中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (4): 1135-1152.doi: 10.4103/NRR.NRR-D-23-00875

• 原著:神经损伤修复保护与再生 • 上一篇    下一篇

体育锻炼和 Nutlin-3a:低级别胶质瘤神经康复的调节者

  

  • 出版日期:2025-04-15 发布日期:2024-07-03
  • 基金资助:
    该研究受到“健康上海行动”专项资金项目(医体融合,创建运动促进健康新模式;项目JKSHZX-2022-02)资助。

Impacts of Nutlin-3a and exercise on murine double minute 2–enriched glioma treatment

Yisheng Chen1, #, Zhongcheng Fan2, #, Zhiwen Luo1, #, Xueran Kang3, #, Renwen Wan1, Fangqi Li1, Weiwei Lin4, Zhihua Han5, Beijie Qi1, Jinrong Lin1, Yaying Sun1, Jiebin Huang6, Yuzhen Xu7, *, Shiyi Chen1, *   

  1. 1Department of Sport Medicine, Huashan Hospital, Fudan University, Shanghai, China; 2Department of Orthopedic Surgery, Hainan Province Clinical Medical Center, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, Hainan Province, China; 3Department of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 4Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; 5Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; 6Department of Infectious Diseases, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China; 7Department of Rehabilitation, The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, China
  • Online:2025-04-15 Published:2024-07-03
  • Contact: Shiyi Chen, MD, PhD, cshiyi@163.com; Yuzhen Xu, PhD, tianyayizhe@126.com.
  • Supported by:
    This work was supported by Project of the Health Shanghai Initiative Special Fund (Medical-Sports Integration, Creating a New Model of Exercise for Health), No. JKSHZX-2022-02 (to SC).

摘要:

最近的研究强调了体育锻炼对胶质瘤预后的影响,有证据表明锻炼可以降低死亡风险并有助于神经再生。SUMO蛋白在癌症进展中的作用,尤其是运动后的作用,以及Sumoylation的潜在抗癌作用正日益受到关注。利用机器学习算法,实验开发出了运动和 SUMO 相关基因特征ESLRS,它反映了体育锻炼在改善低级别胶质瘤(LGG)和其他恶性肿瘤预后方面的益处。通过全面的 CRISPR 筛选,实验验证了特定 ESLRS 基因对 LGG 进展的影响。实验的主要发现之一是,通过分子对接和动态模拟证实了 Nutlin-3a 作为一种强效 MDM2 抑制剂的有效性。Nutlin-3a抑制胶质瘤细胞迁移和激活p53通路的能力是显而易见的,尽管它的功效会随着MDM2的过表达而降低--Nutlin-3a或运动可以克服这一限制。利用 LGG 小鼠模型进行的进一步实验强调了体育锻炼对氧化应激和分子通路调节的影响,从而改善了疾病的预后。值得注意的是,体育锻炼和Nutlin-3a都能改善MDM2过表达小鼠的运动和认知功能。因而,倡导使用天然产品进行治疗的创新策略,并揭示了运动、天然产品和免疫调节在癌症治疗中的相互作用。运动和Nutlin-3a在胶质瘤治疗中具有显著的效果。其中,Nutlin-3a可以抑制胶质瘤细胞的迁移并激活p53通路;而运动则作为一种补充疗法,可以改善预后。这为胶质瘤后制定促进神经康复新的策略提供了新思路。

https://orcid.org/0000-0002-5381-4214 (Shiyi Chen); https://orcid.org/0000-0002-1289-3438 (Yuzhen Xu)

Abstract: Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients, with evidence suggesting exercise may reduce mortality risks and aid neural regeneration. The role of the small ubiquitin-like modifier (SUMO) protein, especially post-exercise, in cancer progression, is gaining attention, as are the potential anti-cancer effects of SUMOylation. We used machine learning to create the exercise and SUMO-related gene signature (ESLRS). This signature shows how physical activity might help improve the outlook for low-grade glioma and other cancers. We demonstrated the prognostic and immunotherapeutic significance of ESLRS markers, specifically highlighting how murine double minute 2 (MDM2), a component of the ESLRS, can be targeted by nutlin-3. This underscores the intricate relationship between natural compounds such as nutlin-3 and immune regulation. Using comprehensive CRISPR screening, we validated the effects of specific ESLRS genes on low-grade glioma progression. We also revealed insights into the effectiveness of Nutlin-3a as a potent MDM2 inhibitor through molecular docking and dynamic simulation. Nutlin-3a inhibited glioma cell proliferation and activated the p53 pathway. Its efficacy decreased with MDM2 overexpression, and this was reversed by Nutlin-3a or exercise. Experiments using a low-grade glioma mouse model highlighted the effect of physical activity on oxidative stress and molecular pathway regulation. Notably, both physical exercise and Nutlin-3a administration improved physical function in mice bearing tumors derived from MDM2-overexpressing cells. These results suggest the potential for Nutlin-3a, an MDM2 inhibitor, with physical exercise as a therapeutic approach for glioma management. Our research also supports the use of natural products for therapy and sheds light on the interaction of exercise, natural products, and immune regulation in cancer treatment.

Key words: exercise and SUMO-related gene signatures (ESLRS), glioblastoma management, low-grade glioma, natural bioactives, neural regeneration, physical exercise