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 .

An 8-week feeding trial was conducted to evaluate the effects of dietary arginine on growth performance, feed utilization, haematological parameters and non-specific immune responses of juvenile Nile tilapia (6.03 g). Five isonitrogenous and isoenergetic diets were formulated to contain graded levels of L-arginine (8.5 g kg À1 , 11.5 kg À1 , 15.3 kg À1 , 18.8 kg À1 and 22.4 kg À1 dry diet) from dietary ingredients and crystalline arginine. Each diet was randomly assigned to triplicate groups of 25 juvenile fish (6.04 AE 0.02 g) three times daily (8:30, 12:30, and 17:00 hours) to apparent satiation. Results showed that the weight gain (WG) and special growth rate (SGR) increased with increasing dietary arginine levels up to 15.3 kg À1 and remained nearly the same thereafter. Arginine supplementation had no impact on the survival, body composition and haematological parameters of tilapia. However, the immune responses (plasma nitric oxide content, total nitric oxide synthase (T-NOS) and lysozyme activity) significantly (P < 0.05) increased with increasing dietary argentine level after stress. Quadratic regression analysis (y = À0.7147x 2 + 25.986x + 147.53 R² = 0.8736) on weight gain against dietary arginine levels indicated that the optimal dietary arginine requirement was estimated to be 18.2 kg À1 of the diet (corresponding to 6.24% of dietary protein on a dry weight basis). The present study indicates that arginine has an immunostimulatory potential to help juvenile Nile tilapia cope with stress conditions such as Streptococcus iniae infection.

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Traditional Chinese medicine (TCM) follows the principle of formulae, in which the pharmacological activity of a single herb can be enhanced or potentiated by addition of other herbs. Nevertheless, the involved synergy mechanisms in formulae remain unknown. Here, a systems-based method is proposed and applied to three representative Chinese medicines in compound saffron formula (CSF): two animal spices (Moschus, Beaver Castoreum), and one herb Crocus sativus which exert synergistic effects for cardiovascular diseases (CVDs). From the formula, 42 ingredients and 66 corresponding targets are acquired based on the ADME evaluation and target fishing model. The network relationships between the compounds and targets are assembled with CVDs pathways to elucidate the synergistic therapeutic effects between the spices and the herbs. The results show that different compounds of the three medicines show similar curative activity in CVDs. Additionally, the active compounds from them shared CVDs-relevant targets (multiple compounds-one target), or functional diversity targets but with clinical relevance (multiple compounds-multiple targets-one disease). Moreover, the targets of them are largely enriched in the same CVDs pathways (multiple targets-one pathway). These results elucidate why animal spices and herbs can have pharmacologically synergistic effects on CVDs, which provides a new way for drug discovery.