BACKGROUND: Traditional Chinese medicine, with the feature of synergistic effects of multi-component, multi-pathway and multi-target, plays an important role in the treatment of cancer, cardiovascular and cerebrovascular diseases, etc. However, chemical components in traditional Chinese medicine are complex and most of the pharmacological mechanisms remain unclear, especially the relationships of chemical components change during the metabolic process.
OBJECTIVE: Our aim is to provide a method based on complex network theory to analyze the causality and dynamic correlation of substances in the metabolic process of traditional Chinese medicine.
METHODS: We proposed a framework named CDCS-TCM to analyze the causality and dynamic correlation between substances in the metabolic process of traditional Chinese medicine. Our method mainly consists two parts. The first part is to discover the local and global causality by the causality network. The second part is to investigate the dynamic correlations and identify the essential substance by dynamic substance correlation network.
RESULTS: We developed a CDCS-TCM method to analyze the causality and dynamic correlation of substances. Using the XiangDan Injection for ischemic stroke as an example, we have identified the important substances in the metabolic process including substance pairs with strong causality and the dynamic changes of the core effector substance clusters.
CONCLUSIONS: The proposed framework will be useful for exploring the correlations of active ingredients in traditional Chinese medicine more effectively and will provide a new perspective for the elucidation of drug action mechanisms and the new drug discovery.

Xiangdan injection (XDI), as a well-known traditional Chinese medicine injection, is of great significance to treat cardiovascular and cerebrovascular diseases. The haptens causing allergic reactions are urged to be detected due to the adverse reaction. In this study, an efficient approach was established to rapidly identify and screen potential haptens in XDI for the first time by combining high performance liquid chromatography-diode array detector-electrospray ionization-ion trap-time of flight-mass spectrometry with human serum albumin-fluorescence detector (HPLC-DAD-ESI-IT-TOF-MS-HSA-FLD). 21 compounds were identified according to their mass spectrum or comparison with reference substances and 8 salvianolic acids in XDI showed interactions with HSA in varying degrees. After that, surface plasmon resonance (SPR) was applied to screen the compounds showing specific affinity with human serum albumin (HSA). Subsequently, active systemic anaphylaxis (ASA) in guinea pigs was carried out to verify the sensitization of active compounds, In the meantime the serum IgE level before and after challenge was measured by the enzyme-linked immunosorbent assay (ELISA). Ultimately, it was tested that salvianolic acid C had a strong sensitization, in addition, lithospermic acid, rosmarinic acid and salvianolic acid B had potential sensitization. This study suggest that the on-line method provides rapid preliminary searching for haptens in XDI, combined with SPR and ASA, offering an efficient, rapid and comprehensive approach to screen haptens.

This study is to explore the effect of Xiangdan Injection on anticoagulation of warfarin in rats. Rats were randomly divided into different groups and then administered, subsequently the blood samples were collected at a set series of time points to measure PT(prothrombin time) and APTT(activated partial thromboplastin time) values, and INR(international normalized ratio) value was calculated. The plasma concentrations of warfarin enantiomers were determined by UPLC-MS/MS technology, and pharmacokinetic parameters were calculated by DAS 2.0 software. Statistical analysis was performed to compare differences between the groups. Single-dose study of warfarin showed that Xiangdan Injection alone had no effects on PT, APTT and INR, but when co-administrated with warfarin, PT and INR values were increased(P<0.01), while APTT was unaffected; after co-administration of the two drugs, C_(max), AUC_(0-t), and AUC_(0-∞) of S-warfarin increased(P<0.01), and t_(1/2) prolonged(P<0.01), while the pharmacokinetic parameters of R-warfarin were not changed significantly. Steady-state study of warfarin showed that after co-administration of the two drugs, the PT and INR values increased(P<0.05), and the plasma concentration of S-warfarin increased(P<0.01), while the plasma concentration of R-warfarin was not changed significantly. The results suggest that Xiangdan Injection itself has no effect on coagulation index, but can enhance the anticoagulant effect of warfarin by slowing metabolism of S-warfarin.

Rat bone marrow-derived mesenchymal stem cells were cultured and passaged in vitro. After induction with basic fibroblast growth factor for 24 hours, passage 3 bone marrow-derived mesenchymal stem cells were additionally induced into dopaminergic neurons using three different combinations with basic fibroblast growth factor as follows: 20% Xiangdan injection; all-trans retinoic acid + glial-derived neurotrophic factor; or sonic hedgehog + fibroblast growth factor 8. Results suggest that the bone marrow-derived mesenchymal stem cells showed typical neuronal morphological characteristics after induction. In particular, after treatment with sonic hedgehog + fibroblast growth factor 8, the expressions of nestin, neuron-specific enolase, microtubuleassociated protein 2, tyrosine hydroxylase and vesicular monoamine transporter-2 in cells were significantly increased. Moreover, the levels of catecholamines in the culture supernatant were significantly increased. These findings indicate that Xiangdan injection, all-trans retinoic acid + glial-derived neurotrophic factor, and sonic hedgehog + fibroblast growth factor 8 can all induce dopaminergic neuronal differentiation from bone marrow-derived mesenchymal stem cells. In particular, the efficiency of sonic hedgehog + fibroblast growth factor 8 was highest.