Food additives are widely used in our daily life, and the side-effects caused by them have gained extensive attention around the world. Notably, constituent-oriented metabolites, in some sense, always contribute to pharmacological changes, inducing toxicity, therapeutic effects, etc. Characterization of the metabolites and their potential functions is of great importance to the practical applications. In this work, an integrated strategy by combining metabolite profiling and network pharmacology was applied to characterize the metabolic features and reveal pharmacological changes of neohesperidin dihydrochalcone (NHDC) in vivo to demonstrate its pharmacological mechanism and potential functions. As a result, a total of 19 metabolites (3 in plasma, 19 in urine, 8 in feces, 3 in heart, 5 in liver, 0 in spleen, 1 in lung, 2 in kidneys and 2 in brain) were screened and 18 of them were characterized for the first time. Phase I metabolic reactions of hydrolysis and phase II reactions of glucuronidation, sulfation, glutamylation, N-butyryl glycylation and lactylation were the main metabolic reactions of NHDC in vivo. Moreover, the results analyzed by network pharmacology revealed that, in addition to common pathways (steroid hormone biosynthesis) of NHDC, metabolites’ targets were involved in pathways in cancer, ovarian steroidogenesis, proteoglycans in cancer, PI3K-Akt signaling pathway and progesterone-mediated oocyte maturation, indicating that these functional changes might result in potential novel functions or other side-effects, such as a disorder of steroid hormones. Our work provided the metabolic features and functional modifications of NHDC in vivo for the first time, and meaningful information for further pharmacological validations or potential functions is supplied.

中文翻译：

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通过体内物质分析和网络药理学剖析新橙皮苷二氢查尔酮（一种食品添加剂）的潜在药理功能

食品添加剂在我们的日常生活中被广泛使用，其带来的副作用已引起世界各国的广泛关注。值得注意的是，在某种意义上，面向成分的代谢物总是有助于药理变化、诱导毒性、治疗效果等。代谢物的表征及其潜在功能对实际应用非常重要。在这项工作中，结合代谢物分析和网络药理学的综合策略被应用于表征代谢特征并揭示新橙皮苷二氢查耳酮（NHDC）在体内的药理变化以证明其药理机制和潜在功能。结果，共筛选出 19 种代谢物（血浆 3 种、尿液 19 种、粪便 8 种、心脏 3 种、肝脏 5 种、脾脏 0 种、肺 1 种、肾脏 2 种和脑中 2 种）和 18他们中的第一次被表征。NHDC在体内的主要代谢反应是水解的I期代谢反应和葡萄糖醛酸化、硫酸化、谷氨酰化、N-丁酰甘氨酰化和乳酸化的II期反应. 此外，网络药理学分析结果表明，除了NHDC的常见途径（类固醇激素生物合成）外，代谢物的靶点还涉及癌症途径、卵巢类固醇生成、癌症中的蛋白多糖、PI3K-Akt信号通路和孕酮介导的通路。卵母细胞成熟，表明这些功能变化可能导致潜在的新功能或其他副作用，例如类固醇激素紊乱。我们的工作中提供的代谢特征和NHDC的功能上的修改体内首次，并且被提供用于进一步的药理学验证或潜在功能的有意义的信息。