To target complex, multi-factorial diseases more effectively, there has been an emerging trend of multi-target drug development based on network biology, as well as an increasing interest in traditional Chinese medicine (TCM) that applies a more holistic treatment to diseases. Thousands of years' clinic practices in TCM have accumulated a considerable number of formulae that exhibit reliable in vivo efficacy and safety. However, the molecular mechanisms responsible for their therapeutic effectiveness are still unclear. The development of network-based systems biology has provided considerable support for the understanding of the holistic, complementary and synergic essence of TCM in the context of molecular networks. This review introduces available sources and methods that could be utilized for the network-based study of TCM pharmacology, proposes a workflow for network-based TCM pharmacology study, and presents two case studies on applying these sources and methods to understand the mode of action of TCM recipes.

Proliferative vitreoretinopathy (PVR) develops as a complication of rhegmatogenous retinal detachment (RRD). The unclear pathological pathways of PVR and RRD have been the biggest obstacle for successful retinal reattachment. In this study, a metabolomics approach using reversed-phase liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) was developed to obtain a systematic view of the pathological processes of RRD and PVR. Through a partial least squares discriminant analysis (PLS-DA) method, 31 biomarkers were identified in the vitreous samples of RRD and PVR patients. Sixteen pathways participated in the development of RRD and PVR. Through analyzing the biological effects of those identified biomarkers, inflammation, proliferation and energy consumption were the three major disturbed biological processes involved in the RRD and PVR development. Inflammation happened in the pathological processes of RRD, and proliferation mainly happened during PVR formation. The established network of biomarkers indicated that the histidine metabolism and citrate cycle were seriously disturbed during the RRD and PVR development. The metabolomics study supplied a systematic view of the development and progression of RRD and PVR on a metabolite level.

A metabolomic approach based on liquid chromatography coupled with quadrupole time-of-flight detector (LC-Q-TOF/MS) was developed to investigate the therapeutic mechanism of a traditional Chinese medicine (TCM) formula Shexiang Baoxin Pill (SBP) and a multi-component medicine polypill (consisting of simvastatin (Sim), atenolol (Ate), ramipril (Ram), hydrochlorthiazide (Hyd) and aspirin (Asp), named as SARHA). Twenty-seven biomarkers were identified in the serum of MI rats. Thirteen related pathways and 4 main pathological processes including oxidative injury, energy metabolism dysfunction, amino acid metabolism dysfunction and inflammation are involved in MI development. Our study revealed that SBP showed better therapeutic effectiveness than the polypill on MI through regulation of the energy metabolism dysfunction, oxidative injury and inflammation. The combination agent polypill had only certain therapeutic effects on inhibiting oxidative injury and inflammation induced by MI. The reverse effect of the polypill on biomarkers related to MI was much better than mono-therapy groups.

A metabolomic method using reversed-phase liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) was developed to obtain a systematic view of the development and progression of myocardial infarction (MI). By combining with partial least squares discriminant analysis (PLS-DA), 16 biomarkers in rat urine were identified and eight of them were related to the pathway of energy metabolism. Among the regulated pathways, the citric acid cycle related network was acutely perturbed. The metabolomic results not only supplied a systematic view of the development and progression of MI but also provided the theoretical basis for the prevention or treatment of MI. The developed method was also used to analyze the therapeutic effects of a traditional Chinese medicine (TCM) named Shexiang Baoxin Pill (SBP), a widely used anti-MI medicine in clinics. The results showed that SBP administration could provide satisfactory effects on MI through partially regulating the perturbed pathway of energy metabolism.

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Huang-Lian-Jie-Du-Tang (HLJDT) is a traditional Chinese medicine (TCM) with anti-inflammatory activity. The present study used a metabolomic approach based on LC-Q-TOF-MS to profile rheumatoid-arthritis- (RA-) related metabolic changes and to investigate the interventional mechanisms of HLJDT in collagen-induced arthritis rats. Forty male Wistar rats were randomly divided into five groups: (1) a model group, (2) a normal control group, (3) a dexamethasone group, (4) a HLJDT group, and (5) a group that received 13 components of HLJDT. Plasma samples were collected 8, 15, and 22 days after the rats were injected with bovine type II collagen. By combining variable importance in the projection values with partial least squares discriminant analysis, 18 potential biomarkers were identified in the plasma samples. The biomarkers were primarily involved in glycerophospholipid metabolism, fatty acid metabolism, tryptophan metabolism, linoleic acid metabolism, phenylalanine metabolism, purine metabolism, arachidonic acid metabolism, and bile acid biosynthesis. Using the potential biomarkers as a screening index, the results suggest that HLJDT can potentially reverse the process of RA by partially regulating fatty acid oxidation and arachidonic acid metabolism. This study demonstrates that a metabolomic strategy is useful for identifying potential RA biomarkers and investigating the underlying mechanisms of a TCM in RA treatment.

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