In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor
► A novel, potent, selective inhibitor of human, rat and mouse sEH, GSK2256294A, is described. ► In vitro, GSK2256294A exhibits concentration-dependent inhibition of EETs metabolism in whole blood. ► In vivo administration of GSK2256294A results in an increased LTX/LTX diol ratio in rat plasma. ► GS...
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| creator | Podolin, Patricia L. Bolognese, Brian J. Foley, Joseph F. Long, Edward Peck, Brian Umbrecht, Sandra Zhang, Xiaojun Zhu, Penny Schwartz, Benjamin Xie, Wensheng Quinn, Chad Qi, Hongwei Sweitzer, Sharon Chen, Stephanie Galop, Marc Ding, Yun Belyanskaya, Svetlana L. Israel, David I. Morgan, Barry A. Behm, David J. Marino, Joseph P. Kurali, Edit Barnette, Mary S. Mayer, Ruth J. Booth-Genthe, Catherine L. Callahan, James F. |
| description | ► A novel, potent, selective inhibitor of human, rat and mouse sEH, GSK2256294A, is described. ► In vitro, GSK2256294A exhibits concentration-dependent inhibition of EETs metabolism in whole blood. ► In vivo administration of GSK2256294A results in an increased LTX/LTX diol ratio in rat plasma. ► GSK2256294A inhibits the initiation and/or maintenance of cigarette smoke-induced pulmonary inflammation in the mouse. ► GSK2256294A promotes the resolution of cigarette smoke-induced pulmonary inflammation in the mouse.
Soluble epoxide hydrolase (sEH, EPHX2) metabolizes eicosanoid epoxides, including epoxyeicosatrienoic acids (EETs) to the corresponding dihydroxyeicosatrienoic acids (DHETs), and leukotoxin (LTX) to leukotoxin diol (LTX diol). EETs, endothelium-derived hyperpolarizing factors, exhibit potentially beneficial properties, including anti-inflammatory effects and vasodilation. A novel, potent, selective inhibitor of recombinant human, rat and mouse sEH, GSK2256294A, exhibited potent cell-based activity, a concentration-dependent inhibition of the conversion of 14,15-EET to 14,15-DHET in human, rat and mouse whole blood in vitro, and a dose-dependent increase in the LTX/LTX diol ratio in rat plasma following oral administration. Mice receiving 10 days of cigarette smoke exposure concomitant with oral administration of GSK2256294A exhibited significant, dose-dependent reductions in pulmonary leukocytes and keratinocyte chemoattractant (KC, CXCL1) levels. Mice receiving oral administration of GSK2256294A following 10 days of cigarette smoke exposure exhibited significant reductions in pulmonary leukocytes compared to vehicle-treated mice. These data indicate that GSK2256294A attenuates cigarette smoke-induced inflammation by both inhibiting its initiation and/or maintenance and promoting its resolution. Collectively, these data indicate that GSK2256294A would be an appropriate agent to evaluate the role of sEH in clinical studies, for example in diseases where cigarette smoke is a risk factor, such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease. |
| doi_str_mv | 10.1016/j.prostaglandins.2013.02.001 |
| format | Article |
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Soluble epoxide hydrolase (sEH, EPHX2) metabolizes eicosanoid epoxides, including epoxyeicosatrienoic acids (EETs) to the corresponding dihydroxyeicosatrienoic acids (DHETs), and leukotoxin (LTX) to leukotoxin diol (LTX diol). EETs, endothelium-derived hyperpolarizing factors, exhibit potentially beneficial properties, including anti-inflammatory effects and vasodilation. A novel, potent, selective inhibitor of recombinant human, rat and mouse sEH, GSK2256294A, exhibited potent cell-based activity, a concentration-dependent inhibition of the conversion of 14,15-EET to 14,15-DHET in human, rat and mouse whole blood in vitro, and a dose-dependent increase in the LTX/LTX diol ratio in rat plasma following oral administration. Mice receiving 10 days of cigarette smoke exposure concomitant with oral administration of GSK2256294A exhibited significant, dose-dependent reductions in pulmonary leukocytes and keratinocyte chemoattractant (KC, CXCL1) levels. Mice receiving oral administration of GSK2256294A following 10 days of cigarette smoke exposure exhibited significant reductions in pulmonary leukocytes compared to vehicle-treated mice. These data indicate that GSK2256294A attenuates cigarette smoke-induced inflammation by both inhibiting its initiation and/or maintenance and promoting its resolution. Collectively, these data indicate that GSK2256294A would be an appropriate agent to evaluate the role of sEH in clinical studies, for example in diseases where cigarette smoke is a risk factor, such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease.