><subject>Medical research</subject><subject>Medical treatment</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Novels</subject><subject>Patients</subject><subject>Pattern recognition</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Staphylococcal enterotoxin H</subject><subject>Triazines - pharmacology</subject><subject>Tumor necrosis factor-TNF</subject><subject>Tumor necrosis factor-α</subject><subject>Ulcerative colitis</subject><subject>Ulcers</subject><subject>Unsaturated fatty acids</subject><subject>γ-Interferon</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11v0zAUhiMEYqPwDxBEQkJw0eKPxElukKZpsEqTNvElrrBOnOPWlRN3dlLYv8dds6lFu0C-iHXynPfYr89JkpeUzCgv6IeVG3wHdrZ2Hc4Ioznh_FFyTCvOpoIR_nhvf5Q8C2FFSM5LIZ4mR5wSwgpCj5NfVx6VNZ1RYFPcgB2gN65LnU7Prs5_stR0S1Ob2xiEFNLObdCmvUfoW-z6VDsfGW2hbaF3_iat3e8INCYgBHyePNFgA74Yv5Pk-6ezb6fn04vLz_PTk4upKvKynyoNBc3LklVlwREYNhkHgZxUQjeQ6zqva0ZUVmgkdaU4rbBqmrrWFWuKnGV8krze6a6tC3K0JkjGKBVFyRmLxHxHNA5Wcu1NC_5GOjDyNuD8QoLvjbIoeanrCjWnec4zzaHMNCVCCNxWb2Jwknwcqw11i42KPniwB6KHfzqzlAu3kSIrsrwUUeDdKODd9YChl60JCq2FDt2wO3eV0yIrIvrmH_Th243UAuIF4nu4WFdtReVJHm3lTJQ8UrMHqLgabI2KfaRNjB8kvD9IiEyPf_oFDCHI-dcv_89e_jhk3-6xSwTbL4Ozw7bNwiGY7UDlXQge9b3JlMjtGNy5IbdjIMcxiGmv9h_oPumu7_lfyM4Cxw</recordid><startdate>20190419</startdate><enddate>20190419</enddate><creator>Reisdorf, William C</creator><creator>Xie, Qing</creator><creator>Zeng, Xin</creator><creator>Xie, Wensheng</creator><creator>Rajpal, Neetu</creator><creator>Hoang, Bao</creator><creator>Burgert, Mark E</creator><creator>Kumar, Vinod</creator><creator>Hurle, Mark R</creator><creator>Rajpal, Deepak K</creator><creator>O'Donnell, Sarah</creator><creator>MacDonald, Thomas T</creator><creator>Vossenkämper, Anna</creator><creator>Wang, Lin</creator><creator>Reilly, Mike</creator><creator>Votta, Bart J</creator><creator>Sanchez, Yolanda</creator><creator>Agarwal, Pankaj</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-9411-0179</orcidid></search><sort><creationdate>20190419</creationdate><title>Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease</title><author>Reisdorf, William C ; Xie, Qing ; Zeng, Xin ; Xie, Wensheng ; Rajpal, Neetu ; Hoang, Bao ; Burgert, Mark E ; Kumar, Vinod ; Hurle, Mark R ; Rajpal, Deepak K ; O'Donnell, Sarah ; MacDonald, Thomas T ; Vossenkämper, Anna ; Wang, Lin ; Reilly, Mike ; Votta, Bart J ; Sanchez, Yolanda ; Agarwal, Pankaj</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-cfa7158829873ea2ed43a6e3096fda5fb5bb20c47fe0b9c319e9ddbbf92d75243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acids</topic><topic>Animals</topic><topic>Anti-inflammatory agents</topic><topic>Arachidonic acid</topic><topic>Biology</topic><topic>Biomarkers</topic><topic>Care and treatment</topic><topic>Colitis</topic><topic>Colitis - chemically induced</topic><topic>Colitis - drug therapy</topic><topic>Colitis - metabolism</topic><topic>Colitis - pathology</topic><topic>Colon</topic><topic>Crohn's Disease</topic><topic>Crohns disease</topic><topic>Cyclohexylamines - pharmacology</topic><topic>Cyclosporin A</topic><topic>Cyclosporins</topic><topic>Cytochrome</topic><topic>Cytochrome P450</topic><topic>Cytochromes P450</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>Dextran Sulfate - toxicity</topic><topic>Disease Models, Animal</topic><topic>Disease susceptibility</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>EDTA</topic><topic>Epoxide hydrolase</topic><topic>Epoxide Hydrolases - antagonists & inhibitors</topic><topic>Fatty acids</topic><topic>Female</topic><topic>Gastroenterology</topic><topic>Gastrointestinal diseases</topic><topic>Gene expression</topic><topic>Gene regulation</topic><topic>Genes</topic><topic>Genetic regulation</topic><topic>Humans</topic><topic>Hydrolases</topic><topic>Immune system</topic><topic>Immunohistochemistry</topic><topic>Inflammation</topic><topic>Inflammatory bowel disease</topic><topic>Inflammatory bowel diseases</topic><topic>Inflammatory Bowel Diseases - drug therapy</topic><topic>Inflammatory Bowel Diseases - metabolism</topic><topic>Inflammatory Bowel Diseases - pathology</topic><topic>Inhibition</topic><topic>Interleukin 1</topic><topic>Interleukin 10</topic><topic>Interleukin 2</topic><topic>Interleukin 4</topic><topic>Intestine</topic><topic>Laboratory rats</topic><topic>Lipid metabolism</topic><topic>Lipids</topic><topic>Medical