Single-Nucleus RNA Sequencing Reveals the Mechanism of Neonatal Hypoxic–Ischemic Encephalopathy and The Neuroprotection Effects of Salvianolic Acid C

IF 11.6 1区 工程技术 Q1 ENGINEERING, MULTIDISCIPLINARY
Xuan Mou, Lu Li, Xinyue Liu, Aolin Zhang, Tao He, Baofeng Rao, Jiatian Zhang, Renjie Chen, Malte Spielmann, Chi Chiu Wang, Bin Cong, Xiaohui Fan
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引用次数: 0

Abstract

Neonatal hypoxic–ischemic encephalopathy (HIE), resulting from perinatal asphyxia-induced hypoxic–ischemic brain damage (HIBD), is a severe neurological disorder that impairs neurodevelopment, and no definitive therapies are available. The polyphenolic natural compound salvianolic acid C (SAC) exhibits antioxidant, anti-inflammatory, and antiapoptotic properties. In this study, we evaluated the efficacy of SAC in treating HIE via animal and human brain organoid experiments. Human brain organoids served as a translational platform for assessing natural product efficacy and clinical effect prediction. Rat brain tissues were harvested at two time points (24 h and 7 d after HIBD and SAC administration) for single-nucleus RNA sequencing. In vitro and in vivo experiments, including microarrays and gene silencing, were employed to confirm the sequencing findings. Our findings demonstrated that during the acute phase of HIBD, SAC suppressed signal transducer and activator of transcription 3+ (Stat3+) astrocyte-driven acute neuroinflammation, decreased inflammatory factor release, and maintained glial–immune homeostasis. During the subacute phase, SAC promoted oligodendrocyte differentiation and facilitated crosstalk between anti-inflammatory microglia and myelinating oligodendrocytes, establishing a regenerative microenvironment and enhancing neuregulin 3 (NRG3)–receptor tyrosine-protein kinase erbB-4 (ErbB4) signaling axis activity. These coordinated mechanisms highlight the dual capacity of SAC in mitigating early injury and driving structural repair in the later stages. This study revealed the pathophysiology of HIE and the multitarget neuroprotective effects of SAC against this disorder at single-cell resolution, advancing the mechanistic foundations for SAC-based therapies in neonatal brain injury.
单核RNA测序揭示新生儿缺氧缺血性脑病发病机制及丹酚酸C的神经保护作用
新生儿缺氧缺血性脑病(HIE)是由围产期窒息引起的缺氧缺血性脑损伤(HIBD)引起的,是一种严重的神经系统疾病,可损害神经发育,目前尚无明确的治疗方法。多酚类天然化合物丹酚酸C (SAC)具有抗氧化、抗炎和抗凋亡的特性。在本研究中,我们通过动物和人脑类器官实验来评估SAC治疗HIE的疗效。人脑类器官可作为天然产物疗效评估和临床效果预测的翻译平台。在两个时间点(HIBD和SAC给药后24 h和7 d)采集大鼠脑组织进行单核RNA测序。体外和体内实验,包括微阵列和基因沉默,被用来证实测序结果。我们的研究结果表明,在HIBD的急性期,SAC抑制星形胶质细胞驱动的急性神经炎症,减少炎症因子释放,维持神经胶质免疫稳态。在亚急性期,SAC促进少突胶质细胞分化,促进抗炎小胶质细胞与髓鞘少突胶质细胞之间的相互作用,建立再生微环境,增强神经调节蛋白3 (NRG3) -受体酪氨酸-蛋白激酶erbB-4 (ErbB4)信号轴活性。这些协调机制突出了SAC在减轻早期损伤和推动后期结构修复方面的双重能力。本研究揭示了HIE的病理生理和SAC在单细胞分辨率下对这种疾病的多靶点神经保护作用,为SAC为基础的新生儿脑损伤治疗提供了机制基础。
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来源期刊
Engineering
Engineering Environmental Science-Environmental Engineering
自引率
1.60%
发文量
335
审稿时长
35 days
期刊介绍: Engineering, an international open-access journal initiated by the Chinese Academy of Engineering (CAE) in 2015, serves as a distinguished platform for disseminating cutting-edge advancements in engineering R&D, sharing major research outputs, and highlighting key achievements worldwide. The journal's objectives encompass reporting progress in engineering science, fostering discussions on hot topics, addressing areas of interest, challenges, and prospects in engineering development, while considering human and environmental well-being and ethics in engineering. It aims to inspire breakthroughs and innovations with profound economic and social significance, propelling them to advanced international standards and transforming them into a new productive force. Ultimately, this endeavor seeks to bring about positive changes globally, benefit humanity, and shape a new future.
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