基于阿洛糖苯乙醇苷的厚朴“下气除满”的机理及其道地成因的研究

Financial supported by a National Natural Science Foundation of China and other national projects, large amount of phenylthanoid glycoside with β-allopyranosyl (PGA), rarely occurred in nature, was found from the bark of Magnolia officinalis (Houpo in Chinese) for the first time, in which, 13 new PGAs were isolated, and the isolation procession of Magnolosides A and B were patented. At the same time, the mechanism of primary processing of Houpo was clarified as “to maintain the content of phenylthanoid glycoside by inhibiting the activity of related enzyme”, i.e., the content of Magnoloside B in processed sample was higher than that in unprocessed sample..After analyzing the data from literature, two kinds of hypotheses were induced. One is that PGA is the chemical foundation of the traditional pharmacological effect of Houpo, named as “Xiaqichuman” in Chinese, through the synergetic interactions among the function adjustment on gastrointestinal tract, and the effects not only on neuropeptides but also on intestinal flora. The other is that germplasm and primary processing were the causes of Houpo geoherb..In order to verify the above mentioned hypotheses, a gastrointestinal motility dysfunction model will be established to test the effect of GPA not only on gastrointestinal tract but also on neuropeptides. At the same time, the method of metagenomics will be used to study the effect of GPA on intestinal flora of model animal. In addition, the effect of gemplasm and primary processing on PGA of Houpo will be analyzed by chemometrics, and the causes of Houpo geoherb will be clarified.

在国家“十一五”课题和国家自然科学基金课题的资助下，我们首次发现厚朴中存在大量自然界罕见的阿洛糖苯乙醇苷类成分（简写为PGA）；分离了13个新化合物；获得了制备木兰苷A和苷B的国家发明专利。同时发现，厚朴产地初加工“发汗”的机制是“杀酶保苷”，即，“发汗”样本中木兰苷B的含量远高于未“发汗”者。.通过对已有研究的分析，我们提出：PGA具有厚朴“下气除满”的功效，其机制为调整胃肠功能、影响脑肠肽、调节肠道菌群的协同作用；种质与产地加工是厚朴道地成因等假说。.为验证上述假说，我们拟建立胃肠动力障碍模型，考察PGA对胃肠功能的调整作用；对胃动素、5-羟色胺等脑肠肽激素分泌的影响；采用宏基因组学方法，考察其对模型动物肠道菌群的回转作用，进而阐明“下气除满”的药效机制。同时，采用化学计量学方法，综合分析不同种质厚朴和产地加工方法对PGA的影响，阐明厚朴道地成因。

中药厚朴具有燥湿消痰、下气除满的功效，被广泛用于治疗消化道疾病。以往厚朴的研究多关注在其脂溶性成分厚朴酚、和厚朴酚上。在前期研究中，我们发现厚朴中存在大量的水溶性苯乙醇苷类成分。基于中药传统为水煎入药，我们提出水溶性的苯乙醇苷类成分是厚朴的有效成分之一，也是评价厚朴道地性的重要指标成分的假说。.本课题首次从调整胃肠功能、脑肠肽作用、肠道菌群作用三个方面，考察厚朴苯乙醇苷类成分对功能性消化不良大鼠的药效活性及作用机制。研究结果表明，厚朴苯乙醇苷类成分能提高功能性消化不良大鼠的胃排空率；调节脑肠肽水平，促进胃肠动力和减轻脏器敏感度；调节肠道菌群的结构，通过影响肠道菌群的代谢通路来调节脑肠肽和短链脂肪酸的分泌，达到改善功能性消化不良症状的作用。.在厚朴道地性研究方面，首次建立了LC-2ECD色谱系统，同时测定了厚朴中7个苯乙醇苷成分的含量；采用UPLC-QTOF/MS技术，首次建立了诊断离子/中性丢失扫描结合化合物全碎片离子指纹图谱分析的方法，鉴定了101个厚朴苯乙醇苷类化合物；建立了苯乙醇苷类化合物异构体的判别模型，推测了14个同分异构体；采用LC-2ECD、UPLC-QTOF/MS、GC-MS技术，对厚朴次生代谢产物进行了系统的研究，发现道地产区与非道地产区厚朴样本中次生代谢成分存在显著差异，并与产区的气温和降水量因子显著相关，提出厚朴道地性形成的模式为多因子关联决定型，即受种源及产地二者的共同影响。.研究结果验证了我们关于厚朴苯乙醇苷类成分的假说，即，水溶性成分既是药效活性成分，也是评价药材道地性的指标成分。有关中药材水溶性成分的研究有待加强。