research</topic><topic>Medical treatment</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Novels</topic><topic>Patients</topic><topic>Pattern recognition</topic><topic>Proteins</topic><topic>Rodents</topic><topic>Staphylococcal enterotoxin H</topic><topic>Triazines - pharmacology</topic><topic>Tumor necrosis factor-TNF</topic><topic>Tumor necrosis factor-α</topic><topic>Ulcerative colitis</topic><topic>Ulcers</topic><topic>Unsaturated fatty acids</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Reisdorf, William C</creatorcontrib><creatorcontrib>Xie, Qing</creatorcontrib><creatorcontrib>Zeng, Xin</creatorcontrib><creatorcontrib>Xie, Wensheng</creatorcontrib><creatorcontrib>Rajpal, Neetu</creatorcontrib><creatorcontrib>Hoang, Bao</creatorcontrib><creatorcontrib>Burgert, Mark E</creatorcontrib><creatorcontrib>Kumar, Vinod</creatorcontrib><creatorcontrib>Hurle, Mark R</creatorcontrib><creatorcontrib>Rajpal, Deepak K</creatorcontrib><creatorcontrib>O'Donnell, Sarah</creatorcontrib><creatorcontrib>MacDonald, Thomas T</creatorcontrib><creatorcontrib>Vossenkämper, Anna</creatorcontrib><creatorcontrib>Wang, Lin</creatorcontrib><creatorcontrib>Reilly, Mike</creatorcontrib><creatorcontrib>Votta, Bart J</creatorcontrib><creatorcontrib>Sanchez, Yolanda</creatorcontrib><creatorcontrib>Agarwal, Pankaj</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Reisdorf, William C</au><au>Xie, Qing</au><au>Zeng, Xin</au><au>Xie, Wensheng</au><au>Rajpal, Neetu</au><au>Hoang, Bao</au><au>Burgert, Mark E</au><au>Kumar, Vinod</au><au>Hurle, Mark R</au><au>Rajpal, Deepak K</au><au>O'Donnell, Sarah</au><au>MacDonald, Thomas T</au><au>Vossenkämper, Anna</au><au>Wang, Lin</au><au>Reilly, Mike</au><au>Votta, Bart J</au><au>Sanchez, Yolanda</au><au>Agarwal, Pankaj</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019-04-19</date><risdate>2019</risdate><volume>14</volume><issue>4</issue><spage>e0215033</spage><epage>e0215033</epage><pages>e0215033-e0215033</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature. To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Follow-up immunohistochemistry analysis verified the presence of EPHX2 protein in infiltrated immune cells from Crohn's patient tissue biopsies. We further demonstrated that GSK2256294, a clinical EPHX2i, reduced the production of IL2, IL12p70, IL10 and TNFα in both ulcerative colitis and Crohn's disease patient-derived explant cultures. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1β in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31002701</pmid><doi>10.1371/journal.pone.0215033</doi><tpages>e0215033</tpages><orcidid>https://orcid.org/0000-0001-9411-0179</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2019-04, Vol.14 (4), p.e0215033-e0215033 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2211678322 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Acids Animals Anti-inflammatory agents Arachidonic acid Biology Biomarkers Care and treatment Colitis Colitis - chemically induced Colitis - drug therapy Colitis - metabolism Colitis - pathology Colon Crohn's Disease Crohns disease Cyclohexylamines - pharmacology Cyclosporin A Cyclosporins Cytochrome Cytochrome P450 Cytochromes P450 Cytokines Cytokines - metabolism Dextran Sulfate - toxicity Disease Models, Animal Disease susceptibility Drug Evaluation, Preclinical - methods EDTA Epoxide hydrolase Epoxide Hydrolases - antagonists & inhibitors Fatty acids Female Gastroenterology Gastrointestinal diseases Gene expression Gene regulation Genes Genetic regulation Humans Hydrolases Immune system Immunohistochemistry Inflammation Inflammatory bowel disease Inflammatory bowel diseases Inflammatory Bowel Diseases - drug therapy Inflammatory Bowel Diseases - metabolism Inflammatory Bowel Diseases - pathology Inhibition Interleukin 1 Interleukin 10 Interleukin 2 Interleukin 4 Intestine Laboratory rats Lipid metabolism Lipids Medical research Medical treatment Mice Mice, Inbred C57BL Novels Patients Pattern recognition Proteins Rodents Staphylococcal enterotoxin H Triazines - pharmacology Tumor necrosis factor-TNF Tumor necrosis factor-α Ulcerative colitis Ulcers Unsaturated fatty acids γ-Interferon |
| title | Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease |
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