Phenotypic screening in influenza-infected zebrafish identifies Nrf2-mediated compound protective against ischemia-reperfusion injury
Summary: Excessive inflammation contributes to tissue injury in conditions including acute respiratory distress syndrome and ischemia-reperfusion. Moderation of inflammation is a potential therapeutic approach. A phenotypic screen of chemical libraries in influenza A-infected zebrafish identified ae...
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| Language: | English |
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Elsevier
2025-08-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225013264 |
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| author | Elyse Latreille Avinash Naraiah Mukkala Rajiv Sanwal Junghwa Yun Kuiru Wei Raluca Petrut Nikki Zamani Farahani Tristan Philip Leo Xu Tom Bateman Chuxi Pan David E. Williams Trevor Moraes Xiao-Yan Wen Ori Rotstein Raymond J. Andersen Warren L. Lee |
| author_facet | Elyse Latreille Avinash Naraiah Mukkala Rajiv Sanwal Junghwa Yun Kuiru Wei Raluca Petrut Nikki Zamani Farahani Tristan Philip Leo Xu Tom Bateman Chuxi Pan David E. Williams Trevor Moraes Xiao-Yan Wen Ori Rotstein Raymond J. Andersen Warren L. Lee |
| author_sort | Elyse Latreille |
| collection | DOAJ |
| description | Summary: Excessive inflammation contributes to tissue injury in conditions including acute respiratory distress syndrome and ischemia-reperfusion. Moderation of inflammation is a potential therapeutic approach. A phenotypic screen of chemical libraries in influenza A-infected zebrafish identified aeroplysinin-1 (Ap) as a compound capable of reducing edema and improving survival. In murine models of lung injury, Ap improved oxygen saturation. Ap also reduced liver injury in a murine model of liver ischemia/reperfusion. RNA sequencing (RNA-seq) and western blotting indicated that Ap acts via the Nrf2 antioxidant pathway and knockdown of Keap1 or Nrf2 attenuated Ap’s effects. Ap was unable to improve oxygen saturation and had no effect on leukocytes in Nrf2-knockout mice. We generated a derivative of Ap that exhibited improved in vitro potency and onset of action; this compound may be useful for the treatment of inflammation. Together, our work demonstrates the value of phenotypic screening in zebrafish and describes an anti-inflammatory compound. |
| format | Article |
| id | doaj-art-6d2d8ae369d240daab829cb796dbf0c0 |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-6d2d8ae369d240daab829cb796dbf0c02025-08-20T02:50:28ZengElsevieriScience2589-00422025-08-0128811306510.1016/j.isci.2025.113065Phenotypic screening in influenza-infected zebrafish identifies Nrf2-mediated compound protective against ischemia-reperfusion injuryElyse Latreille0Avinash Naraiah Mukkala1Rajiv Sanwal2Junghwa Yun3Kuiru Wei4Raluca Petrut5Nikki Zamani Farahani6Tristan Philip7Leo Xu8Tom Bateman9Chuxi Pan10David E. Williams11Trevor Moraes12Xiao-Yan Wen13Ori Rotstein14Raymond J. Andersen15Warren L. Lee16Deparment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Keenan Research Center, St. Michael’s Hospital, Toronto, ON M5B 1T8, CanadaKeenan Research Center, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, CanadaDeparment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Keenan Research Center, St. Michael’s Hospital, Toronto, ON M5B 1T8, CanadaKeenan Research Center, St. Michael’s Hospital, Toronto, ON M5B 1T8, CanadaKeenan Research Center, St. Michael’s Hospital, Toronto, ON M5B 1T8, CanadaKeenan Research Center, St. Michael’s Hospital, Toronto, ON M5B 1T8, CanadaKeenan Research Center, St. Michael’s Hospital, Toronto, ON M5B 1T8, CanadaKeenan Research Center, St. Michael’s Hospital, Toronto, ON M5B 1T8, CanadaKeenan Research Center, St. Michael’s Hospital, Toronto, ON M5B 1T8, CanadaDepartment of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Earth, Ocean, and Atmospheric Sciences, University of British Columbia, Vancouver, BC V6T 1Z4, CanadaDepartment of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, CanadaDeparment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, CanadaKeenan Research Center, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Earth, Ocean, and Atmospheric Sciences, University of British Columbia, Vancouver, BC V6T 1Z4, CanadaDeparment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Keenan Research Center, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON M5B1T8, Canada; Corresponding authorSummary: Excessive inflammation contributes to tissue injury in conditions including acute respiratory distress syndrome and ischemia-reperfusion. Moderation of inflammation is a potential therapeutic approach. A phenotypic screen of chemical libraries in influenza A-infected zebrafish identified aeroplysinin-1 (Ap) as a compound capable of reducing edema and improving survival. In murine models of lung injury, Ap improved oxygen saturation. Ap also reduced liver injury in a murine model of liver ischemia/reperfusion. RNA sequencing (RNA-seq) and western blotting indicated that Ap acts via the Nrf2 antioxidant pathway and knockdown of Keap1 or Nrf2 attenuated Ap’s effects. Ap was unable to improve oxygen saturation and had no effect on leukocytes in Nrf2-knockout mice. We generated a derivative of Ap that exhibited improved in vitro potency and onset of action; this compound may be useful for the treatment of inflammation. Together, our work demonstrates the value of phenotypic screening in zebrafish and describes an anti-inflammatory compound.http://www.sciencedirect.com/science/article/pii/S2589004225013264TherapeuticsMarine organismPhenotypingMolecular interaction |
| spellingShingle | Elyse Latreille Avinash Naraiah Mukkala Rajiv Sanwal Junghwa Yun Kuiru Wei Raluca Petrut Nikki Zamani Farahani Tristan Philip Leo Xu Tom Bateman Chuxi Pan David E. Williams Trevor Moraes Xiao-Yan Wen Ori Rotstein Raymond J. Andersen Warren L. Lee Phenotypic screening in influenza-infected zebrafish identifies Nrf2-mediated compound protective against ischemia-reperfusion injury iScience Therapeutics Marine organism Phenotyping Molecular interaction |
| title | Phenotypic screening in influenza-infected zebrafish identifies Nrf2-mediated compound protective against ischemia-reperfusion injury |
| title_full | Phenotypic screening in influenza-infected zebrafish identifies Nrf2-mediated compound protective against ischemia-reperfusion injury |
| title_fullStr | Phenotypic screening in influenza-infected zebrafish identifies Nrf2-mediated compound protective against ischemia-reperfusion injury |
| title_full_unstemmed | Phenotypic screening in influenza-infected zebrafish identifies Nrf2-mediated compound protective against ischemia-reperfusion injury |
| title_short | Phenotypic screening in influenza-infected zebrafish identifies Nrf2-mediated compound protective against ischemia-reperfusion injury |
| title_sort | phenotypic screening in influenza infected zebrafish identifies nrf2 mediated compound protective against ischemia reperfusion injury |
| topic | Therapeutics Marine organism Phenotyping Molecular interaction |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225013264 |
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