AS-IV Attenuates Oxidative Stress-Induced Apoptosis in Zebrafish via Modulation of the AKT/NRF2/HO-1/Caspase-3 Signaling Axis
As the primary active component of <i>Astragalus membranaceus</i>, Astragaloside IV (AS-IV) is widely recognized in pharmacological research for its multifaceted therapeutic potential, particularly its antioxidative, immunostimulatory, and cardioprotective properties. Oxidative stress is...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-05-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/11/2355 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850160983695163392 |
|---|---|
| author | Jili Dai Zhizhou E Yannan Bi Zetao Yin Yanfang Wang Xingyu Wang Xiaoe Jia Bo Zou |
| author_facet | Jili Dai Zhizhou E Yannan Bi Zetao Yin Yanfang Wang Xingyu Wang Xiaoe Jia Bo Zou |
| author_sort | Jili Dai |
| collection | DOAJ |
| description | As the primary active component of <i>Astragalus membranaceus</i>, Astragaloside IV (AS-IV) is widely recognized in pharmacological research for its multifaceted therapeutic potential, particularly its antioxidative, immunostimulatory, and cardioprotective properties. Oxidative stress is an important mechanism in the induction of many diseases. The present study investigates the antioxidative mechanism of Astragaloside IV in zebrafish, using menaquinone exposure to induce oxidative stress conditions. The findings revealed that AS-IV effectively attenuated oxidative stress-induced mortality and morphological abnormalities in zebrafish. AS-IV exhibited a concentration-dependent protective effect against developmental abnormalities, with progressive reduction in pericardial effusion, body curvature, and growth retardation observed at higher doses. Moreover, AS-IV treatment not only effectively reduced reactive oxygen species (ROS) accumulation and attenuated oxidative DNA damage but also significantly decreased apoptosis in the cardiac region of zebrafish embryos under oxidative stress conditions. Western blot analysis revealed that AS-IV treatment significantly reduced the protein levels of both Cleaved Caspase-3 and γ-H2AX, indicating its ability to inhibit DNA damage-induced apoptosis. AS-IV mediates its antioxidant defense mechanisms through the activation of the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway, inducing the significant upregulation of cytoprotective enzymes. This molecular mechanism underlies the observed phenotypic improvements in oxidative stress-related damage. Upstream analysis demonstrated that AS-IV activates NRF2 primarily through protein kinase B (AKT/PKB) pathway modulation, independent of KEAP1 regulation. Comprehensive mechanistic analysis reveals that Astragaloside IV mitigates oxidative stress-induced apoptosis in zebrafish through coordinated regulation of the AKT/NRF2/HO-1/Caspase-3 signaling axis. |
| format | Article |
| id | doaj-art-c593774f5fbd4b458c2a611d711c5267 |
| institution | OA Journals |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-c593774f5fbd4b458c2a611d711c52672025-08-20T02:23:00ZengMDPI AGMolecules1420-30492025-05-013011235510.3390/molecules30112355AS-IV Attenuates Oxidative Stress-Induced Apoptosis in Zebrafish via Modulation of the AKT/NRF2/HO-1/Caspase-3 Signaling AxisJili Dai0Zhizhou E1Yannan Bi2Zetao Yin3Yanfang Wang4Xingyu Wang5Xiaoe Jia6Bo Zou7Department of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou 014040, ChinaDepartment of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou 014040, ChinaDepartment of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou 014040, ChinaDepartment of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou 014040, ChinaDepartment of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou 014040, ChinaDepartment of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou 014040, ChinaDepartment of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou 014040, ChinaDepartment of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou 014040, ChinaAs the primary active component of <i>Astragalus membranaceus</i>, Astragaloside IV (AS-IV) is widely recognized in pharmacological research for its multifaceted