In Silico System Pharmacology for the Potential Bioactive Ingredients Contained in Xingnaojing Injection (醒脑静注射液) and Its Material Basis for Sepsis Treatment

Objective： To elucidate the action mechanism of Xingnaojing Injection （醒脑静注射液, XNJI） for sepsis, and to target screen the potential bioactive ingredients. Methods： An integrated protocol that combines in silico target screen （molecular docking） and database mapping was employed to find the potential inhibitors from XNJI for the sepsis-related targets and to establish the compound-target （C-T） interaction network. The XNJI＇s bioactive components database was investigated and the sepsis-associated targets were comprehensively constructed; the 3D structure of adenosine receptor A2a and 5-1ipoxygenase proteins were established and evaluated with homology modeling method; system network pharmacology for sepsis treatment was studied between the bioactive ingredients and the sepsis targets using computational biology methods to distinguish inhibitors from non inhibitors for the selected sepsis-related targets and C-T network construction. Results： Multiple bioactive compounds in the XNJI were found to interact with multiple sepsis targets. The 32 bioactive ingredients were generated from XNJI in pharmacological system, and 21 potential targets were predicted to the sepsis disease; the biological activities for some potential inhibitors had been experimentally confirmed, highlighting the reliability of in silico target screen. Further integrated C-T network showed that these bioactive components together probably display synergistic action for sepsis treatment. Conclusions： The uncovered mechanism may offer a superior insight for understanding the theory of the Chinese herbal medicine for combating sepsis. Moreover, the potential inhibitors for the sepsis-related targets may provide a good source to find new lead compounds against sepsis disease.

Autophagosome activity in macrophage for atherosclerotic plaques in ApoE^-/-mice enhanced by Tiaozhi Tongmai Granules

Objective:Atherosclerosis is the fundamental pathophysiologic component of cardiovascular disease,and Tiaozhi Tongmai Granules show great efficiency in the treatment of the disease.However,the mechanism of Tiaozhi Tongmai Granules is still unclear.In this study,we have combined experiments with network pharmacology to explore the antiatherosclerosis mechanism of Tiaozhi Tongmai Granules.Method:120 male ApoE
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mice were randomly divided into three groups:the model group,Chinese herb group and Atorvastatin group.The model group,Atorvastatin group and Chinese herb group were fed with a high-fat diet,a high-fat diet plus atorvastatin(5.1 mg/kg/d)and a high-fat diet plus Tiaozhi Tongmai Granules(16.5 g/kg/d)for 16 weeks,respectively.Atherogenesis was identified by H&E staining.The colocalization of neutral lipid stain BODIPY and microtubule-associated protein 1 light chain 3(LC3)and the colocalization of BODIPY and lysosomal-associated membrane protein 1(LAMP1)within ApoE
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mice aortic plaques were tested using fluorescence confocal microscopy and the Pearson’s coefficients were calculated.To further explore the anti-atherosclerosis mechanism of Tiaozhi Tongmai Granules,the network pharmacology was used to construct the herb-compound-target network.Results:The size of the aortic lipid plaque in the Chinese herb group and Atorvastatin group were smaller compared with the model group on the 16th week.Compared with the model group on the 16th week,the BODIPY and LC3 colocalization rate,the BODIPY and LAMP1 colocalization rate of the Chinese herb group and Atorvastatin group all presented significant increase in the aortic plaque(P<.001),showing that Tiaozhi Tongmai Granules could enhance autophagosome activity in the macrophage.In the herb-compound-target network,17 active compounds and 27 targets were obtained through literature searching and using LHRI&DAVID Bioinformatics.It was found that 23 targets were correlated with the macrophage.Some of them participated in macrophage inflammatory response,and the other targets could promote/inhibit phagocytosis of the macrophage.It was hypothesized that the active compounds of Tiaozhi Tongmai Granules were acting on these targets and having y the biological effects.Conclusions:In the progression stage of atherosclerosis,Tiaozhi Tongmai Granules can still make the macrophage have higher autophagosome activity,and play a role of anti-atherogenesis.

Data Mining and Systems Pharmacology to Elucidate Effectiveness and Mechanisms of Chinese Medicine in Treating Primary Liver Cancer

Objective: To identify specific Chinese medicines(CM) that may benefit patients with primary liver cancer(PLC), and to explore the mechanism of action of these medicines. Methods: In this retrospective, singlecenter study, prescription information from PLC patients was used in combination with Traditional Chinese Medicine Inheritance Supports System to identify the specific core drugs. A system pharmacology approach was employed to explore the mechanism of action of these medicines. Results: Taking CM more than 6 months was significantly associated with improved survival outcomes. In total, 77 putative targets and 116 bioactive ingredients of the core drugs were identified and included in the analysis(P<0.05). A total of 1,036 gene ontology terms were found to be enriched in PLC. A total of 75 pathways identified from Kyoto Encyclopedia of Genes and Genomes were also enriched in this disease, including fluid shear stress, interleukin-17 signaling, signaling between advanced glycan end products and their receptors, cellular senescence, tumor necrosis factor signaling, p53 signaling, cell cycle signaling,steroid hormone biosynthesis, T-helper 17 cell differentiation, and metabolism of xenobiotics by cytochrome. Docking studies suggested that the ingredients in the core drugs exert therapeutic effects in PLC by modulating c-Jun and interleukin-6. Conclusions: Receiving CM for 6 months or more improves survival for the patients with PLC. The core drugs that really benefit for PLC patients likely regulates the tumor microenvironment and tumor itself.