Effects Of Matrine On Cellular Senescence Induced By Oxidative Stress And Its Network Pharmacology

Various injuries could be caused by oxidative stress such as inflammation,organ dysfunction and cellular senescence of animals,and matrine has shown good efficacy in anti-oxidation and inflammation.The present experiments aimed to study the effect on cellular senescence and the target of matrine.This work provided a theoretical basis for its wide application in clinical.The mice were divided into control group,model group,VE positive group(100 mg/kg),matrine low-dose group(3 mg/kg),matrine high-dose group(10 mg/kg).The model of cellular senescence was induced by 150 mg/kg D-galactose(s.c.)for six weeks,After VE or matrine administration,the liver and brain were taken to calculate organ index,paraffin sections were made to observe the changes in cell morphology and quantitative real-time PCR(RT-PCR)was used to detect the level of cellular senescence symbols.After that,we predicted the target of matrine and standardized the treatment,used VINA for molecular docking,selected the possible target of matrine with the threshold of-8.5 kcal/mol.After then we collected the genes that related to cellular senescence,took the intersection with the possible target of matrine to screening the target of matrine may act on cellular senescence and made network pharmacological analysis.Finally,the core targets were found out and the expression of senescence-associated secretory phenotype(SASP)components was measured.Experimental results showed that there was no significant change in organ indexes.Compared with control group,the nuclear size of liver increased significantly(p < 0.001),and the number of surviving cells in hippocampus CA3 area decreased obviously(p < 0.001)in D-galactose treatment group.After treated with VE,low and high doses of matrine,the nuclear size of liver decreased(p < 0.01,p < 0.01,p < 0.05),the number of surviving nerve cells increased significantly(p < 0.001).In cellular senescence model,the gene expression of p16,p21 and p19 increased significantly both in the liver(p < 0.01,p < 0.001,p < 0.01)and hippocampus(p < 0.01,p < 0.05,p < 0.01).However,in the liver,the positive group(p <0.05),low-dose matrine(p < 0.05,p < 0.001,p < 0.01)and high-dose matrine(p < 0.05,p <0.01,p < 0.01)treatment reversed the high expression of p16,p19 and p21 caused by D-galactose.Similarly,in the hippocampus,the positive group(p < 0.01)and the matrine-treated groups at different doses(p < 0.01,p < 0.05,p < 0.01)could also significantly increased the high expression of p16,p19 and p21 caused by D-galactose.After screening,137 matrine high-scoring targets were obtained.Then intersected with high-scoring targets and cellular senescence-related targets,a total of 80 targets that matrine may act on cellular senescence were sought out.These targets were enriched in the energy metabolism related signal pathways and cell metabolism such as cellular positive regulation processes.The key targets such as SRC and NOS2,CHRM1,PARP1 were screened by PPI.By researching some references and molecular docking,we found that matrine has a similar binding position to PARP1 with its inhibitor.SASP secretion measurement results showed that compared with the control group,D-galactose significantly increased the gene expression of IL-1β and IL-6 in the hippocampus(p < 0.001,p < 0.01).Compared with the model group,the use of VE significantly decreased(p < 0.001)the gene expressions of IL-1β and IL-6,both low-dose and high-dose of matrine(p< 0.001)significantly reduced IL-1β expression,and significantly(p < 0.01)inhibited the high expression of IL-6.While in the liver,the expression of IL-6 did not change significantly,but D-galactose significantly increased the expression of IL-1β(p < 0.01).Compared with the model group,VE group and matrine high-dose group(p < 0.01)significantly decreased the gene expression of IL-1β while matrine low-dose group(p < 0.001)significantly inhibited the gene expression of IL-1β.The above results indicate that matrine can reduce the nuclear size of senescent liver cells,attenuate the damage of hippocampal nerve cells,down-regulate the expression of senescent cell-related symbols and ameliorate cellular senescence.The targets of cellular senescence that matrine may act on are enriched in signal pathways such as energy metabolism,and positive regulation of cell metabolism.The result of molecular docking showed that the PARP1 in the key target and the matrine have a similar binding binding position compared with the inhibitor of PARP1.Besides,matrine can reduce the secretion levels of IL-1β and IL-6 which are the phenotypic components of the liver and hippocampus.