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-κB, c-jun and p38 activation, as well as IL-1β, TNF-α, 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.
Highlights
The 2017 updated Statistics of American Heart Association (AHA) reported that coronary artery disease (CAD) and ischemic stroke ranked as number 1st and 2nd top causes of cardiovascular diseases (CVDs) estimated for the global burden of disease[1]
From the bench to the bedside, previous studies on Danhong injection (DHI) for CVDs can mainly documented into three sections: (1) Clinical practices show that DHI has long been extensively used in treatment of stroke and CAD associated diseases (Table 1). (2) Basic researches indicate that DHI can ameliorate cerebral ischemia-reperfusion injury[40,41,42,43], cerebral ischemia damage[44], myocardial reperfusion injury[45,46], myocardial hypertrophy[47], cardiac dysfunction[48] and cardiac ventricular remodeling[48]
A pharmacology network and experimental verification combination approach was introduced in this study, deciphering the potential curative effects and pharmacology actions of DHI in both stroke and CAD treatment, which involves four steps in a workflow (Fig. 1): (1) the ingredients of prescription along with their corresponding targets and diseases associated targets were identify by various databases; (2) the relationship of compound-target-pathway-disease & function were constructed by interaction networks; (3) the key targets, top functions, top canonical pathways and top upstream regulators were uncovered by network analysis; (4) the efficacy of prescription was validated and the accuracy of network analysis was guaranteed by experimental verification
Summary
The 2017 updated Statistics of American Heart Association (AHA) reported that coronary artery disease (CAD) and ischemic stroke ranked as number 1st and 2nd top causes of cardiovascular diseases (CVDs) estimated for the global burden of disease[1]. They share a number of malfunctions such as inflammation[2,3], dysregulated immune system[4], thrombosis[5], lipid metabolism[6], apoptosis[7] and necrosis[7], and several common disease risks, such as atherosclerosis[8,9], hypertension[10,11,12] and diabetes mellitus[2]. Combing system-level investigation with experimental validation, these studies facilitate discovering the potential active ingredients and action mechanisms of TCM
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