2. Academic Validation
  3. Cordycepin ameliorates spaceflight-induced osteoporosis by preventing BMSCs oxidative stress and senescence via interacting with PI3K p110α and regulating PI3K/Akt/FOXO3 signalling

Cordycepin ameliorates spaceflight-induced osteoporosis by preventing BMSCs oxidative stress and senescence via interacting with PI3K p110α and regulating PI3K/Akt/FOXO3 signalling

  • Free Radic Biol Med. 2025 Feb 16:228:108-125. doi: 10.1016/j.freeradbiomed.2024.12.044.
Yu Zhai 1,  Yuyao Zhang 1,  Kexin Xu 2,  Tianling Wang 1,  Zhiqun Bian 1,  Langfan Qu 3,  Feng Wu 3,  Zhilei Hu 1,  Xian Chang 1,  Haiyin Li 1,  Chao Zhang 4,  Changqing Li 5,  Chunmeng Shi 6
Affiliations

Affiliations

  • 1 Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, China; State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China.
  • 2 Institute of Rocket Force Medicine, Third Military Medical University (Army Medical University), 400038, Chongqing, China; State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China; College of Bioengineering, Chongqing University, 400044, Chongqing, China.
  • 3 Institute of Rocket Force Medicine, Third Military Medical University (Army Medical University), 400038, Chongqing, China; State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China.
  • 4 Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, China; State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China. Electronic address: tmmuzc@tmmu.edu.cn.
  • 5 Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, China; State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China. Electronic address: changqli@tmmu.edu.cn.
  • 6 Institute of Rocket Force Medicine, Third Military Medical University (Army Medical University), 400038, Chongqing, China; State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China. Electronic address: shicm@tmmu.edu.cn.
PMID: 39722302 DOI: 10.1016/j.freeradbiomed.2024.12.044
Abstract

Spaceflight-induced osteoporosis (SFOP) is a detrimental healthcare consequence during spaceflight. Weightlessness and ionizing radiation were main environmental factors that contribute to SFOP, especially in the manned deep space voyages. However, currently there is scarce effective method to treat SFOP. This study aims at discovering the role and mechanism of cordycepin (COR) in treating SFOP. A combined ionizing radiation and tail suspension (IR/IS) model is constructed in mice to simulate SFOP. COR injection exhibits certain dose-dependent therapeutic effects including better imageological bone index and improved histological bone regeneration in treating SFOP, which is most prominent at a dose of 20 mg/kg. A combined radiation and microgravity (R/M) model is established to treat BMSCs in vitro. 10 μM COR alleviates oxidative stress and cellular senescence of BMSCs. Through high-throughput Sequencing, molecular docking and microscale thermophoresis (MST), we reveal a novel mechanism that COR interacts with p110α subunit in PI3K isoform α (PI3Kα) and inhibits PI3K kinase activity, which then regulates the PI3K/Akt/FOXO3 signalling. To elevate the bioavailability of COR in the SFOP treatment, a BMSCs-targeted delivery system that uses exosomes (Exos) modified with BMSC-affinity peptide E7 (E7-Exos) is constructed and loaded with COR. E7-Exos loaded COR reduces the dosage of COR to 5 mg/kg while enhancing the therapeutic effect than using 20 mg/kg COR alone in treating SFOP. In conclusion, COR shows promise as a potential agent in SFOP therapy.

Keywords

Bone marrow mesenchymal stem cells; Cordycepin; Exosomes modification; Oxidative stress; Spaceflight-induced osteoporosis.

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