Temperature‐sensitive sodium beta‐glycerophosphate/chitosan hydrogel loaded with all‐trans retinoic acid regulates Pin1 to inhibit the formation of spinal cord injury‐induced rat glial scar

IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Bioengineering & Translational Medicine Pub Date : 2024-10-17 DOI:10.1002/btm2.10729
Rongmou Zhang, Ting Tang, Huafeng Zhuang, Peiwen Wang, Haiming Yu, Hao Xu, Xuedong Yao
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Abstract

Glial scar formation is a major obstacle to nerve regeneration following spinal cord injury (SCI). Pin1 and the PI3K/AKT/CDK2 signaling pathway play crucial roles in neuronal regulation, but research on their involvement in glial scarring remains limited. In this study, we have for the first time observed that Pin1, PI3K, AKT, and CDK2 are upregulated and interact with each other following SCI. Further experiments revealed that Pin1 contributes to the development of glial scars by promoting astrocyte proliferation, inhibiting apoptosis, and activating the PI3K/AKT/CDK2 pathway. Additionally, all‐trans retinoic acid (ATRA), a specific chemical inhibitor of Pin1, effectively suppresses Pin1 expression. However, its clinical application is limited by its short half‐life and susceptibility to inactivation. To address these issues, we have developed a thermosensitive sodium beta‐glycerophosphate (β‐GP)/chitosan (CS) hydrogel loaded with ATRA (β‐GP/CS@ATRA). This hydrogel exhibits favorable morphology and biocompatibility. Compared to free ATRA, the β‐GP/CS@ATRA hydrogel significantly enhances functional motor recovery after SCI and protects spinal cord tissue, thereby inhibiting glial scar formation. Mechanistically, ATRA administration blocks the development of glial scars and the activation of the PI3K/AKT/CDK2 pathway by inhibiting Pin1 expression. This study suggests that combining ATRA with a hydrogel to target Pin1 expression may be a promising strategy for treating glial scar formation following SCI.
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装载全反式维甲酸的温度敏感型β-甘油磷酸钠/壳聚糖水凝胶调节Pin1,抑制脊髓损伤诱导的大鼠神经胶质瘢痕的形成
神经胶质瘢痕的形成是脊髓损伤(SCI)后神经再生的主要障碍。Pin1和PI3K/AKT/CDK2信号通路在神经元调控中发挥着关键作用,但它们参与胶质瘢痕形成的研究仍然有限。在这项研究中,我们首次观察到在脊髓损伤后,Pin1、PI3K、AKT 和 CDK2 上调并相互影响。进一步的实验发现,Pin1 通过促进星形胶质细胞增殖、抑制细胞凋亡和激活 PI3K/AKT/CDK2 通路来促进胶质疤痕的形成。此外,全反式维甲酸(ATRA)是 Pin1 的一种特异性化学抑制剂,能有效抑制 Pin1 的表达。然而,由于其半衰期短且易失活,其临床应用受到了限制。为了解决这些问题,我们开发了一种负载有 ATRA 的热敏性β-甘油磷酸钠(β-GP)/壳聚糖(CS)水凝胶(β-GP/CS@ATRA)。这种水凝胶具有良好的形态和生物相容性。与游离 ATRA 相比,β-GP/CS@ATRA 水凝胶能显著促进 SCI 后的运动功能恢复,保护脊髓组织,从而抑制神经胶质瘢痕的形成。从机理上讲,ATRA 通过抑制 Pin1 的表达,阻止了神经胶质疤痕的形成和 PI3K/AKT/CDK2 通路的激活。这项研究表明,将 ATRA 与水凝胶结合来靶向 Pin1 的表达可能是治疗 SCI 后神经胶质疤痕形成的一种很有前景的策略。
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来源期刊
Bioengineering & Translational Medicine
Bioengineering & Translational Medicine Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
8.40
自引率
4.10%
发文量
150
审稿时长
12 weeks
期刊介绍: Bioengineering & Translational Medicine, an official, peer-reviewed online open-access journal of the American Institute of Chemical Engineers (AIChE) and the Society for Biological Engineering (SBE), focuses on how chemical and biological engineering approaches drive innovative technologies and solutions that impact clinical practice and commercial healthcare products.
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