A systems-based analysis to explore the multiple mechanisms of Shan Zha for treating human diseases.

Shan Zha has garnered increasing attention in the field of functional foods and medicines due to its widely reported healing effects. However, the potential mechanisms of Shan Zha for human health benefits have not been fully interpreted. Therefore, in the current study, a systems-based method that integrates ADME evaluation, target fishing, gene ontology enrichment analysis, network pharmacology, and pathway analysis is proposed to clarify the underlying pharmacological mechanisms of Shan Zha. As a result, 45 active components of Shan Zha that interacted with 161 protein targets were screened and identified. Moreover, gene ontology enrichment, network and pathway analysis indicated that Shan Zha is beneficial for the treatment of cardiovascular system diseases, digestive system diseases, immune system diseases, inflammatory diseases, cancer, and other diseases through multiple mechanisms. Our study not only proposed an integrated method to comprehensively elucidate the complicated mechanisms of Shan Zha for the treatment of various disorders at the system level, but also provided a reference approach for the mechanistic research of other functional foods.

[1]  M. Motilva,et al.  Recent Advances in Biologically Active Compounds in Herbs and Spices: A Review of the Most Effective Antioxidant and Anti-Inflammatory Active Principles , 2013, Critical reviews in food science and nutrition.

[2]  Tingting Fu,et al.  Therapeutic target database update 2018: enriched resource for facilitating bench-to-clinic research of targeted therapeutics , 2017, Nucleic Acids Res..

[3]  K. Kim,et al.  Amygdalin induces apoptosis through regulation of Bax and Bcl-2 expressions in human DU145 and LNCaP prostate cancer cells. , 2006, Biological & pharmaceutical bulletin.

[4]  B. Relja,et al.  Cytokines in Inflammatory Disease , 2019, International journal of molecular sciences.

[5]  Xizhuo Sun,et al.  Systems Pharmacology-Based Method to Assess the Mechanism of Action of Weight-Loss Herbal Intervention Therapy for Obesity , 2019, Front. Pharmacol..

[6]  Jean-Guy Berrin,et al.  Deglycosylation by small intestinal epithelial cell β-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans , 2003, European journal of nutrition.

[7]  J. Um,et al.  Anti-inflammatory activity of hyperoside through the suppression of nuclear factor-κB activation in mouse peritoneal macrophages. , 2011, The American journal of Chinese medicine.

[8]  Ren-yi Yan,et al.  Effects of an aqueous extract of Crataegus pinnatifida Bge. var. major N.E.Br. fruit on experimental atherosclerosis in rats. , 2013, Journal of ethnopharmacology.

[9]  S. N. Devaraj,et al.  Immunomodulatory effect of Hawthorn extract in an experimental stroke model , 2010, Journal of Neuroinflammation.

[10]  F. Dajas.  Life or death: neuroprotective and anticancer effects of quercetin. , 2012, Journal of ethnopharmacology.

[11]  G. Feng,et al.  C33(S), a novel PDE9A inhibitor, protects against rat cardiac hypertrophy through upregulating cGMP signaling , 2017, Acta Pharmacologica Sinica.

[12]  T. Tseng,et al.  Anti-inflammatory potential of flavonoid contents from dried fruit of Crataegus pinnatifida in vitro and in vivo. , 2005, Journal of agricultural and food chemistry.

[13]  Jian-guo Xu,et al.  Antioxidant and DNA-protective activities of chlorogenic acid isomers. , 2012, Journal of agricultural and food chemistry.

[14]  Tianwen Li,et al.  Beta-sitosterol inhibits cell growth and induces apoptosis in SGC-7901 human stomach cancer cells. , 2009, Journal of agricultural and food chemistry.

[15]  H. Korashy,et al.  The Role of Protein Tyrosine Phosphatase (PTP)-1B in Cardiovascular Disease and Its Interplay with Insulin Resistance , 2019, Biomolecules.

[16]  D. Kass,et al.  Expression, activity, and pro-hypertrophic effects of PDE5A in cardiac myocytes. , 2008, Cellular signalling.

[17]  Eric P. Skaar,et al.  The Impact of Dietary Transition Metals on Host-Bacterial Interactions. , 2018, Cell host & microbe.

[18]  Joseph Loscalzo,et al.  Cyclooxygenase inhibition and cardiovascular risk. , 2005, Circulation.

[19]  Lilei Zhang,et al.  Deciphering the binding behavior of flavonoids to the cyclin dependent kinase 6/cyclin D complex , 2018, PloS one.

