Use of Deep‐Learning Assisted Assessment of Cardiac Parameters in Zebrafish to Discover Cyanidin Chloride as a Novel Keap1 Inhibitor Against Doxorubicin‐Induced Cardiotoxicity
Abstract Doxorubicin‐induced cardiomyopathy (DIC) brings tough clinical challenges as well as continued demand in developing agents for adjuvant cardioprotective therapies. Here, a zebrafish phenotypic screening with deep‐learning assisted multiplex cardiac functional analysis using motion videos of...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-10-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202301136 |
| _version_ | 1797648630219276288 |
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| author | Changtong Liu Yingchao Wang Yixin Zeng Zirong Kang Hong Zhao Kun Qi Hongzhi Wu Lu Zhao Yi Wang |
| author_facet | Changtong Liu Yingchao Wang Yixin Zeng Zirong Kang Hong Zhao Kun Qi Hongzhi Wu Lu Zhao Yi Wang |
| author_sort | Changtong Liu |
| collection | DOAJ |
| description | Abstract Doxorubicin‐induced cardiomyopathy (DIC) brings tough clinical challenges as well as continued demand in developing agents for adjuvant cardioprotective therapies. Here, a zebrafish phenotypic screening with deep‐learning assisted multiplex cardiac functional analysis using motion videos of larval hearts is established. Through training the model on a dataset of 2125 labeled ventricular images, ZVSegNet and HRNet exhibit superior performance over previous methods. As a result of high‐content phenotypic screening, cyanidin chloride (CyCl) is identified as a potent suppressor of DIC. CyCl effectively rescues cardiac cell death and improves heart function in both in vitro and in vivo models of Doxorubicin (Dox) exposure. CyCl shows strong inhibitory effects on lipid peroxidation and mitochondrial damage and prevents ferroptosis and apoptosis‐related cell death. Molecular docking and thermal shift assay further suggest a direct binding between CyCl and Keap1, which may compete for the Keap1‐Nrf2 interaction, promote nuclear accumulation of Nrf2, and subsequentially transactivate Gpx4 and other antioxidant factors. Site‐specific mutation of R415A in Keap1 significantly attenuates the protective effects of CyCl against Dox‐induced cardiotoxicity. Taken together, the capability of deep‐learning‐assisted phenotypic screening in identifying promising lead compounds against DIC is exhibited, and new perspectives into drug discovery in the era of artificial intelligence are provided. |
| first_indexed | 2024-03-11T15:34:46Z |
| format | Article |
| id | doaj.art-19c401b617da45ebbc4ab5d719e7f50d |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-11T15:34:46Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-19c401b617da45ebbc4ab5d719e7f50d2023-10-26T20:10:11ZengWileyAdvanced Science2198-38442023-10-011030n/an/a10.1002/advs.202301136Use of Deep‐Learning Assisted Assessment of Cardiac Parameters in Zebrafish to Discover Cyanidin Chloride as a Novel Keap1 Inhibitor Against Doxorubicin‐Induced CardiotoxicityChangtong Liu0Yingchao Wang1Yixin Zeng2Zirong Kang3Hong Zhao4Kun Qi5Hongzhi Wu6Lu Zhao7Yi Wang8College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Road, Xihu District Hangzhou 310058 ChinaCollege of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Road, Xihu District Hangzhou 310058 ChinaState Key Lab of CAD&CG Zhejiang University 866 Yuhangtang Road, Xihu District Hangzhou 310058 ChinaState Key Lab of CAD&CG Zhejiang University 866 Yuhangtang Road, Xihu District Hangzhou 310058 ChinaCollege of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Road, Xihu District Hangzhou 310058 ChinaCollege of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Road, Xihu District Hangzhou 310058 ChinaState Key Lab of CAD&CG Zhejiang University 866 Yuhangtang Road, Xihu District Hangzhou 310058 ChinaCollege of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Road, Xihu District Hangzhou 310058 ChinaCollege of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Road, Xihu District Hangzhou 310058 ChinaAbstract Doxorubicin‐induced cardiomyopathy (DIC) brings tough clinical challenges as well as continued demand in developing agents for adjuvant cardioprotective therapies. Here, a zebrafish phenotypic screening with deep‐learning assisted multiplex cardiac functional analysis using motion videos of larval hearts is established. Through training the model on a dataset of 2125 labeled ventricular images, ZVSegNet and HRNet exhibit superior performance over previous methods. As a result of high‐content phenotypic screening, cyanidin chloride (CyCl) is identified as a potent suppressor of DIC. CyCl effectively rescues cardiac cell death and improves heart function in both in vitro and in vivo models of Doxorubicin (Dox) exposure. CyCl shows strong inhibitory effects on lipid peroxidation and mitochondrial damage and prevents ferroptosis and apoptosis‐related cell death. Molecular docking and thermal shift assay further suggest a direct binding between CyCl and Keap1, which may compete for the Keap1‐Nrf2 interaction, promote nuclear accumulation of Nrf2, and subsequentially transactivate Gpx4 and other antioxidant factors. Site‐specific mutation of R415A in Keap1 significantly attenuates the protective effects of CyCl against Dox‐induced cardiotoxicity. Taken together, the capability of deep‐learning‐assisted phenotypic screening in identifying promising lead compounds against DIC is exhibited, and new perspectives into drug discovery in the era of artificial intelligence are provided.https://doi.org/10.1002/advs.202301136cyanidin chloridedeep learningdoxorubicinKeap1‐Nrf2 interactionzebrafish phenotypic screen |
| spellingShingle | Changtong Liu Yingchao Wang Yixin Zeng Zirong Kang Hong Zhao Kun Qi Hongzhi Wu Lu Zhao Yi Wang Use of Deep‐Learning Assisted Assessment of Cardiac Parameters in Zebrafish to Discover Cyanidin Chloride as a Novel Keap1 Inhibitor Against Doxorubicin‐Induced Cardiotoxicity Advanced Science cyanidin chloride deep learning doxorubicin Keap1‐Nrf2 interaction zebrafish phenotypic screen |
| title | Use of Deep‐Learning Assisted Assessment of Cardiac Parameters in Zebrafish to Discover Cyanidin Chloride as a Novel Keap1 Inhibitor Against Doxorubicin‐Induced Cardiotoxicity |
| title_full | Use of Deep‐Learning Assisted Assessment of Cardiac Parameters in Zebrafish to Discover Cyanidin Chloride as a Novel Keap1 Inhibitor Against Doxorubicin‐Induced Cardiotoxicity |
| title_fullStr | Use of Deep‐Learning Assisted Assessment of Cardiac Parameters in Zebrafish to Discover Cyanidin Chloride as a Novel Keap1 Inhibitor Against Doxorubicin‐Induced Cardiotoxicity |
| title_full_unstemmed | Use of Deep‐Learning Assisted Assessment of Cardiac Parameters in Zebrafish to Discover Cyanidin Chloride as a Novel Keap1 Inhibitor Against Doxorubicin‐Induced Cardiotoxicity |
| title_short | Use of Deep‐Learning Assisted Assessment of Cardiac Parameters in Zebrafish to Discover Cyanidin Chloride as a Novel Keap1 Inhibitor Against Doxorubicin‐Induced Cardiotoxicity |
| title_sort | use of deep learning assisted assessment of cardiac parameters in zebrafish to discover cyanidin chloride as a novel keap1 inhibitor against doxorubicin induced cardiotoxicity |
| topic | cyanidin chloride deep learning doxorubicin Keap1‐Nrf2 interaction zebrafish phenotypic screen |
| url | https://doi.org/10.1002/advs.202301136 |
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