Deciphering the underlying mechanisms of Diesun Miaofang in traumatic injury from a systems pharmacology perspective.

Diesun Miaofang (DSMF) is a traditional herbal formula, which has been reported to activate blood, remove stasis, promote qi circulation and relieve pain. DSMF holds a great promise for the treatment of traumatic injury in an integrative and holistic manner. However, its underlying mechanisms remain to be elucidated. In the present study, a systems pharmacology model, which integrated cluster ligands, human intestinal absorption and aqueous solution prediction, chemical space mapping, molecular docking and network pharmacology techniques were used. The compounds from DSMF were diverse in the clusters and chemical space. The majority of the compounds exhibited drug-like properties. A total of 59 compounds were identified to interact with 16 potential targets. In the herb-compound-target network, the majority of compounds acted on only one target; however, a small number of compounds acted on a large number of targets, up to a maximum of 12. The comparison of key topological properties in compound-target networks associated with the above efficacy intuitively demonstrated that potential active compounds possessed diverse functions. These results successfully explained the polypharmacological mechanism underlying the efficiency of DSMF for the treatment of traumatic injury as well as provided insight into potential novel therapeutic strategies for traumatic injury from herbal medicine.

Understanding the polypharmacological anticancer effects of Xiao Chai Hu Tang via a computational pharmacological model.

Xiao Chai Hu Tang (XCHT), a traditional herbal formula, is widely administered as a cancer treatment. However, the underlying molecular mechanisms of its anticancer effects are not fully understood. In the present study, a computational pharmacological model that combined chemical space mapping, molecular docking and network analysis was employed to predict which chemical compounds in XCHT are potential inhibitors of cancer-associated targets, and to establish a compound-target (C-T) network and compound-compound (C-C) association network. The identified compounds from XCHT demonstrated diversity in chemical space. Furthermore, they occupied regions of chemical space that were the same, or close to, those occupied by drug or drug-like compounds that are associated with cancer, according to the Therapeutic Targets Database. The analysis of the molecular docking and the C-T network demonstrated that the potential inhibitors possessed the properties of promiscuous drugs and combination therapies. The C-C network was classified into four clusters and the different clusters contained various multi-compound combinations that acted on different targets. The study indicated that XCHT has a polypharmacological role in treating cancer and the potential inhibitory components of XCHT require further investigation as potential therapeutic strategies for cancer patients.

[Comparative research on computer simulation of two different therapeutic principles and formulae for osteoarthritis].

OBJECTIVE: To compare the effect of reinforcing Shen method (RSM) and activating blood method (ABM) in treating osteoarthritis (OA) at the molecular level. METHODS: The physical and chemical characteristics of components from respective recipes of RSM and ABM, and network features of component-target interaction network were analyzed by computer simulation methods including chemical space, molecular docking, and biological network, etc. RESULTS: The chemical components of RSM and ABM were scarcely scattered with larger overlapping. Among established networks, the distribution of network features was partially similar in RSM and ABM. The average target number correlated with each component was 1.86 in RSM and 2.11 in ABM respectively. Each average target number was respectively correlated with 4.46 compounds and 3.93 compounds, reflecting multi-component and multi-target actions. CONCLUSION: Computer simulation could intuitively trace out similarities and differences of two different methods and their interaction with targets, which revealed that the compatibility of RSM and ABM could have broader protein targets and potential synergism at the molecular level.

In silico search for multi-target therapies for osteoarthritis based on 10 common Huoxue Huayu herbs and potential applications to other diseases.

Huoxue Huayu (HXHY) has been widely used in traditional Chinese medicine (TCM) as a key therapeutic principle for osteoarthritis (OA), and related herbs have been widely prescribed to treat OA in the clinic. The aims of the present study were to explore a multi-target therapy for OA using 10 common HXHY herbs and to investigate their potential applications for treatment of other diseases. A novel computational simulation approach that integrates chemical structure, ligand clusters, chemical space and drug­likeness evaluations, as well as docking and network analysis, was used to investigate the properties and effects of the herbs. The compounds contained in the studied HXHY herbs were divided into 10 clusters. Comparison of the chemical properties of these compounds to those of other compounds described in the DrugBank database indicated that the properties of the former are more diverse than those of the latter and that most of the HXHY-derived compounds do not violate the 'Lipinski's rule of five'. Docking analysis allowed for the identification of 39 potential bioactive compounds from HXHY herbs and 11 potential targets for these compounds. The identified targets were closely associated with 49 diseases, including neoplasms, musculoskeletal, nervous system and cardiovascular diseases. Ligand­target (L­T) and ligand­target­disease (L­T­D) networks were constructed in order to further elucidate the pharmacological effects of the herbs. Our findings suggest that a number of compounds from HXHY herbs are promising candidates for mult­target therapeutic application in OA and may exert diverse pharmacological effects, affecting additional diseases besides OA.

