Cardiotoxicity and Cardioprotection by Artesunate in Larval Zebrafish

Publication type:
Journal article
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000507234600001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1177/1559325819897180
Externe Identifier
  • Clarivate Analytics Document Solution ID: KC5RM
  • PubMed Identifier: 31975974
ISSN
1559-3258
Ausgabe der Veröffentlichung
1
Zeitschrift
DOSE-RESPONSE
Schlüsselwörter
  • cancer
  • malaria
  • natural products
  • network pharmacology
  • toxicology
Artikelnummer
ARTN 1559325819897180
Datum der Veröffentlichung
2020
Status
Published
Titel
Cardiotoxicity and Cardioprotection by Artesunate in Larval Zebrafish
Sub types
  • Article
Ausgabe der Zeitschrift
18

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:p> Although artesunate (ART) is generally accepted as a safe and well-tolerated first-line treatment of severe malaria, cases of severe side effects and toxicity of this compound are also documented. This study applied larval zebrafishes to determine the acute toxicity and efficacy of ART and performed RNA-sequencing analyses to unravel the underlying signaling pathways contributing to ART’s activities. Results from acute toxicity assay showed that a single-dose intravenous injection of ART from 3.6 ng/fish (1/9 maximum nonlethal concentration) to 41.8 ng/fish (lethal dose 10%) obviously induced pericardial edema, circulation defects, yolk sac absorption delay, renal edema, and swim bladder loss, indicating acute cardiotoxicity, nephrotoxicity, and developmental toxicity of ART. Efficacy assay showed that ART at 1/2 lowest observed adverse effect level (LOAEL) exerted cardioprotective effects on zebrafishes with verapamil-induced heart failure. Artesunate significantly restored cardiac malformation, venous stasis, cardiac output decrease, and blood flow dynamics reduction. No adverse events were observed with this treatment, indicating that ART at doses below LOAEL was effective and safe. These results indicate that ART at low doses was cardioprotective, but revealed cardiotoxicity at high doses. RNA-sequencing analysis showed that gene expression of frizzled class receptor 7a ( fzd7a) was significantly upregulated in zebrafishes with verapamil-induced heart failure and significantly downregulated if ART at 1/2 LOAEL was coadministrated, indicating that fzd7a-modulated Wnt signaling may mediate the cardioprotective effect of ART. For the first time, this study revealed the biphasic property of ART, providing in-depth knowledge on the pharmacological efficacy-safety profile for its therapeutic and safe applications in clinic. </jats:p>
Autoren
DOI
10.1177/1559325819897180
eISSN
1559-3258
ISSN
1559-3258
Ausgabe der Veröffentlichung
1
Zeitschrift
Dose-Response
Sprache
en
Online publication date
2020
Paginierung
155932581989718 - 155932581989718
Datum der Veröffentlichung
2020
Status
Published
Herausgeber
SAGE Publications
Herausgeber URL
http://dx.doi.org/10.1177/1559325819897180
Datum der Datenerfassung
2020
Titel
Cardiotoxicity and Cardioprotection by Artesunate in Larval Zebrafish
Ausgabe der Zeitschrift
18

