Chen Jing, Ren Can, Yao Chong, Baruscotti Mirko, Wang Yi, Zhao Lu
Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences Zhejiang University Hangzhou China.
Huzhou Central Hospital, Affiliated Huzhou Hospital Zhejiang University School of Medicine Huzhou China.
MedComm (2020). 2023 Aug 24;4(5):e352. doi: 10.1002/mco2.352. eCollection 2023 Oct.
Enhanced P53 signaling may lead to hematopoietic disorders, yet an effective therapeutic strategy is still lacking. Our study, along with previous research, suggests that P53 overactivation and hematopoietic defects are major consequences of zinc deficiency. However, the relationship between these two pathological processes remains unclear. In this study, we observed a severe reduction in the number of hematopoietic stem cells (HSCs) and multi-lineage progenitor cells in zebrafish treated with the zinc chelator ,,','-tetrakis(2-pyridylmethyl)ethylenediamine and showed the indispensable role of P53 signaling in the process. Next, we took advantage of HSCs-labeled transgenic zebrafish and conducted a highly efficient phenotypic screening for small molecules against P53-dependent hematopoietic disorders. Hydroxysafflor yellow A (HSYA), a natural chalcone glycoside, exhibited potent protection against hematopoietic failure in zinc-deficient zebrafish and strongly inhibited the P53 pathway. We confirmed the protective effect of HSYA in zinc-deficient mice bone marrow nucleated cells, which showed a significant suppression of P53 signaling and oxidative stress. Furthermore, the hematopoietic-protective activity of HSYA was validated using a mice model of myelotoxicity induced by 5-FU. In summary, our work provides an effective phenotypic screening strategy for identifying hematopoietic-protective agents and reveals the novel role of HSYA as a promising lead compound in rescuing hematopoietic disorders associated with P53 overactivation.
增强的P53信号传导可能导致造血系统紊乱，但仍缺乏有效的治疗策略。我们的研究以及先前的研究表明，P53过度激活和造血缺陷是锌缺乏的主要后果。然而，这两个病理过程之间的关系仍不清楚。在本研究中，我们观察到用锌螯合剂N,N,N',N'-四(2-吡啶甲基)乙二胺处理的斑马鱼中造血干细胞(HSC)和多谱系祖细胞数量严重减少，并表明P53信号传导在该过程中起不可或缺的作用。接下来，我们利用标记有HSC的转基因斑马鱼，对针对P53依赖性造血系统紊乱的小分子进行了高效的表型筛选。羟基红花黄色素A(HSYA)是一种天然查耳酮糖苷，对缺锌斑马鱼的造血功能衰竭具有强大的保护作用，并强烈抑制P53通路。我们证实了HSYA对缺锌小鼠骨髓有核细胞的保护作用，其显示出对P53信号传导和氧化应激的显著抑制。此外，使用5-氟尿嘧啶诱导的骨髓毒性小鼠模型验证了HSYA的造血保护活性。总之，我们的工作提供了一种有效的表型筛选策略来鉴定造血保护剂，并揭示了HSYA作为一种有前途的先导化合物在挽救与P53过度激活相关的造血系统紊乱中的新作用。
