Toward novel therapeutics for functional constipation: from traditional Chinese medicine herbal formula MaZiRenWan to cyclic spexin analogues

Abstract

Functional constipation (FC) is a major gastrointestional (GI) disorder which affects about 14% population worldwide. However, due to efficacy and safety concerns, more than 50% FC patients are not completely satisfied with current conventional therapies, thus alternative therapies are needed. A substantial part of FC patients have symptom of slow colonic motility, while therapy targeting a single pathway cannot benefit all of them. In this thesis, we searched for novel FC therapeutics from two distinct sources, both of which can improve colonic motility significantly: (1) MaZiRenWan (MZRW), an herb formula from Traditional Chinese Medicine (TCM); and (2) Spexin (SPX), a newly identified neuropeptide that is deregulated in FC. On the basis of efficacy validation for MZRW by randomized, placebo-controlled clinical studies, we investigated the bioactive compounds and pharmacological actions of MZRW. Firstly, a machine-learning based method, namely MOST, was developed to relate bioactive compounds with their mechanism-of-action targets. MOST demonstrated good performance in 7-fold cross-validation (over 87% accuracy) and temporal validation (over 76% accuracy). In the case laxative effect, MOST predicted that acetylcholinesterase (ACHE) was the mechanism-of-action target of aloe-emodin; in vivo studies validated this prediction. Secondly, we analyzed the bioactive compounds and mechanism-of-actions of MZRW with combination of UPLC-QTOF-MS/MS, clustering analysis, organ bath, and MOST approaches. 97 compounds were identified in MZRW extract, and 35 of them can be found in plasma and feces samples of rats with oral administration of MZRW. Chemical space analysis suggested that these compounds can be classified into component groups, while the corresponding pharmacology can be studied with representative compounds. Emodin, amygdalin, albiflorin, honokiol, and naringin were shown to induce spontaneous contractions of rat colonic smooth muscle in vitro. Biological targets in ACh-, estrogen-, prostaglandin-, cannabinoid-, and purine signaling pathways are able to explain the prokinetic effects of representative compounds and component groups. Pharmacological actions of MZRW are mixture of five classic paradigms. Thirdly, the latest results of three-armed, randomized and controlled clinical study showed that MZRW demonstrated comparable efficacy with the first line drug Senna, the first line drug for constipation in HK, during treatment period, both were better than placebo; and the efficacy was more sustainable in follow-up period when comparing that of Senna and placebo. These data suggested the unique pharmacological profile of MZRW for FC. With pharmacometabolomic analysis, we found that change of oleamide is negatively correlated (pearson r = -0.59, p

Date of Award	25 Aug 2017
Original language	English
Supervisor	Zhaoxiang BIAN (Supervisor)