五子二参汤滋阴佐阳靶向调控多元醇代谢网络轨迹的生精机制研究

Male infertility is an important disease. The program has obtained therapeutic effects on Male infertility by taking Wuzi Ershen Decoction (WZESD) which can Zi Yin Zuo Yang, but the multitarget mechanism has been unknown. Our perclincial study on metabonomics has proved that men who have Kidney yin deficiency of spermatogenesis disorders have more sorbitan in serum and seminal fluid compared with healthy people, which may activate polyhydric alcohol metabolism pathways. Based on it, we have found lately that WZESD inhibit the activity of aldose reductase in Kidney yin deficiency of Male infertility, a rate-limiting enzyme in polyhydric alcohol metabolism pathways, and reduce sorbitol. Thus, we propose that WZESD can produce sperm by targetting polyhydric alcohol metabolism pathways trace. To validate this hypothesis, the program will be guided by holistic view of Chinese medicine and systems biology, applied the target polyhydric alcohol metabolism pathways and aimed at the target molecule network groups mediated by polyhydric alcohol metabolism which WZESD can regulate accurately. What´s more, we will catch WZESD network trace with the methods of systems biology and validate it by molecular biology in vivo and vitro. We can better understand the mechanism of WZESD producing sperm which based on polyhydric alcohol metabolism. The program will provide new evidence for WZESD via Zi Yin Zuo Yang to treat Male infertility.

男性不育是临床医疗的重大疾病。项目组创制五子二参汤滋阴佐阳治疗男性不育取得了生精的满意疗效，但其多靶点作用机制有待揭示。我们前期临床代谢组学研究证实：生精障碍肾阴虚患者血浆和精液的失水山梨醇水平较健康人明显增高，提示其涉及多元醇代谢通路激活。以此为线索，近来动物实验发现：五子二参汤抑制肾阴虚生精障碍大鼠精液多元醇代谢关键限速酶-醛糖还原酶活性，明显减少山梨醇水平。据此提出“五子二参汤调控多元醇代谢网络轨迹发挥生精效应”的科学假说。为验证该设想，本项目将以中医整体观和系统生物学为指导思想，运用以多元醇代谢网络为核心的靶向代谢组学方法，锚定五子二参汤精准调控多元醇代谢介导的网络靶标分子群；采用生物信息学手段捕获五子二参汤的网络调控轨迹；最终结合体内外实验，采用分子生物学方法验证该调控轨迹；以揭示全方靶向调控多元醇代谢介导网络的生精机制。本项目将为解析五子二参汤滋阴佐阳发挥生精效应提供新证据。

少弱精子症是男性不育的主要原因。目前，西医治疗少弱精子症的药物较少，治疗效果也不明显，而传统中药方剂五子二参汤在改善男性生殖功能方面具有良好疗效。为阐释五子二参汤的具体作用机制，我们采用“组学分析—生物信息学预测—分子生物学验证”的研究策略，锚定五子二参汤精准调控多元醇代谢及其介导的网络靶标分子群，利用生物信息学分析手段，捕获该方调控该疾病的多靶点的网络轨迹，最终结合体内外实验，采用分子生物学方法验证该网络轨迹，揭示全方靶向调控多元醇代谢及介导网络的生精机制。我们对不育患者精浆进行全面的代谢谱分析，发现17种代谢物的水平与精子参数显著相关，我们首次报道了异戊烯基焦磷酸、2-磷酸甘油酸和γ-谷氨酰基硒-甲基半胱氨酸与精子畸形率呈负相关，肌酸核苷与精子浓度呈负相关。生物标志物涉及丙酮酸代谢、谷胱甘肽代谢等多元醇代谢介导的网络通路。此外，利用网络药理学发现五子二参汤靶向少弱精子症的79个特异性蛋白靶点主要参与细胞对有机环状化合物的应答、细胞凋亡过程的调控、一氧化氮的生物合成和代谢、氧化应激和蛋白磷酸化调节等生物过程及靶向多元醇代谢介导通路的关键指标AR、NO等。本研究将有助于为男性不育的病理研究提供了新的可能线索，有助于为未来男性不育在病因学、诊断和治疗方面的研究奠定基础。

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