The Study On Inhibitory Effects And Mechanism Of Scutellaria Baicalensis Georgi On Liver And Pulmonary Fibrosis With Guidance Of "Homotherapy For Heteropathy" Based On Metabonomics

Objective:Under the guidance of the traditional chinese medicine(TCM)theory of homotherapy for heteropathy,urinary and serum metabolomics associated with histological progression were utilized to explore the pathogenesis of liver fibrosis(LF)and pulmonary fibrosis(PF),and to reveal the material basis for the "different disease with same syndrome" by identifying and selecting the common differential metabolites and signal transduction network between LF and PF;based on the above research,the therapeutic effect and mechanism of Raix Scutellariae decoction and Baicalin on LF and PF were clarified from three aspects about serum biochemistry,pathology and metabolomics.Methods:Liver fibrosis rat model was established by subcutaneous injection of CCL4 and pulmonary fibrosis rat model was established bytracheal cartilage ring clearance injection of bleomycin.Liver tissue of LF model group and lung tissue of PF model group were collected for histopathological examination at weeks 2,4,6,8 and weeks 1,3,5 respectively.Urine of LF and PF model group collected in every week;serum of LF model group collected at weeks 2,4,6,8;serum of PF model group collected at week 5 were used for metabonomic analysis by LC-Q-TOF-MS.Differential metabolites of LF and PF were identified by date acquired from metabolomics combined with related information of HMDB,MassBank and PUBMED.Then,the key biomarkers were selected by hierarchical clustering analysis,MetPA(Metabolomics Pathway Analysis)and the receiver-operating characteristic(ROC)analysis.Finally,analysising the changes of key biomarkers in progressive LF and PF were analysised and their biological significances were clarified.Comprehensive analysis these results,to selecte the common differential metabolites and pathways between LF and PF which were regarded as material basis of the“different disease with same syndrome”.Based on LF and PF rat model,different doses of Raix Scutellariae decoction and Baicalin were administered.Their anti-fibrosis effects were observed by detecting tissue HYP,blood biochemical indices,anti-oxidation ability combined with the histopathological changes.Then,urinary and serum Metabolic profiling was performed to clarify their mechanisms of anti-fibrosis by analyzing impact of the drug on content of potential biomarkers.Results:1.41 differential metabolites in urine of LF rat and 46 in serum were identified.From these,we selected 19 metabolites as the key potential biomarker,which involving Perturbations of tryptophan,valine,leucine and isoleucine,TCA cycle,sphingolipid,bie acid biosynthesis and glycerophospholipid metabolisms.These may be the most relevant metabolic pathways about LF.56 differential metabolites in urine of PF rat and 48 in serum were identified.From these,we selected 14 metabolites as the key potential biomarker,which involving taurine and hypotaurine metabolism,glutathione metabolism,valine,leucine and isoleucine biosynthesis,nicotinate and nicotinamide metabolism,pentose and glucuronate interconversions,primary bile acid biosynthesis.These may be the most relevant metabolic pathways about PF.2.16 differential metabolites in urine and 14 in serum,9 metabolic pathways in urine and 12 in serum were found both in LF and PF.Glyoxylate and dicarboxylate metabolism,tryptophan,valine,leucine and isoleucine biosynthesis,TCA cycle,sphingolipid,bie acid biosynthesis and glycerophospholipid metabolisms were the main metabolic pathways.3.Middle or low dose of Raix Scutellariae decoction and Baicalin can improve LF by regulating 9 key potential biomarkers which involving tryptophan metabolism,valine,leucine and isoleucine metabolism,sphingolipid metabolism,glyoxylate and dicarboxylate metabolism;they also can improve PF by regulation 4 key potential biomarkers which involving taurine and hypotaurine metabolism,glutathione metabolism,glycometabolism and glycerophospholipid metabolisms.In addition,their anti-fibrosis effect has the same therapeutic targets including prolyl-Threonine,adrenochrome,3-Indole carboxylic acid glucuronide,3-Methyldioxyindole,13E-Tetranor-16-carboxy-LTE4 in urine,and lysoPC(17:0),lysoPC(18:0),stearoylcarnitine,leukotriene C5,D-Urobilinogen,S-(PGA2)-glutathione in serum.Conclusions:Metabonomics technology provide scientific foundation for TCM theory of homotherapy for heteropathy in treatment of LF and PF.Radix scutellariae decoction and baicalin can effectively improve liver and pulmonary fibrosis with many channels.Their anti-fibrosis effect has the same therapeutic targets(including Adrenochrome et al)and the middle and low dosages are beneficial.