Introduction: Head and neck tumors account for more than 6% of all cancers. The primary treatment for tumors of the head and neck is radiation therapy, which can induce oropharyngeal mucositis as a side effect. At present, there is no widely available therapeutic for the treatment of oropharyngeal mucositis in clinical practice. Based on the traditional prescription Liushen Wan, the pathogenesis and pathology, we developed a new Chinese medicine prescription and made Zhenhuang submicron emulsion (ZHSE) spray, which has an efficacious therapeutic effect for oropharyngeal mucositis. However, its mechanism is unclear.
Methods: This research explored the mechanism behind the modulatory effects of ZHSE by a strategy of metabolomics and network pharmacology. Multivariate data analyses, including unsupervised principal component analysis (PCA) and supervised orthogonal partial least squares discriminant analysis (OPLS-DA), were performed. Potential biomarkers were identified depending on the mass-charge ratio of the selected compound. Statistical and pathway enrichment analysis was performed in the KEGG pathway database. Network pharmacology combining metabolomic analyses was conducted to illustrate the key targets and pathways.
Results: Critical metabolic pathways were investigated, 56f biomarkers were enriched and key metabolites such as linoleic acid, 9,10-epoxyoctadecenoic acid, acetoacetic acid and citric acid were identified. A complex network of “compound-target-potential metabolite” interactions was drawn to illuminate the regulation of chemical constituents on key metabolites. These findings manifest that ZHSE regulates endogenous metabolite disorders during the treatment of oropharyngeal mucositis by various constituents, interacting with multiple targets associated with inflammation and pain.
Conclusion: In this work, we determined several critical biomarkers and metabolic pathways and identified the possible regulatory mechanism by which ZHSE functions in the treatment of oropharyngeal mucositis. This study provides a new perspective on integrating metabolomics and network pharmacology for exploring improved therapy for head and neck tumors based on the traditional classic prescription of LSW.

Keywords: metabolomics, network pharmacology, mucositis, traditional Chinese medicine, head and neck tumors


中文翻译：

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代谢组学结合网络药理学策略揭示真黄亚微米乳治疗头颈癌放射治疗口咽黏膜炎并发症的潜在机制

简介：头颈部肿瘤占所有癌症的 6% 以上。头颈部肿瘤的主要治疗方法是放射治疗，其可诱发口咽粘膜炎作为副作用。目前，临床上还没有广泛适用的治疗口咽粘膜炎的治疗方法。我们根据传统方剂六神丸的病机病理，研制出中药新方，制成真黄亚微米乳剂（ZHSE）喷雾剂，对口咽黏膜炎有很好的治疗作用。然而，其机制尚不清楚。
方法：本研究通过代谢组学和网络药理学的策略探索了 ZHSE 调节作用背后的机制。进行了多变量数据分析，包括无监督主成分分析 (PCA) 和监督正交偏最小二乘判别分析 (OPLS-DA)。根据所选化合物的质荷比确定潜在的生物标志物。在 KEGG 通路数据库中进行了统计和通路富集分析。进行了结合代谢组学分析的网络药理学，以说明关键目标和途径。
结果：研究了关键代谢途径，富集了 56f 生物标志物，并鉴定了亚油酸、9,10-环氧十八烯酸、乙酰乙酸和柠檬酸等关键代谢物。绘制了一个复杂的“化合物-靶点-潜在代谢物”相互作用网络，以阐明化学成分对关键代谢物的调控。这些发现表明，ZHSE 在口咽粘膜炎治疗过程中通过多种成分调节内源性代谢紊乱，与炎症和疼痛相关的多个靶点相互作用。
结论：在这项工作中，我们确定了几个关键的生物标志物和代谢途径，并确定了 ZHSE 在口咽粘膜炎治疗中发挥作用的可能调节机制。本研究为整合代谢组学和网络药理学提供了一个新的视角，以探索基于LSW传统经典处方的头颈部肿瘤的改进治疗。

关键词：代谢组学，网络药理学，粘膜炎，中药，头颈部肿瘤