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Network pharmacology exploration reveals endothelial inflammation as a common mechanism for stroke and coronary artery disease treatment of Danhong injection.

ABSTRACT: Although Danhong injection (DHI) is the most widely prescribed Chinese medicine for both stroke and coronary artery disease (CAD), its underlying common molecular mechanisms remain unclear. An integrated network pharmacology and experimental verification approach was used to decipher common pharmacological mechanisms of DHI on stroke and CAD treatment. A compound-target-disease & function-pathway network was constructed and analyzed, indicating that 37 ingredients derived from DH (Salvia miltiorrhiza Bge., Flos Carthami tinctorii and DHI) modulated 68 common targets shared by stroke and CAD. In-depth network analysis results of the top diseases, functions, pathways and upstream regulators implied that a common underlying mechanism linking DHI's role in stroke and CAD treatment was inflammatory response in the process of atherosclerosis. Experimentally, DHI exerted comprehensive anti-inflammatory effects on LPS, ox-LDL or cholesterol crystal-induced NF-?B, c-jun and p38 activation, as well as IL-1?, TNF-?, and IL-10 secretion in vascular endothelial cells. Ten of 14 predicted ingredients were verified to have significant anti-inflammatory activities on LPS-induced endothelial inflammation. DHI exerts pharmacological efficacies on both stroke and CAD through multi-ingredient, multi-target, multi-function and multi-pathway mode. Anti-endothelial inflammation therapy serves as a common underlying mechanism. This study provides a new understanding of DHI in clinical application on cardiovascular and cerebrovascular diseases.

SUBMITTER: Lyu M

PROVIDER: S-EPMC5684234 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Network pharmacology exploration reveals endothelial inflammation as a common mechanism for stroke and coronary artery disease treatment of Danhong injection.

Lyu Ming M Yan Chun-Lin CL Liu Hai-Xin HX Wang Tai-Yi TY Shi Xin-Hui XH Liu Jin-Ping JP Orgah John J Fan Guan-Wei GW Han Ji-Hong JH Wang Xiao-Ying XY Zhu Yan Y

Scientific reports 20171113 1

Although Danhong injection (DHI) is the most widely prescribed Chinese medicine for both stroke and coronary artery disease (CAD), its underlying common molecular mechanisms remain unclear. An integrated network pharmacology and experimental verification approach was used to decipher common pharmacological mechanisms of DHI on stroke and CAD treatment. A compound-target-disease & function-pathway network was constructed and analyzed, indicating that 37 ingredients derived from DH (Salvia miltior ...[more]

PMID: 29133791

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Project description:Background: Hemorrhagic transformation, neurotoxicity, short treatment time windows, and other defects are considered as the major limitations for the thrombolytic therapy. This study is devoted to figure out whether Danhong injection (DHI) combined with tissue-plasminogen activator (t-PA) could extend the treatment time windows and ameliorate brain injury, hemorrhagic complication and BBB disruption after focal embolic stroke. Methods:In vitro, the combined concentrations of DHI and t-PA were added to wells reacted with plasminogen and D-Val-Leu-Lys-AMC. The optimum ratio of the combination of DHI plus t-PA was explored by detecting relative fluorescent. In vivo experiments, we firstly investigated the optimal dose of t-PA and Danhong injection for focal embolic stroke. The neurological deficit score, infarct volume and brain edema were assessed. Secondly, we proved that the combination group extended the thrombolytic window for treatment of focal embolic stroke. The neurological deficit score, infarct volume, brain edema and hemorrhagic complication were assessed, while levels of BAX, Bcl-2 and caspase-3 in brain tissue were analyzed by real-time polymerase chain reaction. Finally, to ask whether combination therapy with DHI plus t-PA protected the blood-brain barrier in a rat model of focal embolic stroke, neurological deficit score, ELISA, RT-PCR, western blot and fluorescence were used to detect the indicators of blood-brain barrier, such as tight junction protein, blood-brain barrier permeability and related gene expression. Results:In vitro, plasmin activity assays showed that the combination of t-PA with DHI at about 1:1.6 w/v ratio increased by almost 1.4-fold the plasmin-generating capability of t-PA. In vivo experiments, the results showed that the combination of Danhong injection (4 mL/kg) and t-PA (2.5 mg/kg) could extend the t-PA treatment time windows to 4.5 h. And the combination t-PA (2.5 mg/kg) with DHI (4 mL/kg) ameliorated neurological score, cerebral infarction, brain edema, brain hemorrhage, and BBB disruption. Conclusion: Combination therapy with Danhong injection (4 mL/kg) plus t-PA (2.5 mg/kg) could extend the t-PA treatment time windows to 4.5 h, ameliorate BBB disruption, reduce infarction, brain swelling and hemorrhage after ischemic stroke.

