Pharmacological Effects Of Panax Notoginseng Saponins R1 On Acute Lung Injury In Rats With Sepsis

Objective: Panax notoginseng saponin R1 is the main effective component of the Chinese medicine Panax notoginseng.A large number of studies have shown that it can be used against many symptoms,including inhibiting lung injury by regulating oxidative stress,inflammation and apoptosis.However,its targets and mechanisms are complicated.Exploring its possible targets will help the development of anti-lung injury drugs based on the structure of notoginsenoside R1.In this study,based on network pharmacology,we preliminarily investigated the possible effects of notoginsenoside R1 on LPS-induced acute lung injury,and verified the protective effect of notoginsenoside R1 in LPS-induced sepsis rat acute lung injury model.Methods: The potential targets of notoginsenoside R1 were screen with Swiss Target Prediction,Pharmapper,Binding DB and CTD.Using CTD,Gene Cards,and Dis Ge Net databases to screen the molecular targets involved in the pathological progression of lung injury with the keywords of "Lung Injury" and "Acut Lung Injury",combined with literature reports,duplicate genes and false positive genes were removed,and further a Venn diagram is used to confirm the co-targets of component and diseases,and the obtained data was imported into Cytoscape 3.7.2 software to construct a prediction network of "component-disease-target".And predict the target of notoginsenoside R1 in acute lung injury,and then perform the gene ontology(GO)function enrichment analysis of the core target and the Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis.Wistar rats were given intraperitoneal injection of normal saline and 5 mg/kg/d,10 mg/kg/d,20mg/kg/d(low,medium and high)doses of notoginsenoside R1 and dexamethasone 2 mg/kg/d It is the positive control group.After one week,a sepsis rat model was established,and the wet-to-dry ratio,histology.Inflammatory factors IL-1β and IL-6 and TNF-α in serum and alveolar lavage fluid of rats with toxic acute lung injury after administration of notoginsenoside R1 were detected.Results: The database screened a total of 2595 core disease targets and285 drug targets,of which 150 were component and diseases shared targets,of which 36 were core targets.The core target proteins are mainly distributed in lipid rafts,membrane microdomains,platelet granules and other regions;functionally are mainly related to cytokine binding,cytokine activity,growth factor binding,integrin binding,etc.;mainly involves biological processes including lipopolysaccharide response,bacterial molecular response,establishment of positive regulatory protein localization,regulation of reactive oxygen metabolism process and leukocyte migration.The analysis of GO semantic similarity indicates that notoginsenoside R1 may regulate key links such as IL-17 signaling pathway and TNF signaling pathway by regulating targets such as MAPK1,MAPK3,IL-1β and so on.The results of pharmacological experiments show that,similar to dexamethasone,medium and high doses of notoginsenoside R1 can significantly reduce the wet-to-dry ratio and lung pathological damage of the lungs,and improve the pathological injury of the lung.Notoginsenoside R1 decreased the inflammatory cytokines TNF-α and IL-1β in serum and alveolar lavage fluid,while the expression of IL-6 showed no difference among all groups.Conclusions: There are a total of 285 predicted targets related to the pharmacological effects of notoginsenoside R1,and a total of 2595 targets related to acute lung injury.Disease and component shared 150 targets.Among them,36 core targets with confidence levels greater than 0.9 were verified,including STAT3 and TNF,IL6,MAPK1,MAPK3,RELA,MAPK8,IL1 B,IL10,IL2,etc.Bioinformatics analysis showed that the anti-ALI targets of notoginsenoside R1 is mainly concentrated in the lipid and micromembrane structure regions,which is related to the signals of cytokines,growth factors and integrins,and involves lipopolysaccharide response,ROS response and leukocyte migration.The treatment of sepsis with notoginsenoside R1 was possible achieved by regulating targets such as MAPK1,MAPK3,IL-1β,IL-6and TNF-α and multiple pathways to achieve the effects of inhibiting pulmonary edema,anti-inflammatory and improving lung disease.Animal experiments further confirmed the effect of notoginsenoside R1 on sepsis induced ALI.Notoginsenoside R1 decreased the levels of TNF-α and IL-1β in serum and alveolar lavage fluid.However,the contribution of inflammatory factors including IL-6 to the pharmacological mechanism of Panax notoginsenoside R1 in sepsis induced ALI remains to be further explored.