Systems Pharmacology Dissection of the Integrated Treatment for Cardiovascular and Gastrointestinal Disorders by Traditional Chinese Medicine

Abstract

Though cardiovascular diseases (CVDs) and gastrointestinal disorders (GIDs) are different diseases associated with different organs, they are highly correlated clinically. Importantly, in Traditional Chinese Medicine (TCM), similar treatment strategies have been applied in both diseases. However, the etiological mechanisms underlying them remain unclear. Here, an integrated systems pharmacology approach is presented for illustrating the molecular correlations between CVDs and GIDs. Firstly, we identified pairs of genes that are associated with CVDs and GIDs and found that these genes are functionally related. Then, the association between 115 heart meridian (HM) herbs and 163 stomach meridian (SM) herbs and their combination application in Chinese patent medicine was investigated, implying that both CVDs and GIDs can be treated by the same strategy. Exemplified by a classical formula Sanhe Decoration (SHD) treating chronic gastritis, we applied systems-based analysis to introduce a drug-target-pathway-organ network that clarifies mechanisms of different diseases being treated by the same strategy. The results indicate that SHD regulated several pathological processes involved in both CVDs and GIDs. We experimentally confirmed the predictions implied by the effect of SHD for myocardial ischemia. The systems pharmacology suggests a novel integrated strategy for rational drug development for complex associated diseases.Over the past decade, there has been a marked increase in our understanding that there are higher prevalence rates of gastrointestinal disease (GIDs) in patients with cardiovascular disease (CVDs) 1,2 with similar dysfunctional phenotypes, such as rib pain, stomach pain, nausea and vomiting. However, the underlying co-occurrence mechanisms of CVDs and GIDs are unclear, thereby hampering development of drugs for both diseases in humans 3 . In modern Western medicine, usually, it has been observed that cardiovascular diseases have an etiological relationship with gastrointestinal disorders. Several studies have reported that the risk of cardiovascular disease in patients with gastrointestinal disease appears to be far greater than in the general population 4 . Moreover, some gastrointestinal disorders may increase patients' risk of cardiovascular disease as well. For example, patients with chronic gastrointestinal ischemia have an increased CVDs' risk and excess mortality 5 . Furthermore, the pathophysiological mechanisms between the two organs would supply realistic treatment for CVDs and GIDs 6 . For example, Iranian traditional physicians have introduced several remedies for heart-stomach association ailments in a previous study 7 . In addition, novel studies demonstrated the close relationship between gastroesophageal reflux disease (GERD) and the development of atrial fibrillation (AF), notably, acid-suppressive therapy is an effective strategy for the management of AF and may help to minimize the use of anti-arrhythmic agents 8,9 .

Systems Pharmacological Approach of Pulsatillae Radix on Treating Crohn’s Disease

“…Thus, to explore the beneficial effects of PR on Crohn's disease, it was important to determine the tissue mRNA expression profiles of target proteins at the organ level [34]. The target organ location network was used with the Dataset: GeneAtlas U133A, gcrma (http://biogps.org).…”

Uncovering the action mechanism of polydatinvianetwork pharmacological target prediction

“…15 The average value of DL for Drugbank compounds $0.18 has been reported as a standard for screening bioactive drug compounds in systematic analysis of TCM. 14,16,17 As shown in Table 1, the DL value of PD was calculated to be 0.5 by TCMSP, indicating PD possessed a good drug-likeness.…”

“…Meanwhile, it also provides a systematic evaluation about pharmacokinetic properties for natural compounds, which included drug-likeness (DL), oral bioavailability (OB), Caco-2 permeability (Caco-2), blood-brain barrier permeability (BBB) and Lipinski's rule of ve (MW, Alog P, TPSA, Hdon, Hacc). 14,16,17 DL is a qualitative notion used in drug design, and it also helps to optimize pharmacokinetic and pharmaceutical properties, such as chemical stability and solubility. A databasedependent model is constructed on account of the molecular descriptors and Tanimoto coefficient.…”

“…A databasedependent model is constructed on account of the molecular descriptors and Tanimoto coefficient. 16,17 Oral bioavailability (OB) is also one of the most important pharmacokinetic properties of medicine by orally because it plays an key role for the efficiency of the drug delivery to the systemic circulation in human body. Its value was evaluated by OBioavail 1.1 model in the TCMSP database.…”

Computational methods and applications for quantitative systems pharmacology

“…Systems pharmacology methods are frequently used in exploration of pharmacodynamic material basis and MoA of traditional Chinese medicine (TCM) [130][131][132][133][134][135][136][137][138][139]. The recent applications of these QSP methods in TCM are summarized in Table 2 Erigeron breviscapus ADME pharmacokinetic screening, target fishing, protein-protein interaction network analysis and in vitro experiments verification [141] Eucommia ulmoides Oliv.…”