[20]  Shihai Yang,et al.  Vanillic Acid Suppresses HIF-1α Expression via Inhibition of mTOR/p70S6K/4E-BP1 and Raf/MEK/ERK Pathways in Human Colon Cancer HCT116 Cells , 2019, International journal of molecular sciences.

[21]  A. Bode,et al.  Kaempferol inhibits UVB-induced COX-2 expression by suppressing Src kinase activity. , 2010, Biochemical pharmacology.

[22]  Chang-Ju Kim,et al.  Inhibition of cytochrome P450 activities by oleanolic acid and ursolic acid in human liver microsomes. , 2004, Life sciences.

[23]  A. Furey,et al.  Hawthorn (Crataegus spp.) in the treatment of cardiovascular disease , 2010, Pharmacognosy reviews.

[24]  Mengjun Dai,et al.  Hyperoside Attenuates Hepatic Ischemia-Reperfusion Injury by Suppressing Oxidative Stress and Inhibiting Apoptosis in Rats. , 2019, Transplantation proceedings.

[25]  Ling Zhao,et al.  Inflammatory responses and inflammation-associated diseases in organs , 2015, Oncotarget.

[26]  T. Miyazaki,et al.  Stigmasterol reduces plasma cholesterol levels and inhibits hepatic synthesis and intestinal absorption in the rat. , 2006, Metabolism: clinical and experimental.

[27]  Ariel D. Quiroga,et al.  Quercetin prevents liver carcinogenesis by inducing cell cycle arrest, decreasing cell proliferation and enhancing apoptosis. , 2014, Molecular nutrition & food research.

[28]  Yu Huang,et al.  Hypocholesterolemic activity of hawthorn fruit is mediated by regulation of cholesterol-7α-hydroxylase and acyl CoA: cholesterol acyltransferase , 2002 .

[29]  Yanwei Xing,et al.  Roles and Mechanisms of Hawthorn and Its Extracts on Atherosclerosis: A Review , 2020, Frontiers in Pharmacology.

[30]  Y. Yamori,et al.  Dietary polyphenols regulate endothelial function and prevent cardiovascular disease. , 2015, Nutrition.

[31]  Baoru Yang,et al.  Characterization of phenolic compounds in Chinese hawthorn (Crataegus pinnatifida Bge. var. major) fruit by high performance liquid chromatography–electrospray ionization mass spectrometry , 2010 .

[32]  Yun Jiang,et al.  Research on mechanism of charred hawthorn on digestive through modulating "brain-gut" axis and gut flora. , 2019, Journal of ethnopharmacology.

[33]  T. Shibamoto,et al.  Role of transition metals, Fe(II), Cr(II), Pb(II), and Cd(II) in lipid peroxidation , 2008 .

[34]  Hun-Kuk Park,et al.  Amygdalin suppresses lipopolysaccharide-induced expressions of cyclooxygenase-2 and inducible nitric oxide synthase in mouse BV2 microglial cells , 2007, Neurological research.

[35]  Q. Qi,et al.  Rebalancing of the gut flora and microbial metabolism is responsible for the anti-arthritis effect of kaempferol , 2019, Acta Pharmacologica Sinica.

[36]  D. Couper,et al.  Cyclooxygenase Polymorphisms and Risk of Cardiovascular Events: The Atherosclerosis Risk in Communities (ARIC) Study , 2008, Clinical pharmacology and therapeutics.

[37]  Myeon-Hyeon Wang,et al.  Anti-inflammatory effect of the water fraction from hawthorn fruit on LPS-stimulated RAW 264.7 cells , 2011, Nutrition research and practice.

[38]  M. Takei,et al.  Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs , 2012, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[39]  Minoru Kanehisa,et al.  Molecular network analysis of diseases and drugs in KEGG. , 2013, Methods in molecular biology.

[40]  Zhenzhong Wang,et al.  Systems pharmacology to decipher the combinational anti-migraine effects of Tianshu formula. , 2015, Journal of ethnopharmacology.

[41]  J. Inoue,et al.  Kaempferol stimulates gene expression of low-density lipoprotein receptor through activation of Sp1 in cultured hepatocytes , 2016, Scientific Reports.

[42]  J. Um,et al.  The Beneficial Effect of Vanillic Acid on Ulcerative Colitis , 2010, Molecules.