Data source: Crossref

Abstract
Although artesunate (ART) is generally accepted as a safe and well-tolerated first-line treatment of severe malaria, cases of severe side effects and toxicity of this compound are also documented. This study applied larval zebrafishes to determine the acute toxicity and efficacy of ART and performed RNA-sequencing analyses to unravel the underlying signaling pathways contributing to ART's activities. Results from acute toxicity assay showed that a single-dose intravenous injection of ART from 3.6 ng/fish (1/9 maximum nonlethal concentration) to 41.8 ng/fish (lethal dose 10%) obviously induced pericardial edema, circulation defects, yolk sac absorption delay, renal edema, and swim bladder loss, indicating acute cardiotoxicity, nephrotoxicity, and developmental toxicity of ART. Efficacy assay showed that ART at 1/2 lowest observed adverse effect level (LOAEL) exerted cardioprotective effects on zebrafishes with verapamil-induced heart failure. Artesunate significantly restored cardiac malformation, venous stasis, cardiac output decrease, and blood flow dynamics reduction. No adverse events were observed with this treatment, indicating that ART at doses below LOAEL was effective and safe. These results indicate that ART at low doses was cardioprotective, but revealed cardiotoxicity at high doses. RNA-sequencing analysis showed that gene expression of <i>frizzled class receptor 7a</i> (<i>fzd7a</i>) was significantly upregulated in zebrafishes with verapamil-induced heart failure and significantly downregulated if ART at 1/2 LOAEL was coadministrated, indicating that <i>fzd7a</i>-modulated Wnt signaling may mediate the cardioprotective effect of ART. For the first time, this study revealed the biphasic property of ART, providing in-depth knowledge on the pharmacological efficacy-safety profile for its therapeutic and safe applications in clinic.
Addresses
  • The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China.
Autoren
DOI
10.1177/1559325819897180
eISSN
1559-3258
Externe Identifier
  • PubMed Identifier: 31975974
  • PubMed Central ID: PMC6958657
Funding acknowledgements
  • National Natural Science Foundation of China: 81774331
Open access
true
ISSN
1559-3258
Ausgabe der Veröffentlichung
1
Zeitschrift
Dose-response : a publication of International Hormesis Society
Sprache
eng
Medium
Electronic-eCollection
Online publication date
2020
Open access status
Open Access
Paginierung
1559325819897180
Datum der Veröffentlichung
2020
Status
Published
Publisher licence
CC BY-NC
Datum der Datenerfassung
2020
Titel
Cardiotoxicity and Cardioprotection by Artesunate in Larval Zebrafish.
Sub types
  • brief-report
  • Journal Article
Ausgabe der Zeitschrift
18

Files

https://journals.sagepub.com/doi/pdf/10.1177/1559325819897180 https://europepmc.org/articles/PMC6958657?pdf=render

Data source: Europe PubMed Central

Abstract
Although artesunate (ART) is generally accepted as a safe and well-tolerated first-line treatment of severe malaria, cases of severe side effects and toxicity of this compound are also documented. This study applied larval zebrafishes to determine the acute toxicity and efficacy of ART and performed RNA-sequencing analyses to unravel the underlying signaling pathways contributing to ART's activities. Results from acute toxicity assay showed that a single-dose intravenous injection of ART from 3.6 ng/fish (1/9 maximum nonlethal concentration) to 41.8 ng/fish (lethal dose 10%) obviously induced pericardial edema, circulation defects, yolk sac absorption delay, renal edema, and swim bladder loss, indicating acute cardiotoxicity, nephrotoxicity, and developmental toxicity of ART. Efficacy assay showed that ART at 1/2 lowest observed adverse effect level (LOAEL) exerted cardioprotective effects on zebrafishes with verapamil-induced heart failure. Artesunate significantly restored cardiac malformation, venous stasis, cardiac output decrease, and blood flow dynamics reduction. No adverse events were observed with this treatment, indicating that ART at doses below LOAEL was effective and safe. These results indicate that ART at low doses was cardioprotective, but revealed cardiotoxicity at high doses. RNA-sequencing analysis showed that gene expression of frizzled class receptor 7a (fzd7a) was significantly upregulated in zebrafishes with verapamil-induced heart failure and significantly downregulated if ART at 1/2 LOAEL was coadministrated, indicating that fzd7a-modulated Wnt signaling may mediate the cardioprotective effect of ART. For the first time, this study revealed the biphasic property of ART, providing in-depth knowledge on the pharmacological efficacy-safety profile for its therapeutic and safe applications in clinic.
Date of acceptance
2019
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/31975974
DOI
10.1177/1559325819897180
Externe Identifier
  • PubMed Central ID: PMC6958657
ISSN
1559-3258
Ausgabe der Veröffentlichung
1
Zeitschrift
Dose Response
Schlüsselwörter
  • cancer
  • malaria
  • natural products
  • network pharmacology
  • toxicology
Sprache
eng
Country
United States
Paginierung
1559325819897180
PII
10.1177_1559325819897180
Datum der Veröffentlichung
2020
Status
Published online
Titel
Cardiotoxicity and Cardioprotection by Artesunate in Larval Zebrafish.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
18

Data source: PubMed

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