The hidden bioactive molecules: miRNAs loaded in extracellular vesicles might act as bioactive constituents in European mistletoe

隐藏的生物活性分子：细胞外囊泡中装载的 miRNA 可能充当欧洲槲寄生的生物活性成分

• 批准号: 412271215
• 负责人: Dr. Wenyan Xie, Ph.D.
• 金额: --
• 依托单位: Klinik für Pädiatrie mit Schwerpunkt Onkologie und Hämatologie (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/412271215?language=en
• 关键词: hidden; bioactive; molecules; miRNAs; loaded

Herbal products are globally accepted as a valid complementary system of therapy in the form of pharmaceuticals or food supplements. Often their bioactive constituents and corresponding interactions with human have not been comprehensively characterized. Various studies around the world have been initiated to develop scientific evidence-based herbal therapies. New plant bioactive molecules are being discovered. MicroRNAs (miRNAs) are a class of approximately 22 nucleotides single-stranded non-coding RNAs that play crucial roles in gene expression. Recently, the cross-kingdom of plant derived miRNAs has attracted great attraction. For example, the rice miRNAs have been suggested to enter mammalian bloodstream and have a functional role in mammalian metabolism. Plant-derived miR159 can target human genes and suppress breast cancer cell growth in vitro and in vivo. These studies suggested that human genes can be regulated by dietary plant miRNAs, providing thrilling clues that medicinal plants miRNAs might be the hidden bioactive compounds regulating human health and diseases. Mistletoe (Viscum album L.) has been used traditionally in Europe for centuries for the treatment of cancer and cardiovascular diseases but their scientific background is still controversially discussed. By using high-throughput Illumina sequencing and bioinformatics analysis, our previous study indicated that mistletoe miRNAs might be involved in the pharmacological effects of mistletoe. Further experimental validations are currently urgent to confirm the bioactivities of these plant miRNAs. Considering plant miRNAs are not stable in enzymatic environment such as herb extracts and mammalian body fluids, being encapsulated into extracellular vesicles (EVs) that are membrane-enclosed nano-sized particles released by cells, could offer miRNAs nano-shuttles allowing them to travel long distances. Herein, we propose that mistletoe miRNAs might serve as an independent category of active ingredients and might be responsible for or at least contribute to the pharmacological effects (e.g. anti-tumor effect) of mistletoe. Mistletoe EVs might act as effective vehicles to deliver miRNAs with intact functionality, and mediate the cross-kingdom regulation of mistletoe miRNAs. Proposed investigations will be focused on the profiling of cross-kingdom regulatory miRNAs, identification of mammalian targets and visualization of mistletoe EVs mediated miRNA delivery. If our hypothesis is proven, it will promote our understanding of miRNA-based bioactive ingredients in medicinal plants provide scientific support for folk medicinal use and clinical use of medicinal plants. More importantly, it will open new ways for the development of miRNA-based therapies to prevent or treat human diseases.

草药产品是全球公认的有效的补充系统的治疗形式的药品或食品补充剂。通常它们的生物活性成分及其与人体的相互作用尚未得到全面的表征。世界各地已经开展了各种研究，以开发科学证据为基础的草药疗法。新的植物生物活性分子正在被发现。MicroRNAs （miRNAs）是一类约22个核苷酸的单链非编码rna，在基因表达中起着至关重要的作用。近年来，植物源性mirna的跨界研究引起了极大的关注。例如，水稻mirna被认为可以进入哺乳动物的血液，并在哺乳动物的代谢中发挥功能作用。植物源性miR159在体内体外均可靶向人类基因，抑制乳腺癌细胞生长。这些研究表明，人类基因可以通过膳食植物mirna进行调控，这为药用植物mirna可能是调节人类健康和疾病的隐藏生物活性化合物提供了令人兴奋的线索。槲寄生（Viscum album L.）在欧洲被传统地用于治疗癌症和心血管疾病已有几个世纪了，但它们的科学背景仍在争论中。通过高通量Illumina测序和生物信息学分析，我们的前期研究表明槲寄生mirna可能参与了槲寄生的药理作用。目前迫切需要进一步的实验验证来确认这些植物mirna的生物活性。考虑到植物miRNAs在酶促环境（如草药提取物和哺乳动物体液）中不稳定，将其封装到细胞外囊泡（ev）中，即细胞释放的膜封闭纳米级颗粒，可以为miRNAs提供纳米穿梭器，使其能够长距离旅行。在此，我们提出槲寄生mirna可能作为一个独立的活性成分类别，并且可能负责或至少有助于槲寄生的药理作用（例如抗肿瘤作用）。槲寄生ev可能作为递送功能完整的mirna的有效载体，并介导槲寄生mirna的跨界调控。拟议的研究将集中在跨王国调控miRNA的分析，哺乳动物靶点的鉴定和槲寄生ev介导的miRNA传递的可视化。如果我们的假设得到证实，将促进我们对药用植物中基于mirna的生物活性成分的认识，为药用植物的民间用药和临床应用提供科学支持。更重要的是，它将为开发基于mirna的疗法来预防或治疗人类疾病开辟新的途径。