Computational pharmacological comparison of Salvia miltiorrhiza and Panax notoginseng used in the therapy of cardiovascular diseases.

The herb pair comprising Salvia miltiorrhiza (SM) and Panax notoginseng (PN) has been used as a classical formula for cardiovascular diseases (CVDs) in China and in western countries. However, the pharmacology of SM and PN in this herb pair has not been fully elucidated. The aim of this study was to compare the mechanisms of SM and PN at the molecular level for the treatment of CVDs. We used a systems pharmacology approach, integrating ligand clustering, chemical space, docking simulation and network analysis, to investigate these two herbal medicines. The compounds in SM were attached to clusters 2, 3, 5, 6, 8 and 9, while the compounds in PN were attached to clusters 1, 2, 4, 5, 6, 7, 8 and 10. The distributions of chemical space between the compounds from SM and PN were discrete, with the existence of small portions of overlap, and the majority of the compounds did not violate 'Lipinski's rule of five'. Docking indicated that the average number of targets correlated with each compound in SM and PN were 5.0 and 3.6, respectively. The minority nodes in the SM and PN drug-target networks possessed common values of betweenness centrality, closeness centrality, topological coefficients and shortest path length. Furthermore, network analyses revealed that SM and PN exerted different modes of action between compounds and targets. These results suggest that the method of computational pharmacology is able to intuitively trace out the similarities and differences of two herbs and their interaction with targets from the molecular level, and that the combination of two herbs may extend their activities in different potential multidrug combination therapies for CVDs.

Network pharmacology-based prediction of the multi-target capabilities of the compounds in Taohong Siwu decoction, and their application in osteoarthritis.

Taohong Siwu decoction (THSWD), a formulation prescribed in traditional Chinese medicine (TCM), has been widely used in the treatment of osteoarthritis (OA). TCM has the potential to prevent diseases, such as OA, in an integrative and holistic manner. However, the system-level characterization of the drug-target interactions of THSWD has not been elucidated. In the present study, we constructed a novel modeling system, by integrating chemical space, virtual screening and network pharmacology, to investigate the molecular mechanism of action of THSWD. The chemical distribution of the ligand database and the potential compound prediction demonstrated that THSWD, as a natural combinatorial chemical library, comprises abundant drug-like and lead-like compounds that may act as potential inhibitors for a number of important target proteins associated with OA. Moreover, the results of the 'compound-target network' analysis demonstrated that 19 compounds within THSWD were correlated with more than one target, whilst the maximum degree of correlation for the compounds was seven. Furthermore, the 'target-disease network' indicated that THSWD may potentially be effective against 69 diseases. These results may aid in the understanding of the use of THSWD as a multi-target therapy in OA. Moreover, they may be useful in establishing other pharmacological effects that may be brought about by THSWD. The in silico method used in this study has the potential to advance the understanding of the molecular mechanisms of TCM.

Computational approaches for exploring the potential synergy and polypharmacology of Duhuo Jisheng Decoction in the therapy of osteoarthritis.

The Duhuo Jisheng Decoction (DHJSD), a traditional Chinese medicine (TCM), has been widely used to treat osteoarthritis (OA). However, the mechanisms of action of the DHJSD have not been clearly elucidated. In the present study, the compounds in the DHJSD were characterized by three computational methods; the ligand clustering, chemical space distribution and network construction and analysis methods. The compounds that formed the medical composition of the DHJSD were divided into 10 clusters and possessed a broad diversity in chemical space distribution. The compounds also had the same coverage of chemical space as the OA drug/drug­like compounds from DrugBank. In addition, multiple active compounds were identified as able to target multiple proteins in the drug­target association networks (D­T networks). A certain number of key compounds in the D­T networks have been previously reported in the literature. The present study also constructed drug­drug association networks (D­D networks) and classified the DHJSD compounds into five clusters. The clusters represented multiple diverse combinations binding to the OA targets. These results suggested that the DHJSD had drug­ and lead­like compounds with potential synergy and polypharmacology against OA.

Observation on effects of aconitine via acupoint injection in rabbits.

