Systems Pharmacology-based Analysis Of Molecular Mechanism For The Co-treatment Of Cardiovascular And Gastric Disorders

Though cardiovascular diseases(CVDs) and gastrointestinal disorders(GIDs) are different diseases associated with different organs, they are highly correlated clinically. Importantly, CVDs and GIDs have also been found having etiological correlations in modern medicine, yet the biological basis underlying the correlation are still unclear.In traditional C hinese medicine s similar treatment strategies have been applied when dealing with CVDs or GIDs, and some herbs/formula are found to exert good therapeutic effects in both of the diseases. What are the molecular mechanisms that connect the CVDs and GIDs, and why the same herbs/formula can be used to treat the different diseases of different organs? To solve these problems above, the main work was as follows:Firstly, we illustrated the molecular mechanisms of the co-treatment between CVDs(31 types, such as coronary heart disease, heart failure and etc.) and GIDs(13 types, such as chronic gastritis). By the analysis of Protein-Protein Interaction(PPI) network, we found that: 1) 288 and 353 genes associated with CVDs(31 types) and GIDs(13 types) were collected respectively. Therein, 47 shared genes of CVDs and GIDs were identified, such as ACE(angiotensin I converting enzyme) is highly correlated with heart failure and gastric cancer. 2) Furthermore, the functional enrichment analysis indicated that genes associated with CVDs and GIDs were involved in identical biological processes, such as cell proliferation, cell apoptosis, cell necrosis and the response to extracellular stimulus. 3) By the system analysis of microRN A regulation networks of cardiomyopathy and gastritis, we found that micro RNAs of both diseases are focus on the processes of bacterial response, immunology, and TNF-signal transduction. These results above indicated that the high biological correlation of CVDs and GIDs. Secondly, we dissected the mechanisms of action of C hinese medicine for CVDs and GIDs from the therapeutic perspective. 1) Firstly, 115 and 163 herbs associated with CVDs and GIDs were analyzed systematically, the Fisher test indicated that the significant correlation between them. 2) Then, all the Chinese Patent Medicine was analyzed, among them, 68.75% herbs occurred in the formulae for the treatment of CVDs. In addition, the herbs associated with CVDs accounted for about 80.68% in formulae for the treatment of GIDs. The results above il ustrated the high correlation of CVDs and GIDs therapeutically.Thirdly, to further reveal the molecular mechanisms of co-treatment for CVDs and GIDs, Sanhe Decoction(SHD), which was a classical formula in the treatment of chronic gastric was selected for the system pharmacology study. 1) By the ADME(absorption, distribution, metabolism, excretion) screen analysis, 59 potential active compounds were obtained to considered to be effective ingredients, such as M01(Luteolin), M02(Q uercetin), M03(Isorhamnetin), M08(Galangin), M16(Sugeonyl acetate) and M52(Tanshinone IIA) etc.2) By the target fishing of weighted ensemble similarity(WES), 70 protein targets were identified, including 9 targets associated with both CVDs and GIDs: AR(Androgen Receptor), ESR1(Estrogen Receptor), ACHE(Acetylcholinesterase), NR3C1(Glucocorticoid receptor), GLO1(Glyoxalase I), MMP9(Matrix metalloproteinase 9), CYP2A6(C ytochrome P450 2A6), PLA2G2A(Phospholipase A2 group IIA) and PLK2(Polo-Like Kinase 2).3) By the enrichment analysis of target-pathway network, we found that the active compounds of Sanhe Decoction acted on multiple pathways, including calcium signaling pathway, cGMP-PKG signaling pathway and vascular smooth muscle contraction pathway. 4) The tissue specificity attribution analysis showed that the active ingredients can target onto the heart, stomach, thymus and whole blood to treat CVDs and GIDs effectively. 5) Furthermore, network pharmacology analysis indicated the synergistic effect of the multiple targets to treat CVDs and GIDs. 6) Finally, the rat myocardial ischemia model and molecular biology experiment were developed, we found that SHD could significantly attenuate pathological changes of myocardial cells. In addition, SHD significantly increased the activity of antioxidant enzymes superoxide dismutase(SOD) and decreased levels of serum creatine kinase(CK), cyclic adenosine monophosphate(c AMP) and cardiac troponin I(cTnI), highlighting the potential biological mechanisms of SHD.In conclusion, in this work, we dissected the potential molecular biological mechanisms between CVDs and GIDs by the systems pharmacology approach. More importantly, the analysis of Chinese medicine formulae revealed that the potential scientific connotation that the same herbs can treat different diseases simultaneously, which suggests a novel integrated strategy for rational drug development for complex associated diseases, prompting the novel drug development.