Discovery Of The Thirst Attractor And Its Application In The Intervention Of Type 2 Diabete

Background:Diabetes is a chronic,complex and multifactorial disease caused by persistent hyperglycemia.Its pathogenesis has not been fully explained.However,it is reported that insufficient insulin secretion or insulin resistance is the main cause of disease.Among,type 2 diabetes(T2DM)is the highest incidence of all diabetes cases,accounting for more than 90%.Long-term hyperglycemia may lead to a series of complications,including retinopathy,kidney disease,and peripheral neuropathy,which seriously endangering the the patient’s life.Today,the clinical treatment of diabetes is mainly oral administration of Western medicine,such as metformin,two dipeptidyl peptidase inhibitor 4,glucagon like peptide-1,thiazolidinediones,sulfonylurea.Unpleasantly,these drugs have side effects,longterm use of drug efficacy reduction and drug resistance,and can not prevent the development of complications.So,it can not be used for long-term treatment of diabetes.Compared with western medicine,traditional Chinese medicine(TCM)has high safety and less adverse effects in the treatment diabetes,and has a good effect on reducing sugar.However,the mechanism of most traditional Chinese medicine prescriptions is not clear.In addition,The current research on the network model of diabetes is focused on specific targets and signaling pathways,and the mathematical model established mainly presents a constant state of the disease at a certain stage,which is unrealistic for the chronic progressive disease of diabetes.Therefore,it is difficult to explain the origin of dynamic and network specific variation from the system level,and it is difficult to clarify the pathogenesis of the disease,which may be the reason that diabetes can not be cured at present.Objective:On the one hand,To find new therapeutic strategies for diabetes by analyzing the mechanisms of TCM "xiaoke" formulas.On the other hand,Study of diabetes at the system level,find "xiaoke"attractors,which provide insight into the pathogenesis and the potential therapeutic targets of diabetes.Methods:Frist,construct the biological action network of xiaoke formula-chemical constituent-constituent targets-special "xiaoke" related genes-PPI(Protein-protein interaction)and xiaoke related genes-diabetes related genes interaction pathway network by TCM grammer system.Analysis of the action mechanism of Xiaoke formula and the relationship between xiaoke-related genes and diabetes-related genes respectively.Among,xiaoke-related genes are got by frequency statistics(the over 95.88%frequency of occurences of each constituent targets in the 291 TCM formulas is served as "xiaoke"-related genes).Then,based on the multi-organ or multi-tissue T2DM comprehensive pathway network that have been built,we add activation or inhibition relationship among nodes by literature and database(KEGG,Genecards)search.Besides,we also delete or add some nodes,which will form a new comprehensive T2DM biomolecular network.Further,analysis of the action mechanism of metformin to verify the reliability of network construction.Then,the xiaoke-related genes were introduced into the T2DM biological network.Cytoscape is used to calculate the topological parameters of the whole biological network,including degree,clustering coefficient,topological coefficient,betweenness,closeness and eccentricity,and we find the key nodes of the network based on cluster analysis.Finally,we found "xiaoke" attractors based on the Boolean network model from the dynamic point of view,analyzing the pathogenesis and discoverying the potential therapeutic target of the disease.Here,the 291 TCM Xiaoke formulas were derived from the dictionary of TCM prescription,chemical composition mainly comes from the mechanism auxiliary analysis system of TCM,The target of chemical composition were obtained from the chEMBL database and diabetes-related genes are got from the DisGeNET database.Results:The results show that "xiaoke" formulas and 14 special "xiaoke"-related genes were significantly associated with the multi-biological processes,which are closely related to diabetes and diabetic complications.Besides,interrupting these "xiaoke"-related genes will affect diabetes-related genes directly or indirectly.By clustering analysis,all nodes in T2DM bio-molecular network are divided into two categories.Among,some of the nodes in the red category have been proven to the target of the treatment of T2DM,the other part is also closely linked to diabetes,which can be used as a potential therapeutic target for diabetes.From the view of dynamics,we have found six attractors in the systerm,including point attractors and Attractor ring.In the main attractor state,the gene NF-KB and IL1B t are in the active state,which contribute to the development of T2DM,and belond to "xiaoke"attractors.Through the analysis of the disease attractor,the pathogenesis of T2DM is related to the occurrence of inflammation,B cell imbalance,DNA damage induced by oxidative stress and mitochondrial dysfunction.The intervention of NF-κB,ILIB,NF-κB and IL1B were performed by structural intervention.It was found that the main "xiaoke"attractors disappeared,and the stability of the normal attractors increased.Which is the expected transformation state.In addition,gene CYP2D6,NFKB1,CYP3A4,JUN,AR,PIN1,NR3C1 and TSHR inhibit or activate the expression of IL1B and NF-κB,and affect the state of disease attractors,which may be potential therapeutic targets of T2DM.Conclusion:The 14 "xiaoke"-related genes of APEX1,EHMT2,TSHR,CBX1,FEN1,GMNN,JUN,KMT2A,MAPT,POLI,USP1,PIN1,POLB and POLK can be served as the candidate genes for anti-diabetic drug design.Compared with diabetes-related genes in DisGeNET,the intervention of 14 "xiaoke"-related genes by TCM formulas have the potential to not only lower blood glucose,but also reduce some side effects occurrence and inhibits diabetic complications development.These discoveries would contribute to new strategies discovery for the therapy of diabetes.Based on topological parameter calculation and cluster analysis,we find that the method of finding key nodes in biological networks has certain reliability,which is beneficial to the research of diabetic drug targets.From the dynamic point of view of the analysis of the steady state of the system,we found that the underlying pathogenesis of T2DM is associated with the production of inflammation,impaired B cell function,and increased oxidative stress.We can considering from these directions to find a way for treating the disease,rather than just lowering blood sugar.The structural intervention analysis of biological networks found that CYP2D6,NFKB1,CYP3A4,JUN,AR,PIN1,NR3C1,TSHR can be used as potential targets for the treatment of T2DM.These findings will provide a reference for the discovery of new diabetes treatment strategies.