OBJECTIVE: To investigate the ability of the pericardium meridian (PM) to mitigate or enhance the cardiotoxic effects of aconitine injected at specific acupoint and non-acupoint sites in rabbits. METHODS: This study consisted of 3 experiments that were designed to test the effects of injection of 30 µg/kg of aconitine at acupoints on the PM (Test 1), at non-acupoint sites on the PM (Test 2), and at acupoints on other meridians and non-meridian sites (Test 3). In Test 1, 24 rabbits were randomly assigned to receive injections at Quze (PC3), Tianquan (PC2), or intramuscularly. In Test 2, 24 rabbits were randomly assigned to receive injections of aconitine at non-acupoint I, non-acupoint II, or intramuscularly. In Test 3, 48 rabbits were randomly assigned to receive injections at Neiguan (PC6), Sanyinjiao (SP6), Yangjiao (GB35), a non-meridian and non-acupoint site (NMNA), intravenously, and intramuscularly. Electrocardiographs of the rabbits were performed before, during and after injection to determine the incidence of arrhythmia, latency of ventricular rhythm, and recovery rate after aconitine injection. The recovery time index and extent of arrhythmia scores were calculated. RESULTS: In all groups the incidence of arrhythmia was 100%, and the latency of ventricular rhythm was less than 30 min. In Tests 1 and 2, the recovery rates of the Quze and non-acupoint II groups were significantly higher than those of the muscular group (P < 0.05). In Test 3, the recovery time index and extent of arrhythmia scores of the Neiguan group were low. There were no significant differences between the other acupoint groups, or the NMNA group, when compared with the group receiving aconitine intramuscularly. CONCLUSIONS: Acupoints or non-acupoints along the PM could reduce the severity of the arrhythmia induced by aconitine in healthy rabbits. Meridians play an important role in protecting body functions.

[Effect of water extracts from duhuo jisheng decoction on expression of chondrocyte G1 phase regulator mRNA].

OBJECTIVE: To investigate the effect of water extracts from Duhuo Jisheng decoction on chondrocyte G1 phase. METHODS: Chondrocytes were collected from four-week-old SD rats to establish the chondrocyte in vitro culture system. The third generation of chondrocytes was intervened. MTT method was used to measure the effect of water extracts from different concentrations of Duhuo Jisheng decoction on chondrocyte activity. The expressions of Chondrocyte Cyclin D1, CDK4, CDK6 and P21 mRNA in the blank group and low, middle and high-dose groups (100, 200, 400 mg x L(-1)) were detected by RT-PCR method. RESULT: The MTT assay showed that the chondrocyte activity significantly increased within specific drug concentrations (50-800 mg x L(-1)) (P < 0.01); After the intervention for 24 h, the expressions of CyclinD1, CDK4 and CDK6 mRNA in all dose groups notably increased (P < 0.05), with the maximum expressions at the concentration of 200 mg x L(-1); The expression of P21 mRNA decreased, particularly at the concentration of 200 mg x L(-1) (P < 0.01). CONCLUSION: Water extracts from Duhuo Jisheng decoction can promote chondrocyte proliferation by effecting the expression of chondrocyte G1 phase regulator mRNA.

[Computational simulation of multi-target research on the material basis of Caulis sinomenii in treating osteoarthritis].

OBJECTIVE: To explore the material basis of Caulis sinomenii (CS) in treating osteoarthritis (OA), and to give a pharmacodynamic illustration for the multi-targeting therapeutics of CS. METHODS: The computational methods, consisting of molecular docking and biological network were carried out to search the database targeting twelve important OA related enzymes: ASAMTS4, ASAMTS5, MMP-1, MMP-3, MMP-13, MMP-8, MMP-2, COX-2, COX-1, IL-1beta, TNF-alpha, iNOS, and map the ligand-target interaction networks about molecules from CS and DrugBank. After that, an aggregate analysis was performed to analyze the mechanisms of compositions in CS. RESULTS: Totally 14 had good interaction in all molecules in database with two or more than two of the OA correlated enzymes, and 6 molecules had interaction with four or more enzymes. Moreover, both herb ligand-target interaction network and drug ligand-target interaction network were similar in the interaction profiles and network features, which revealed multi-drugs effects in CS. CONCLUSIONS: There were a lot of multi-target molecules in CS, providing pharmacodynamic illustrations for the multi-target therapeutics of Chinese medicine. Meanwhile, they supplied certain reference and inspiration for finding out new drugs for OA therapy.

Potential synergistic and multitarget effect of herbal pair Chuanxiong Rhizome-Paeonia Albifora Pall on osteoarthritis disease: a computational pharmacology approach.