therapeutic potential, particularly its antioxidative, immunostimulatory, and cardioprotective properties. Oxidative stress is an important mechanism in the induction of many diseases. The present study investigates the antioxidative mechanism of Astragaloside IV in zebrafish, using menaquinone exposure to induce oxidative stress conditions. The findings revealed that AS-IV effectively attenuated oxidative stress-induced mortality and morphological abnormalities in zebrafish. AS-IV exhibited a concentration-dependent protective effect against developmental abnormalities, with progressive reduction in pericardial effusion, body curvature, and growth retardation observed at higher doses. Moreover, AS-IV treatment not only effectively reduced reactive oxygen species (ROS) accumulation and attenuated oxidative DNA damage but also significantly decreased apoptosis in the cardiac region of zebrafish embryos under oxidative stress conditions. Western blot analysis revealed that AS-IV treatment significantly reduced the protein levels of both Cleaved Caspase-3 and γ-H2AX, indicating its ability to inhibit DNA damage-induced apoptosis. AS-IV mediates its antioxidant defense mechanisms through the activation of the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway, inducing the significant upregulation of cytoprotective enzymes. This molecular mechanism underlies the observed phenotypic improvements in oxidative stress-related damage. Upstream analysis demonstrated that AS-IV activates NRF2 primarily through protein kinase B (AKT/PKB) pathway modulation, independent of KEAP1 regulation. Comprehensive mechanistic analysis reveals that Astragaloside IV mitigates oxidative stress-induced apoptosis in zebrafish through coordinated regulation of the AKT/NRF2/HO-1/Caspase-3 signaling axis.https://www.mdpi.com/1420-3049/30/11/2355AS-IVNRF2oxidative stressnetwork pharmacologyzebrafish |
| spellingShingle | Jili Dai Zhizhou E Yannan Bi Zetao Yin Yanfang Wang Xingyu Wang Xiaoe Jia Bo Zou AS-IV Attenuates Oxidative Stress-Induced Apoptosis in Zebrafish via Modulation of the AKT/NRF2/HO-1/Caspase-3 Signaling Axis Molecules AS-IV NRF2 oxidative stress network pharmacology zebrafish |
| title | AS-IV Attenuates Oxidative Stress-Induced Apoptosis in Zebrafish via Modulation of the AKT/NRF2/HO-1/Caspase-3 Signaling Axis |
| title_full | AS-IV Attenuates Oxidative Stress-Induced Apoptosis in Zebrafish via Modulation of the AKT/NRF2/HO-1/Caspase-3 Signaling Axis |
| title_fullStr | AS-IV Attenuates Oxidative Stress-Induced Apoptosis in Zebrafish via Modulation of the AKT/NRF2/HO-1/Caspase-3 Signaling Axis |
| title_full_unstemmed | AS-IV Attenuates Oxidative Stress-Induced Apoptosis in Zebrafish via Modulation of the AKT/NRF2/HO-1/Caspase-3 Signaling Axis |
| title_short | AS-IV Attenuates Oxidative Stress-Induced Apoptosis in Zebrafish via Modulation of the AKT/NRF2/HO-1/Caspase-3 Signaling Axis |
| title_sort | as iv attenuates oxidative stress induced apoptosis in zebrafish via modulation of the akt nrf2 ho 1 caspase 3 signaling axis |
| topic | AS-IV NRF2 oxidative stress network pharmacology zebrafish |
| url | https://www.mdpi.com/1420-3049/30/11/2355 |
| work_keys_str_mv | AT jilidai asivattenuatesoxidativestressinducedapoptosisinzebrafishviamodulationoftheaktnrf2ho1caspase3signalingaxis AT zhizhoue asivattenuatesoxidativestressinducedapoptosisinzebrafishviamodulationoftheaktnrf2ho1caspase3signalingaxis AT yannanbi asivattenuatesoxidativestressinducedapoptosisinzebrafishviamodulationoftheaktnrf2ho1caspase3signalingaxis AT zetaoyin asivattenuatesoxidativestressinducedapoptosisinzebrafishviamodulationoftheaktnrf2ho1caspase3signalingaxis AT yanfangwang asivattenuatesoxidativestressinducedapoptosisinzebrafishviamodulationoftheaktnrf2ho1caspase3signalingaxis AT xingyuwang asivattenuatesoxidativestressinducedapoptosisinzebrafishviamodulationoftheaktnrf2ho1caspase3signalingaxis AT xiaoejia asivattenuatesoxidativestressinducedapoptosisinzebrafishviamodulationoftheaktnrf2ho1caspase3signalingaxis AT bozou asivattenuatesoxidativestressinducedapoptosisinzebrafishviamodulationoftheaktnrf2ho1caspase3signalingaxis |