PerspectiveSystems-biology dissection of mechanisms and chemical basis of herbal formula in treating chronic myocardial ischemia
Introduction
Combination therapy, modulating the activities of multiple targets to achieve therapeutic efficacies, has been a promising choice for treatment of disease, especially complex diseases, such as HIV, cancer and diabetes disease [1], [2], [3]. The main reason is that complex diseases normally involve networked physiological systems featured as redundancy and multifunctionality, which limits the therapeutic opportunity of single-agent applications [4]. In comparison, combinations of drugs are thought to be more effective to counter this complex situation due to the synergistic action or negative regulation of resistance [5], [6].
Indeed, the concept of combinatorial therapy has been advocated and practiced in traditional medical treatments for thousands of years, such as traditional Chinese medicine (TCM), which often use botanical mixtures (or named formulae) characterized as multi-component and multi-function to treat disease [7], [8], [9]. In development, considerable knowledge has been accumulated concerning clinical efficacy and safety of herbal formulae in targeting complex diseases. However, essential chemical ingredients have not been identified in most formulae, and especially precise mechanisms of formulae remain to be addressed, which hamper the modernization of traditional medical systems.
Chronic myocardial ischemia (MI) is defined by the result of a partial or complete blockage of coronary arteries. Cardiac dysfunction caused by MI and its long-term sequence such as heart failure (HF) profoundly impact patient prognosis and quality of life, and have been a major cause of death and disability worldwide [10], [11]. Till now, a series of classical agents, such as angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, angiotensin II receptor antagonists, vasodilators and beta-blockers have been proved to be cardioprotective in both preclinical and clinical studies [12]. However, many of these drugs play functional roles in biological processes outside the scope of the drug’s intended effects. For example, vasodilators improve the clinical symptoms at an early stage, but the long-term treatments lead to increased mortality [13]. ACE inhibitors and beta-blockers improve myocardial function in the long-term use but do not produce beneficial effects in the treatment of early-stage hemodynamic disorders [14]. Alternatively, there is a growing interest in the use of traditional medicine for long-term prevention of heart attack in high risk patients. For example, the study of TCM has led to design of some formulae for prevention and treatment of heart failure in the basic and clinical research, such as Qili Qiangxin Capsules and Qishenkeli (QSKL) [15], [16].
QSKL is a traditional Chinese medicine that has long been used for the routine treatment of coronary heart disease (CHD) and chronic heart failure (CHF) in China. It consists of six Chinese herbs Astragalus propinquus Schischkin., root and rhizome (APS), Salvia miltiorrhiza Bunge., root and rhizome (SMB), Lonicera japonica Thunb., flower (LGT), Aconitum carmichaelii Debeaux., lateral root (ACD), Glycyrrhiza glabra L., root and rhizome (GGL), and Scrophularia ningpoensis Hemsl., root (SNH), and is widely produced in China in accordance with the Chinese Pharmacopoeia standard of quality control. Previously, our preclinical and clinical studies have proved the therapeutic effects of QSKL on HF and partially explored its molecular mechanism characterized by multi-targets and multi-functions [17], [18], [19]. However, the chemical basis of QSKL is still unknown that link the therapeutic effects and explicit molecular targets of QSKL in its effects on myocardial function.
In this work, based on an array of computational and experimental approaches, we propose a systems-biology strategy for identification of key active ingredients of QSKL and dissection of underlying mechanisms (Fig. 1). The proposed methodology mainly includes three categories: (1) transcriptome-based understanding of the drug actions and exploration of potential therapeutic targets; (2) systematical ligand-target interaction prediction methods to build relationships between therapeutic targets and effective herbal molecules; and (3) combined biological network analysis and experimental validation to discover the chemical basis and their molecular actions. This strategy in dissecting the complexity of clinically effective formulae at the chemical, molecular, cellular, and organism levels may be an effective path to explore the value of traditional medicine.