OBJECTIVE: To study the polypharmacological mechanism of herbal pair Chuanxiong Rhizome-Paeonia Albifora Pall (HP CXR-PAP) on the treatment for osteoarthritis (OA). METHODS: Chemical space was used to discuss the similarities and differences between the molecule sets of HP CXR-PAP and drugs. Docking protocol was used to study the interaction between HP CXR-PAP and OA target enzymes. The similarities and differences of HP CXR-PAP and drugs in target spaces were elucidated by network features. RESULTS: The plots between the molecule sets of HP CXR-PAP and drugs in chemical space had the majority in the same region, and compounds from HP CXR-PAP covered a much larger additional region of space than drug molecules, which denoted the diverse structural properties in the molecule set of HP CXR-PAP. The molecules in HP CXR-PAP had the properties of promiscuous drugs and combination drug, and both HP CXR-PAP ligand-target interaction network and drug ligand-target interaction network were similar in the interaction profiles and network features, which revealed the effects of multicomponent and multitarget. CONCLUSION: The clue of potential synergism was obtained in curing OA disease by Chinese medicine, which revealed the advantages of Chinese medicine for targeting osteoarthritis disease.

Experimental study on the suppression of sodium nitroprussiate-induced chondrocyte apoptosis by Tougu Xiaotong Capsule (透骨消痛胶囊)-containing serum.

OBJECTIVE: To study the mechanism of action of Tougu Xiaotong Capsule (透骨消痛胶囊, TGXTC) ex vivo in suppressing chondrocyte (CD) apoptosis induced by sodium nitroprussiate (SNP). METHODS: Thirty New Zealand rabbits, 2 months old, were randomized by lottery into five groups, six in each: the blank group treated with saline, the positive control group treated with Zhuanggu Guanjie Pill (壮骨关节丸, 70 mg/kg), and the three experimental groups, EGA, EGB, and EGC, treated with low dose (35 mg/kg), moderate dose (70 mg/kg), and high dose (140 mg/kg) of TGXTC, respectively. All treatments were administered via gastrogavage twice a day for 3 days. Arterial blood was collected from the abdominal aorta and drug or drug metabolites-containing serum was prepared. CDs obtained from knee joints of 16 four-week-old New Zealand rabbits were cultured to the third passage and confirmed by toluidine blue staining. SNP of various final concentrations (0, 0.5, 1.0, and 2.0 mmol/L) was used to induce CD apoptosis, and the dosage-effect relationship of SNP in inducing CD apoptosis was determined. Serum samples from the blank, control, and three dosages of TGXTC-treated rabbits were tested in the CD culture in the presence of SNP. Cell apoptosis was determined by Hoechst 33342 staining, viability of CDs was quantified by MTT, CD apoptosis rate was determined by annexin V-FITC/PI staining, levels of p53 and Bcl-2 mRNA expression in CDs were determined with RT-PCR, and contents of caspase-3 and caspase-9 proteins were determined by colorimetry. RESULTS: CD apoptosis was induced by SNP at all concentrations tested and in a dose-dependent manner. The SNP concentration of 1 mmol/L and treatment duration of 24 h appeared to be optimal and were selected for the study. Serum samples from the positive control rabbits and from the two higher doses of TGXTC-treated rabbits showed reduction of SNP-induced CD apoptosis, decrease in p53 mRNA expression, inhibition of catalytic activities of caspase-3 and caspase-9, and increase in Bcl-2 mRNA expression when compared with the serum from the blank group (P<0.05). CONCLUSION: TGXTC-containing sera antagonized SNP-induced CD apoptosis and the molecular basis for the action was associated with up-regulation of Bcl-2, down-regulation of p53 expression, and inhibition of caspase-3 and caspase-9 catalytic activities.

Computational pharmacology study of tougu xiaotong granule in preventing and treating knee osteoarthritis.

OBJECTIVE: To study the pharmacological properties of Tougu Xiaotong Granule (TGXTG) in preventing and treating knee osteoarthritis (KOA) at the molecular level. METHODS: The computational methods, including principal component analysis, molecular docking, target-ligand space distribution, and the predictions of absorption, distribution, metabolism, excretion and toxicity (ADMET), were introduced to characterize the molecules in TGXTG. RESULTS: The structural properties of molecules in TGXTG were more: diverse than those of the drug/drug-like molecules, and TGXTG could interact with significant target enzymes related to KOA. In addition, the cluster of effective components was preliminarily identified by the target-ligand space distributions. As to the results of ADMET properties, some of them were unsatisfactory, and were merely regarded as references here. CONCLUSION: Based on this computational pharmacology study, TGXTG is a broad-spectrum recipe inhibiting many important target enzymes, which could effectively postpone the degeneration of spectrum cartilage by coordinately inhibiting the biological effects of cytokines, matrix metallopeptidase 3, and oxygen free radicals. radicals.