</description><identifier>ISSN: 1098-8823</identifier><identifier>DOI: 10.1016/j.prostaglandins.2013.02.001</identifier><identifier>PMID: 23434473</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>8,11,14-Eicosatrienoic Acid - analogs & derivatives ; 8,11,14-Eicosatrienoic Acid - metabolism ; Administration, Oral ; Adult ; Animals ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Chemokine CXCL1 - biosynthesis ; Chronic obstructive pulmonary disease ; Cigarette smoke-exposure model ; Cyclohexylamines - pharmacology ; Dose-Response Relationship, Drug ; Epoxide Hydrolases - antagonists & inhibitors ; Epoxide Hydrolases - metabolism ; Epoxyeicosatrienoic acids ; Exotoxins - metabolism ; Female ; Humans ; Inflammation ; Inflammation - enzymology ; Inflammation - etiology ; Inflammation - pathology ; Inflammation - prevention & control ; Leukocyte Count ; Leukocytes - drug effects ; Leukocytes - metabolism ; Leukocytes - pathology ; Leukotoxin ; Lung - drug effects ; Lung - enzymology ; Lung - pathology ; Male ; Mice ; Mice, Knockout ; Middle Aged ; Oxidative Stress - drug effects ; Rats ; Soluble epoxide hydrolase inhibitor ; Stearic Acids - metabolism ; Tobacco Smoke Pollution - adverse effects ; Triazines - pharmacology</subject><ispartof>Prostaglandins & other lipid mediators, 2013-07, Vol.104-105, p.25-31</ispartof><rights>2013 Elsevier Inc.</rights><rights>Copyright © 2013 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-cf7af332bb9cc585a680def2fb30a05acd171583b69f8e34ec9dbf96b7fb5ea23</citedby><cites>FETCH-LOGICAL-c386t-cf7af332bb9cc585a680def2fb30a05acd171583b69f8e34ec9dbf96b7fb5ea23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1098882313000075$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23434473$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Podolin, Patricia L.</creatorcontrib><creatorcontrib>Bolognese, Brian J.</creatorcontrib><creatorcontrib>Foley, Joseph F.</creatorcontrib><creatorcontrib>Long, Edward</creatorcontrib><creatorcontrib>Peck, Brian</creatorcontrib><creatorcontrib>Umbrecht, Sandra</creatorcontrib><creatorcontrib>Zhang, Xiaojun</creatorcontrib><creatorcontrib>Zhu, Penny</creatorcontrib><creatorcontrib>Schwartz, Benjamin</creatorcontrib><creatorcontrib>Xie, Wensheng</creatorcontrib><creatorcontrib>Quinn, Chad</creatorcontrib><creatorcontrib>Qi, Hongwei</creatorcontrib><creatorcontrib>Sweitzer, Sharon</creatorcontrib><creatorcontrib>Chen, Stephanie</creatorcontrib><creatorcontrib>Galop, Marc</creatorcontrib><creatorcontrib>Ding, Yun</creatorcontrib><creatorcontrib>Belyanskaya, Svetlana L.</creatorcontrib><creatorcontrib>Israel, David I.</creatorcontrib><creatorcontrib>Morgan, Barry A.</creatorcontrib><creatorcontrib>Behm, David J.</creatorcontrib><creatorcontrib>Marino, Joseph P.</creatorcontrib><creatorcontrib>Kurali, Edit</creatorcontrib><creatorcontrib>Barnette, Mary S.</creatorcontrib><creatorcontrib>Mayer, Ruth J.</creatorcontrib><creatorcontrib>Booth-Genthe, Catherine L.</creatorcontrib><creatorcontrib>Callahan, James F.</creatorcontrib><title>In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor</title><title>Prostaglandins & other lipid mediators</title><addtitle>Prostaglandins Other Lipid Mediat</addtitle><description>► A novel, potent, selective inhibitor of human, rat and mouse sEH, GSK2256294A, is described. ► In vitro, GSK2256294A exhibits concentration-dependent inhibition of EETs metabolism in whole blood. ► In vivo administration of GSK2256294A results in an increased LTX/LTX diol ratio in rat plasma. ► GSK2256294A inhibits the initiation and/or maintenance of cigarette smoke-induced pulmonary inflammation in the mouse. ► GSK2256294A promotes the resolution of cigarette smoke-induced pulmonary inflammation in the mouse.
