Molecular mechanism of Sishen pills in the treatment of diar... : Medicine

Diabetic enteropathy (DE), a chronic nonspecific inflammatory disease, is a common complication of diabetes mellitus. The main clinical manifestations are intractable painless diarrhea, watery loose stools, and alternating diarrhea and constipation, and a few patients present symptoms of anal incontinence.[1] As the disease progresses, severe diarrhea and steatorrhea can occur. DE is more common in diabetic patients who are dependent on insulin, have a long course of diabetes, and have unstable blood sugar levels. Diabetic diarrhea has been experienced by approximately 10% to 20% of patients with diabetes.[2] Despite advances in modern medicine, the pathogenesis of this disease is not fully understood. Many studies have shown that the pathogenesis of DE mainly includes hyperglycemia, gastrointestinal autonomic neuropathy, gastrointestinal microangiopathy, gastrointestinal smooth muscle changes, imbalance of intestinal flora, mental factors, and inflammation.[3,4] Routine stool examination yields mostly normal results. A barium meal examination of the digestive tract may show signs of small intestinal malabsorption, and colonoscopy may identify signs of colonic mucosal congestion and edema. This complication not only affects the quality of life of patients with diabetes but also hinders the effective control of diabetes. Modern medicine is mostly based on control of the primary disease, the use of nutrient vessels, improvements in the microcirculation, adjustment of the microecology, and other drug therapies. At present, no specific Western medicine drugs are available to treat this condition; however, the long-term use of medications can produce drug resistance and results in repeated effects, and thus, the disease easily relapses. The occurrence of long-term severe diarrheal diabetic enteropathy (DDE) may cause ion disorders, acid-base imbalance, dehydration, and even death, which seriously affects the quality of life of the patients and can be life threatening. Traditional Chinese medicine (TCM) has a clear clinical effect on the treatment of DDE and few side effects. Therefore, there is an urgent need to develop effective TCM for the treatment of DDE and to meet the actual clinical needs.

DDE belongs to the categmedicineory of “diarrhea” in Chinese medicine. TCM principles suggest that the onset of this disease is closely related to the spleen and kidney, and Sishen pills are a classic prescription for the treatment of diarrhea. This treatment is a combination of Ershen pills and Wu Wei Zi powder known as Puji’s Prescriptions. Later generations supplemented and improved these prescriptions with reference to “Zhengsheng” to obtain the current Sishen pills, which can relieve diarrhea while affecting astringent intestines. Warming the kidney and the spleen simultaneously yields a remarkable effect. Modern medicine uses Sishen pills for the treatment of intestinal diseases such as ulcerative colitis (UC),[5] allergic colitis,[6] diarrheal irritable bowel syndrome,[7] and postoperative diarrhea after colorectal cancer.[8] Modern pharmacology shows that Sishen pills can inhibit excessive activation of inflammatory pathways,[9–11] prevent cancer to a certain extent, regulate the body’s immune balance, repair the intestinal mucosal barrier, inhibit intestinal propulsion, improve gastrointestinal function, and effectively treat intestinal inflammatory diseases. Among the components, single herbs exhibit different degrees of antidiarrheal, anti-inflammatory, immune regulation, and other effects.

Compared with the single-target therapeutic effect of chemical drugs, TCM compound prescriptions are generally composed of several TCMs and include more components, complex structures, and different properties. Compound treatments exert multicomponent, multitarget, and multichannel overall therapeutic effects in the treatment of complex chronic diseases with multiple causes. This study aimed to use a combination of network pharmacology and molecular docking methods to gain an in-depth understanding of the mechanism of action of Sishen pills in the treatment of DDE and to provide a reliable basis for further clinical research.

The TCM system pharmacology database platform (TCMSP, http://tcmspw.com/tcmsp.php) and TCM molecular mechanism biological information analysis tool (BATMAN-TCM, http://bionet.ncpsb.org/batman-tcm/) were used to search for the chemical components and protein targets of each Chinese medicinal component of Sishen pills (composed of psoralen, Evodia, nutmeg, schisandra, ginger, and jujube). By analyzing the results from previous studies on the pharmacokinetics (absorption, distribution, metabolism and excretion; ADME) of the active ingredients of TCMs,[12] the TCMSP database sets the oral bioavailability (OB) of drugs to ≥30% and the drug-likeness (DL) of biologically active molecules to ≥0.18. The TCMSP database was used to screen the active ingredients of TCMs and obtain the corresponding protein target information. Additionally, the BATMAN database uses a score cutoff ≥20 and a P value cutoff