[43]  H. Kovacic,et al.  Rutin inhibits proliferation, attenuates superoxide production and decreases adhesion and migration of human cancerous cells. , 2016, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[44]  Philip R. Cohen,et al.  The development and therapeutic potential of protein kinase inhibitors. , 1999, Current opinion in chemical biology.

[45]  Hua Yu,et al.  A Novel Chemometric Method for the Prediction of Human Oral Bioavailability , 2012, International journal of molecular sciences.

[46]  R. Liu,et al.  Phenolic contents and cellular antioxidant activity of Chinese hawthorn "Crataegus pinnatifida". , 2015, Food chemistry.

[47]  Xue Xu,et al.  Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease. , 2013, Journal of ethnopharmacology.

[48]  M. Wan,et al.  Anti-HIV triterpene acids from Geum japonicum. , 1996, Journal of natural products.

[49]  L. Ye,et al.  Ionic liquid-based one-step micellar extraction of multiclass polar compounds from hawthorn fruits by ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. , 2014, Journal of agricultural and food chemistry.

[50]  R. Jiao,et al.  Protective effects of kaempferol against reactive oxygen species-induced hemolysis and its antiproliferative activity on human cancer cells. , 2016, European journal of medicinal chemistry.

[51]  Qipeng Yuan,et al.  Isolation, purification and immunobiological activity of a new water-soluble bee pollen polysaccharide from Crataegus pinnatifida Bge. , 2009, Carbohydrate Polymers.

[52]  T. Tseng,et al.  Inhibitory effect of hot-water extract from dried fruit of Crataegus pinnatifida on low-density lipoprotein (LDL) oxidation in cell and cell-free systems. , 2003, Journal of agricultural and food chemistry.

[53]  Xuetong Chen,et al.  Systems Pharmacology Dissection of Multi-Scale Mechanisms of Action for Herbal Medicines in Stroke Treatment and Prevention , 2014, PloS one.

[54]  H. Wagner,et al.  Search for potential angiotensin converting enzyme (ACE)-inhibitors from plants. , 2001, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[55]  Thaned Kangsamaksin,et al.  Lupeol and stigmasterol suppress tumor angiogenesis and inhibit cholangiocarcinoma growth in mice via downregulation of tumor necrosis factor-α , 2017, PloS one.

[56]  H. Babich,et al.  Differential in vitro cytotoxicity of (-)-epicatechin gallate (ECG) to cancer and normal cells from the human oral cavity. , 2005, Toxicology in vitro : an international journal published in association with BIBRA.

[57]  A. C. Ogbonna,et al.  Functional components and medicinal properties of food: a review , 2015, Journal of Food Science and Technology.

[58]  Haixia Yang,et al.  Procyanidin B2 inhibits NLRP3 inflammasome activation in human vascular endothelial cells. , 2014, Biochemical pharmacology.

[59]  L Bohlin,et al.  Cox-2 inhibitory effects of naturally occurring and modified fatty acids. , 2001, Journal of natural products.

[60]  Grace Guo,et al.  Intake of stigmasterol and β-sitosterol alters lipid metabolism and alleviates NAFLD in mice fed a high-fat western-style diet. , 2018, Biochimica et biophysica acta. Molecular and cell biology of lipids.

[61]  Y. Taufiq-Yap,et al.  The crucial roles of inflammatory mediators in inflammation: A review , 2018, Veterinary world.

[62]  A. Y. Chen,et al.  A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. , 2013, Food chemistry.

[63]  Shanshan Wang,et al.  Hyperoside attenuates dextran sulfate sodium-induced colitis in mice possibly via activation of the Nrf2 signalling pathway , 2017, Journal of Inflammation.

[64]  S. Ye,et al.  Relative Antioxidant Activities of Quercetin and Its Structurally Related Substances and Their Effects on NF-κB/CRE/AP-1 Signaling in Murine Macrophages , 2013, Molecules and cells.

[65]  Yonghua Wang,et al.  Systems Pharmacology Dissection of the Anti-Inflammatory Mechanism for the Medicinal Herb Folium Eriobotryae , 2015, International journal of molecular sciences.

[66]  Jinan Wang,et al.  Systems approaches and polypharmacology for drug discovery from herbal medicines: an example using licorice. , 2013, Journal of ethnopharmacology.

[67]  F. Hofmann,et al.  Function of cGMP-dependent protein kinases as revealed by gene deletion. , 2006, Physiological reviews.