Section snippets
QSKL promotes cardiac repair and improves myocardial function
After 8 weeks of treatment, echocardiographic, hemodynamic and physicochemical evaluation were conducted to assess the cardiac function in the three groups to evaluate the role of QSKL in preventing heart from myocardial ischemia. In comparison with the sham group, myocardial ischemia caused a significant decline in LVEF and FS (P < 0.05 and P < 0.001, for LVEF and FS, respectively; Fig. 2A), indicating an impairment of heart function. When treating with QSKL at 0.33 g/kg, LVEF and FS were
Discussion
In our study, we proposed a systems-biology strategy that combines bioinformatical and experimental methodologies for exploring material basis and molecular mechanism of herbal mixture. Using QSKL as an example, this study indicated the fact that multiple components in this formula regulate multiple disease-causing functions simultaneously to exert its therapeutic effects. Especially, a transcriptome-based inference method was utilized to identify therapeutic targets that directly bind with
Myocardial ischemia pig model and treatment protocol
All experiments in this study were performed in accordance with the Principles of Laboratory Animal Care (NIH publication no. 85-23, revised 1985) and Guidelines for Animal Experiments at Beijing University of Chinese Medicine. All efforts were made to minimize the number of the animals used and their suffering. The day before surgery, all animals received aspirin (325 mg orally) and were fasted for 12 h. Prior to surgical procedure, all animals received prophylactic antibiotics and buprenorphine
Statistical analysis
Inhibitory effects on the parameters measured were compared by analyzing the means for differences using Student’s t-test and ANOVA test. Student’s t-test was applied to compare the means of two groups. ANOVA test was used to compare the means of multiple groups. Differences were considered to be significant when p < 0.05. Values were reported as mean ± SEM of three parallel samples.
Authors’ contributions
SZG carried out the study and wrote the manuscript; WW designed the study; PL, BZF, KG and WXZ carried out the study, collected the data and conducted the analysis; JXC designed the study and JXW operated the machine.
Competing interests
The authors declare that they have no competing interests.
Acknowledgments
This research was supported by The Molecular Network Regulatory Mechanism Research on Reversing Cardiac Fibrosis by the Principles of Warming Yang, Tonifying Qi, Promoting Blood Circulation and Detoxication (No. 81530100), Systems Biological Methods of TCM Syndrome Research (No. 81522051), Program for New Century Excellent Talents in University (No. NCET-13-0692) and National Natural Science Fund (No. 81403319).
References (46)
- et al.
Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial
Lancet
(2009) - et al.
Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial
Lancet
(2009) - et al.
The orange book: the food and drug administration's advice on therapeutic equivalence
Am. Pharm.
(1990) - et al.
Docetaxel-based combination therapy for castration-resistant prostate cancer
Ann. Oncol. Off. J. Eur. Soc. Med. Oncol.
(2010) Cancer as a robust system: implications for anticancer therapy
Nat. Rev. Cancer
(2004)- et al.
Mechanisms of drug combinations: interaction and network perspectives
Dressnat. Rev. Drug Discov.
(2009) - et al.
The emerging paradigm of network medicine in the study of human disease
Circ. Res.
(2012) ‘Back to the future' for Chinese herbal medicines
Dressnat. Rev. Drug Discov.
(2007)- et al.
Where is the hope for drug discovery? Let history tell the future
Drug Discov Today
(2008) Made in China
Nature
(2011)
Clinical epidemiology of heart failure
Heart
Third universal definition of myocardial infarction
Cor Vasa
ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines
J. Am. Coll. Cardiol.
Do prescription stimulants increase the risk of adverse cardiovascular events? : A systematic review
BMC Cardiovasc. Disord.
New insights into mechanisms of action of carvedilol treatment in chronic heart failure patients?a matter of time for contractility
J. Card. Fail.
A multicenter, randomized, double-blind, parallel-group, placebo-controlled study of the effects of qili qiangxin capsules in patients with chronic heart failure
J. Am. Coll. Cardiol.
Chinese herbal medicine in the treatment of chronic heart failure: three-stage study protocol for a randomized controlled trial
Evidence-based Complement. Altern. Med.
Time-course of the effects of QSYQ in promoting heart function in ameroid constrictor-induced myocardial ischemia pigs
Evidence-based Complement. Altern. Med.: eCAM.
Drug target prediction based on the herbs components: the study on the multitargets pharmacological mechanism of qishenkeli acting on the coronary heart disease
Evidence-based Complement. Altern. Med. (eCAM).
Cardioprotective effects of qishenyiqi mediated by angiotensin II type 1 receptor blockade and enhancing angiotensin-converting enzyme 2
Evidence-based Complement. Altern. Med.
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Nat. Protoc. Erecipes Res.
B-Type natriuretic peptide levels: diagnostic and prognostic in congestive heart failure
Circulation
Insights from systems pharmacology into cardiovascular drug discovery and therapy
BMC Syst. Biol.
Cited by (0)
- 1
These authors contributed to this research equally.