| BackgroundPsoriasis is a common,chronic inflammatory skin disease,with characteristic rash of erythematous scaly-like lesions as its main clinical manifestation,or associated with joint invasion,which can cause serious disability.About 2%to 3%of the world's population is affected and the incidence is gradually increased.Psoriasis is hard to cure because of relapse or serious adverse impact to the patient' s physical and mental health.Studies show that psoriasis is an inflammatory autoimmune disease with genetic background,but the etiology and pathogenesis are still unclear.T cells and keratinocytes are regards as the key elements of the pathology.Modern theraputic drugs usually target at proliferation of keratinocytes and abnormal regulation of T cells,such as retinoids,immunosuppressors,cytotoxic medicine,etc.Because of side effects or poor efficacy,current methods still have limitations.Doctors usually prescribe according to patient's symptoms.Western medicine cannot fully meet the needs of patients because the treatment often needs a long time.With thousands of years of clinical application and validation,Traditional Chinese Medicine(TCM)for psoriasis shows its unique effect,but the pharmacodynamic mechanism is unknown,which greatly limits the development of TCM.Traditional pharmacological research for TCM is hard to reflect its regulation of "multi-drug,multi-component,multi-organ",corresponding to TCM basic theory "holism concept".With the development of systems biology,systems pharmacology and network biology,the British scholar Hopkins first proposed the concept of network pharmacology in 2007.We cannot only assess the active effect,the targets and pharmacodynamic mechanism of action with the data collections of molecules,drug targets and disease pathway,operating on software of computational chemistry through the network association established between the drug-target-disease.But also can be used in reverse screening for effective drugs.The research method of network pharmacology is popular in drug action and targets prediction,new drug development and TCM modernization.Therefore,it is a new means with more systematic and advancement in the study of TCM beyond traditional methods.Objective1.Establish the pharmacological network system of TCM in the relations of formula-drug-target-disease.Use the methods of pharmacological calculation to predict the role of TCM in disease pathways,the mechanism of action in the treatment of psoriasis,active ingredients in TCM formula.Besides,it could be used to elucidate functions of formula,develop efficient drugs with multi-target,explore the relationship of Chinese symptom-formula-drug-target-disease on systemic level.On the platform of internet,we can access the relations of classic and efficacy formulas,mechanisms and diseases of proposed prescription by freely operations,which makes happen that it provides us a more quickly transformed platform of innovative basic researches to clinical researches.2.Analyze active molecular components,predict possible mechanisms of action and develop new indications in Siwu decoction for psoriasis,interpretate multi-target,multi-component,multi-pathway of Siwu decoction on role of regulating psoriasis on molecular level.3.Explore potential active molecular group of hospital efficacy formula"YinxieLing" in the treatment of psoriasis and its possible mechanisms of action and new indications,subsequently,it has provide a way on the basis of cell experiments and clinical researches and a means to develop new type drugs of "YinxieLing" with efficacy ingredients on molecular level interpretation.Methods1.It had four steps to accomplish the computer forecast database of effective natural drugs,including data collection and processing,and the molecular docking and networking platform construction.First,select key words in two works of "Chinese Materia Medica " and" Chinese Pharmacopoeia"herbs",such as parts of pharmacological actions,clinical applications,indications that contains the words "skin" "inflammatory"“immune T-cells" "vasculitis" "psoriasis".Second,retrieve and download molecules informations from Beilstein database and "Chinese herbs database "(CHDD).Furthermore,according to the pathogenesis of psoriasis and therapeutic medicine,target proteins associated with psoriasis were searched from TTD(http://bidd.nus.edu.sg/)and DrugBank(http://www.drugbank.ca/)database.Than optimized molecules and target proteins were computerized by molecular docking chemical methods in order to create directly relevance of formular-herbal drugs-molecules-protein-diseases.The results of computer virtual screening would be presented in the form of online platform.2.Retrieve informations of Siwu decoction by the query of psoriasis effective natural medicines computer forecast database:including 295 molecules from Angelica sinensis,Rehmannia glutinosa,Ligusticum chuanxiong,Paeoni lactiflora,the relationships between the molecules and the molecules,the molecules and target proteins,molecules and diseases relationship.Select docking sore ? 5 and inport their mutual interaction into Cytoscape2.8.1 software,construct and analyze the molecule-target network.3.Retrieve informations of YinxinLing decoction by the query of psoriasis effective natural medicines computer forecast database:including 921 molecules from Angelica sinensis,Ligusticum chuanxiong,Paeoni lactiflora,the relationships between the molecules and the molecules,the molecules and target proteins,molecules and diseases relationship.Select docking sore ? 6 and import their mutual interaction into Cytoscape2.8.1 software,construct and analyze the molecule-target network.Results1.Psoriasis natural product network pharmacology database(PsNPD):1)PsNPD contains 38 formulas,1,759 kinds of medicinal herbs,1,749 kinds of animals,plants,minerals,27,287 natural product molecules and their physical information,two-dimensional structure,three-dimensional structure,and relationships between 51 target proteins and 27878 molecules.2)Build an online platform for real-time information retrieval system.3)Molecular structures in PsNPD are diverse and have better drug-like properties.4)The distribution of chemical space in two-dimension shows:wide range overlap between natural medicine and western medicines,that reveals natural medicines contain a large number of potential therapeutic agents for psoriasis.5)5-lipoxygenase in the arachidonic acid pathway is a major target for natural medicine in psoriasis treatment.6)Hypericum perforatum L.,Pseudolarix amailis,Sophora alopecuroides,Smilax china contain high level of active pharmaceutical ingredients,in which several hypericins show the best results.2.Research of Siwu decoction for psoriasis treatment:1)It has good properties for oral absorption.2)Metalloproteinase 2(the Macrophage metalloelastase2 MMP2),MMP9,nitric oxide synthase(Nitric oxide synthase,inducible,iNOS),dihydrofolate reductase(Dihydrofolate reductase,DHFR)are the main targets for the treatment of psoriasis with Siwu decoction.3)Angelica sinensis is the central link in Siwu decoction.Rehmannia glutinosa plays an important role in efficacy for psoriasis which trends to be the monarch in Siwu decoction.4)Analysis of Diseases network:autoimmune diseases is also one of major indications.3.YinxieLing decoction for the treatment of psoriasis:1)Experience formula YinxieLing has good oral absorption.2)MMP-2,mitogen-activated protein kinase(mitogen-activated protein kinase MAPK11),MMP-9 and MAPK-14 are the main targets for the treatment of psoriasis with Siwu decoction.3)YinxieLing may have similar role of cytotoxic drugs for psoriatic therapy.It may also have therapeutic effects against tumors,rheumatoid arthritis,and Crohn's disease.ConclusionThis study has built a natural drugs information database related to psoriasis,with successful application of network pharmacology and multidisciplinary advanced research tools.With the established molecule-target,target-target,molecule-molecule network,we tried to explore the mechanism of clinical effective prescription.The results show that natural drugs are a huge resource of active molecules for drug development because of diverse structures and good drug-like properties.The study finds that a main target of natural medicine for psoriasis.treatment is FLAP in arachidonic acid metabolic pathway.The finds explain the possible action mechanism of clinical effective prescription(Siwu decoction and YinxieLing),in psoriasis treatment from systemic level.Analysis of massive data with.network pharmacology method,breaks the limitation of traditional scientific research "only see the trees,ignore the forest," that attributes to both of active compounds exploration and drug action mechanism.It also provides an scientific theoretical support for TCM about "different diseases with the same prescription". |
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