[68]  W Patrick Walters,et al.  Prediction of 'drug-likeness'. , 2002, Advanced drug delivery reviews.

[69]  S. Ghosh,et al.  Intestinal Barrier Dysfunction, LPS Translocation, and Disease Development , 2020, Journal of the Endocrine Society.

[70]  Trey Ideker,et al.  Cytoscape 2.8: new features for data integration and network visualization , 2010, Bioinform..

[71]  P. He,et al.  Determination of Active Ingredients of Hawthorn by Capillary Electrophoresis with Electrochemical Detection , 2006 .

[72]  Liang Wenhua,et al.  Chlorogenic acid (CGA): A pharmacological review and call for further research. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[73]  Hong Zhou,et al.  Crataegus pinnatifida: Chemical Constituents, Pharmacology, and Potential Applications , 2014, Molecules.

[74]  H. Kayahara,et al.  Quantification of the polyphenols and triterpene acids in chinese hawthorn fruit by high-performance liquid chromatography. , 2006, Journal of agricultural and food chemistry.

[75]  Rajarshi Dey.  Hypothesis tests with precedence probabilities and precedence‐type tests , 2018 .

[76]  J. Sprent,et al.  The role of interleukin-2 during homeostasis and activation of the immune system , 2012, Nature Reviews Immunology.

[77]  S. Bonovas,et al.  Intravenous Versus Oral Iron for the Treatment of Anemia in Inflammatory Bowel Disease , 2016, Medicine.

[78]  Y. Kwan,et al.  Cholesterol lowering and vascular protective effects of ethanolic extract of dried fruit of Crataegus pinnatifida, hawthorn (Shan Zha), in diet-induced hypercholesterolaemic rat model , 2013 .

[79]  Xiaohong Tan,et al.  Effects of dietary hawthorn extract on growth performance, immune responses, growth‐ and immune‐related genes expression of juvenile golden pompano (Trachinotus ovatus) and its susceptibility to Vibrio harveyi infection , 2017, Fish & shellfish immunology.

[80]  M. Yin,et al.  Antioxidative and anti-inflammatory protection of oleanolic acid and ursolic acid in PC12 cells. , 2008, Journal of food science.

[81]  Yanmin Zhang,et al.  Chlorogenic acid prevents inflammatory responses in IL‑1β‑stimulated human SW‑1353 chondrocytes, a model for osteoarthritis. , 2017, Molecular medicine reports.

[82]  A. Scalbert,et al.  Chlorogenic acid is absorbed in its intact form in the stomach of rats. , 2006, The Journal of nutrition.

[83]  V. Adam,et al.  Polyphenolic Profile and Biological Activity of Chinese Hawthorn (Crataegus pinnatifida BUNGE) Fruits , 2012, Molecules.

[84]  B. Neel,et al.  TNF-stimulated MAP kinase activation mediated by a Rho family GTPase signaling pathway. , 2011, Genes & development.

[85]  N. Menković,et al.  Anti-inflammatory, gastroprotective, free-radical-scavenging, and antimicrobial activities of hawthorn berries ethanol extract. , 2008, Journal of agricultural and food chemistry.

[86]  Hong Wang,et al.  β-Sitosterol and stigmasterol ameliorate dextran sulfate sodium-induced colitis in mice fed a high fat Western-style diet. , 2017, Food & function.

[87]  Xiu-Mei Li,et al.  Quercetin Inhibits the Proliferation and Aflatoxins Biosynthesis of Aspergillus flavus , 2019, Toxins.

[88]  A. Kucharska,et al.  Antioxidant activity and anti‐inflammatory effect of fruit extracts from blackcurrant, chokeberry, hawthorn, and rosehip, and their mixture with linseed oil on a model lipid membrane , 2016 .

[89]  Baoru Yang,et al.  Quantitative analysis of phenolic compounds in Chinese hawthorn (Crataegus spp.) fruits by high performance liquid chromatography-electrospray ionisation mass spectrometry. , 2011, Food chemistry.

[90]  B. Kennedy,et al.  Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. , 1999, Science.

[91]  Hsi-Chin Wu,et al.  Apoptotic effects of protocatechuic acid in human breast, lung, liver, cervix, and prostate cancer cells: potential mechanisms of action. , 2009, Journal of agricultural and food chemistry.

[92]  T. Tseng,et al.  Effects of polyphenols derived from fruit of Crataegus pinnatifida on cell transformation, dermal edema and skin tumor formation by phorbol ester application. , 2007, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.