Project description:Doxorubicin (DOX) is a potent chemotherapeutic agent that is used against various types of human malignancies. However, the associated risk of cardiotoxicity has limited its clinical application. Danhong injection (DHI) is a Chinese medicine with multiple pharmacological activities and is widely used for treating cardiovascular diseases. The aim of the present study was to evaluate the potential protective effect of DHI on DOX-induced cardiotoxicity in vivo and to investigate the possible underlying mechanisms. First, a sensitive and reliable HPLC-ESI-Q-TOF-MS/MS method was developed to comprehensively analyze the chemical compositions of DHI. A total of 56 compounds were identified, including phenolic acids, tanshinones, and flavonoids. Then, a DOX-induced chronic cardiotoxicity rat model was established to assess the therapeutic effect of DHI. As a result, DHI administration prevented the reduction in body weight and heart weight, and improved electrocardiogram performance. Additionally, the elevated levels of serum biochemical indicators were reduced, and the activities of oxidative enzymes were restored in the DOX-DHI group. Network pharmacology analysis further revealed that these effects might be attributed to 14 active compounds (e.g., danshensu, salvianolic acid A, salvianolic acid B, rosmarinic acid, and tanshinone IIA) and 15 potential targets (e.g., CASP3, SOD1, NOS3, TNF, and TOP2A). The apoptosis pathway was highly enriched according to the KEGG analysis. Molecular docking verified the good binding affinities between the active compounds and the corresponding apoptosis targets. Finally, experimental validation demonstrated that DHI treatment significantly increased the Bcl-2 level and suppressed DOX-induced Bax and caspase-3 expression in rat heart tissue. Furthermore, DHI treatment obviously decreased the apoptosis rate of DOX-treated H9c2 cells. These results indicate that DHI attenuated DOX-induced cardiotoxicity via regulating the apoptosis pathway. The present study suggested that DHI is a promising agent for the prevention of DOX-induced cardiotoxicity.

Project description:BackgroundDanhong injection (DHI) is widely used in the treatment of cardiovascular and cerebrovascular diseases, and its safety and effectiveness have been widely recognized and applied in China. However, the potential molecular mechanism of action for the treatment of arrhythmia is not fully understood.AimIn this study, through network pharmacology and in vitro cell experiments, we explored the active compounds of DHI for the treatment of arrhythmia and predicted the potential targets of the drug to investigate its mechanism of action.Materials and methodsFirst, the potential therapeutic effect of DHI on arrhythmia was investigated in an in vitro arrhythmia model using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), in which calcium transients were recorded to evaluate the status of arrhythmia. Next, the active compounds and key targets in the treatment of arrhythmia were identified through network pharmacology and molecular docking, and the key signaling pathways related to the treatment of arrhythmia were analyzed. Furthermore, we used real-time quantitative reverse transcription PCR (qRT-PCR) to verify the expression levels of key genes.ResultsEarly afterdepolarizations (EADs) were observed during aconitine treatment in hiPSC-CMs, and the proarrhythmic effect of aconitine was partially rescued by DHI, indicating that the antiarrhythmic role of DHI was verified in an in vitro human cardiomyocyte model. To further dissect the underlying molecular basis of this observation, network pharmacology analysis was performed, and the results showed that there were 108 crosstargets between DHI and arrhythmia. Moreover, 30 of these targets, such as AKT1 and HMOX1, were key genes. In addition, the mRNA expression of AKT1 and HMOX1 could be regulated by DHI.ConclusionDHI can alleviate aconitine-induced arrhythmia in an in vitro model, presumably because of its multitarget regulatory mechanism. Key genes, such as AKT1 and HMOX1, may contribute to the antiarrhythmic role of DHI in the heart.

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Network pharmacology exploration reveals endothelial inflammation as a common mechanism for stroke and coronary artery disease treatment of Danhong injection.

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Network pharmacology exploration reveals endothelial inflammation as a common mechanism for stroke and coronary artery disease treatment of Danhong injection.

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