Soluble epoxide hydrolase (sEH, EPHX2) metabolizes eicosanoid epoxides, including epoxyeicosatrienoic acids (EETs) to the corresponding dihydroxyeicosatrienoic acids (DHETs), and leukotoxin (LTX) to leukotoxin diol (LTX diol). EETs, endothelium-derived hyperpolarizing factors, exhibit potentially beneficial properties, including anti-inflammatory effects and vasodilation. A novel, potent, selective inhibitor of recombinant human, rat and mouse sEH, GSK2256294A, exhibited potent cell-based activity, a concentration-dependent inhibition of the conversion of 14,15-EET to 14,15-DHET in human, rat and mouse whole blood in vitro, and a dose-dependent increase in the LTX/LTX diol ratio in rat plasma following oral administration. Mice receiving 10 days of cigarette smoke exposure concomitant with oral administration of GSK2256294A exhibited significant, dose-dependent reductions in pulmonary leukocytes and keratinocyte chemoattractant (KC, CXCL1) levels. Mice receiving oral administration of GSK2256294A following 10 days of cigarette smoke exposure exhibited significant reductions in pulmonary leukocytes compared to vehicle-treated mice. These data indicate that GSK2256294A attenuates cigarette smoke-induced inflammation by both inhibiting its initiation and/or maintenance and promoting its resolution. Collectively, these data indicate that GSK2256294A would be an appropriate agent to evaluate the role of sEH in clinical studies, for example in diseases where cigarette smoke is a risk factor, such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease.</description><subject>8,11,14-Eicosatrienoic Acid - analogs & derivatives</subject><subject>8,11,14-Eicosatrienoic Acid - metabolism</subject><subject>Administration, Oral</subject><subject>Adult</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Chemokine CXCL1 - biosynthesis</subject><subject>Chronic obstructive pulmonary disease</subject><subject>Cigarette smoke-exposure model</subject><subject>Cyclohexylamines - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Epoxide Hydrolases - antagonists & inhibitors</subject><subject>Epoxide Hydrolases - metabolism</subject><subject>Epoxyeicosatrienoic acids</subject><subject>Exotoxins - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Inflammation - enzymology</subject><subject>Inflammation - etiology</subject><subject>Inflammation - pathology</subject><subject>Inflammation - prevention & control</subject><subject>Leukocyte Count</subject><subject>Leukocytes - drug effects</subject><subject>Leukocytes - metabolism</subject><subject>Leukocytes - pathology</subject><subject>Leukotoxin</subject><subject>Lung - drug effects</subject><subject>Lung - enzymology</subject><subject>Lung - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Middle Aged</subject><subject>Oxidative Stress - drug effects</subject><subject>Rats</subject><subject>Soluble epoxide hydrolase inhibitor</subject><subject>Stearic Acids - metabolism</subject><subject>Tobacco Smoke Pollution - adverse effects</subject><subject>Triazines - pharmacology</subject><issn>1098-8823</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqN0E9PwjAYBvAeNILoVzA9ePCy2a7b6BIvhoiSkHjBc9M_b6VkrNgOIn56S0ATb56aps_zvukPoVtKckpofb_KN8HHXr63sjOui3lBKMtJkRNCz9CQkoZnnBdsgC5jXBGSnim5QIOClawsx2yIFrMO71wfPE4TsDtcdh7rpQxS9xDcl-yd77C3WOLO76DF0bdb1QKGjf90BvByb4JvZYTUXjrleh-u0LmVbYTr0zlCb9OnxeQlm78-zyaP80wzXveZtmNpGSuUarSueCVrTgzYwipGJKmkNnRMK85U3VgOrATdGGWbWo2tqkAWbITujnOTwscWYi_WLmpokwb4bRSU8URQl5Sm6MMxqhNYDGDFJri1DHtBiThYipX4aykOloIUIlmm-s1p01atwfyWfyBTYHoMQPrvzkEQUTvoNBgXQPfCePe_Td8gjpKU</recordid><startdate>201307</startdate><enddate>201307</enddate><creator>Podolin, Patricia L.</creator><creator>Bolognese, Brian J.</creator><creator>Foley, Joseph F.</creator><creator>Long, Edward</creator><creator>Peck, Brian</creator><creator>Umbrecht, Sandra</creator><creator>Zhang, Xiaojun</creator><creator>Zhu, Penny</creator><creator>Schwartz, Benjamin</creator><creator>Xie, Wensheng</creator><creator>Quinn, Chad</creator><creator>Qi, Hongwei</creator><creator>Sweitzer, Sharon</creator><creator>Chen, Stephanie</creator><creator>Galop, Marc</creator><creator>Ding, Yun</creator><creator>Belyanskaya, Svetlana L.</creator><creator>Israel, David I.</creator><creator>Morgan, Barry A.</creator><creator>Behm, David J.</creator><creator>Marino, Joseph P.</creator><creator>Kurali, Edit</creator><creator>Barnette, Mary S.</creator><creator>Mayer, Ruth J.</creator><creator>Booth-Genthe, Catherine L.</creator><creator>Callahan, James F.</creator><general>Elsevier Inc</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>7X8</scope></search><sort><creationdate>201307</creationdate><title>In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor</title><author>Podolin, Patricia L. ; Bolognese, Brian J. ; Foley, Joseph F. ; Long, Edward ; Peck, Brian ; Umbrecht, Sandra ; Zhang, Xiaojun ; Zhu, Penny ; Schwartz, Benjamin ; Xie, Wensheng ; Quinn, Chad ; Qi, Hongwei ; Sweitzer, Sharon ; Chen, Stephanie ; Galop, Marc ; Ding, Yun ; Belyanskaya, Svetlana L. ; Israel, David I. ; Morgan, Barry A. ; Behm, David J. ; Marino, Joseph P. ; Kurali, Edit ; Barnette, Mary S. ; Mayer, Ruth J. ; Booth-Genthe, Catherine L. ; Callahan, James F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-cf7af332bb9cc585a680def2fb30a05acd171583b69f8e34ec9dbf96b7fb5ea23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>8,11,14-Eicosatrienoic Acid - analogs & derivatives</topic><topic>8,11,14-Eicosatrienoic Acid - metabolism</topic><topic>Administration, Oral</topic><topic>Adult</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Chemokine CXCL1 - biosynthesis</topic><topic>Chronic obstructive pulmonary disease</topic><topic>Cigarette smoke-exposure model</topic><topic>Cyclohexylamines - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Epoxide Hydrolases - antagonists & inhibitors</topic><topic>Epoxide Hydrolases - metabolism</topic><topic>Epoxyeicosatrienoic acids</topic><topic>Exotoxins - metabolism</topic><topic>Female</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Inflammation - enzymology</topic><topic>Inflammation - etiology</topic><topic>Inflammation - pathology</topic><topic>Inflammation - prevention & control</topic><topic>Leukocyte Count</topic><topic>Leukocytes - drug effects</topic><topic>Leukocytes - metabolism</topic><topic>Leukocytes - 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Academic</collection><jtitle>Prostaglandins & other lipid mediators</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Podolin, Patricia L.</au><au>Bolognese, Brian J.</au><au>Foley, Joseph F.</au><au>Long, Edward</au><au>Peck, Brian</au><au>Umbrecht, Sandra</au><au>Zhang, Xiaojun</au><au>Zhu, Penny</au><au>Schwartz, Benjamin</au><au>Xie, Wensheng</au><au>Quinn, Chad</au><au>Qi, Hongwei</au><au>Sweitzer, Sharon</au><au>Chen, Stephanie</au><au>Galop, Marc</au><au>Ding, Yun</au><au>Belyanskaya, Svetlana L.</au><au>Israel, David I.</au><au>Morgan, Barry A.</au><au>Behm, David J.</au><au>Marino, Joseph P.</au><au>Kurali, Edit</au><au>Barnette, Mary S.</au><au>Mayer, Ruth J.</au><au>Booth-Genthe, Catherine L.</au><au>Callahan, James F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor</atitle><jtitle>Prostaglandins & other lipid mediators</jtitle><addtitle>Prostaglandins Other Lipid Mediat</addtitle><date>2013-07</date><risdate>2013</risdate><volume>104-105</volume><spage>25</spage><epage>31</epage><pages>25-31</pages><issn>1098-8823</issn><abstract>► A novel, potent, selective inhibitor of human, rat and mouse sEH, GSK2256294A, is described. ► In vitro, GSK2256294A exhibits concentration-dependent inhibition of EETs metabolism in whole blood. ► In vivo administration of GSK2256294A results in an increased LTX/LTX diol ratio in rat plasma. ► GSK2256294A inhibits the initiation and/or maintenance of cigarette smoke-induced pulmonary inflammation in the mouse. ► GSK2256294A promotes the resolution of cigarette smoke-induced pulmonary inflammation in the mouse.
Soluble epoxide hydrolase (sEH, EPHX2) metabolizes eicosanoid epoxides, including epoxyeicosatrienoic acids (EETs) to the corresponding dihydroxyeicosatrienoic acids (DHETs), and leukotoxin (LTX) to leukotoxin diol (LTX diol). EETs, endothelium-derived hyperpolarizing factors, exhibit potentially beneficial properties, including anti-inflammatory effects and vasodilation. A novel, potent, selective inhibitor of recombinant human, rat and mouse sEH, GSK2256294A, exhibited potent cell-based activity, a concentration-dependent inhibition of the conversion of 14,15-EET to 14,15-DHET in human, rat and mouse whole blood in vitro, and a dose-dependent increase in the LTX/LTX diol ratio in rat plasma following oral administration. Mice receiving 10 days of cigarette smoke exposure concomitant with oral administration of GSK2256294A exhibited significant, dose-dependent reductions in pulmonary leukocytes and keratinocyte chemoattractant (KC, CXCL1) levels. Mice receiving oral administration of GSK2256294A following 10 days of cigarette smoke exposure exhibited significant reductions in pulmonary leukocytes compared to vehicle-treated mice. These data indicate that GSK2256294A attenuates cigarette smoke-induced inflammation by both inhibiting its initiation and/or maintenance and promoting its resolution. Collectively, these data indicate that GSK2256294A would be an appropriate agent to evaluate the role of sEH in clinical studies, for example in diseases where cigarette smoke is a risk factor, such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23434473</pmid><doi>10.1016/j.prostaglandins.2013.02.001</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1098-8823 |
| ispartof | Prostaglandins & other lipid mediators, 2013-07, Vol.104-105, p.25-31 |
| issn | 1098-8823 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1381096411 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | 8,11,14-Eicosatrienoic Acid - analogs & derivatives 8,11,14-Eicosatrienoic Acid - metabolism Administration, Oral Adult Animals Anti-Inflammatory Agents, Non-Steroidal - pharmacology Chemokine CXCL1 - biosynthesis Chronic obstructive pulmonary disease Cigarette smoke-exposure model Cyclohexylamines - pharmacology Dose-Response Relationship, Drug Epoxide Hydrolases - antagonists & inhibitors Epoxide Hydrolases - metabolism Epoxyeicosatrienoic acids Exotoxins - metabolism Female Humans Inflammation Inflammation - enzymology Inflammation - etiology Inflammation - pathology Inflammation - prevention & control Leukocyte Count Leukocytes - drug effects Leukocytes - metabolism Leukocytes - pathology Leukotoxin Lung - drug effects Lung - enzymology Lung - pathology Male Mice Mice, Knockout Middle Aged Oxidative Stress - drug effects Rats Soluble epoxide hydrolase inhibitor Stearic Acids - metabolism Tobacco Smoke Pollution - adverse effects Triazines - pharmacology |
| title | In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T20%3A22%3A49IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=In%20vitro%20and%20in%20vivo%20characterization%20of%20a%20novel%20soluble%20epoxide%20hydrolase%20inhibitor&rft.jtitle=Prostaglandins%20&%20other%20lipid%20mediators&rft.au=Podolin,%20Patricia%20L.&rft.date=2013-07&rft.volume=104-105&rft.spage=25&rft.epage=31&rft.pages=25-31&rft.issn=1098-8823&rft_id=info:doi/10.1016/j.prostaglandins.2013.02.001&rft_dat=%3Cproquest_cross%3E1381096411%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1381096411&rft_id=info:pmid/23434473&rft_els_id=S1098882313000075&rfr_iscdi=true |