| Type 2 diabetes mellitus(T2DM)is a chronic disease associated with obesity and insulin resistance.It is characterized by insufficient insulin secretion,elevated blood glucose levels and lipid disorders.With the change in the quality of life and diet,the rate of diabetic patients is increasing exponentially.At present,clinical treatment of type 2 diabetes is mainly through oral hypoglycemic drugs to restore normal blood glucose levels,and long-term use of hypoglycemic drugs can produce side effects such as headache,nausea,diarrhea,and hepatotoxicity.Therefore,there is an urgent need to seek active substances from natural plants with diabetic ameliorating effects.Rosa roxbunghii Tratt,also known as Mulizi,Chungui,and Rosaceae,has rich vitamin C,phenolic compounds,organic acids and trace elements,and many other nutrients.It has the effect of stomachic,anti-eating,anti-diarrhea,preventing aging,lowering cholesterol,lowering blood sugar,anti-cancer and so on.Our group found that Rosa roxbunghii ellagic acid has antioxidant activity and a hypoglycemic effect,but its regulatory mechanism is still unclear.To this end,this thesis exposes the regulatory mechanism of Rosa roxbunghii ellagic acid on metabolic disorders in db/db mice from a multi-omics perspective.The main findings are as follows:1.Study on the effect of Rosa roxbunghii ellagic acid on the intervention of type 2 diabetes.Analysis of the effect of Rosa roxbunghii ellagic acid on glycolipid metabolism in type 2 diabetes by transcriptome high-throughput sequencing(RNA-seq)of mouse liver tissues.It was found that Rosa roxbunghii ellagic acid reduced fasting blood glucose(FBG)in db/db mice by 46.12%.Compared with the model group,pyruvate kinase(PK)and hexokinase(HK)increased by 77.47% and 74.53%,respectively,and glucose-6-phosphate dehydrogenase(G6PD)level decreased by 46.22% in the Rosa roxbunghii ellagic acid group.It also improved total cholesterol(TC)and triglycerides(TG)significantly,reducing cholesterol synthesis and controlling disorders of glucolipid metabolism.On the level of inflammatory factors,compared with the model group,interleukin 1(IL-1),interleukin 6(IL-6),tumor necrosis factor-alpha(TNF-α),and monocyte chemotactic protein 1(MCP-1)were reduced by 49.84%,45.90%,38.11%,and 40.88%,respectively,under the intervention of Rosa roxbunghii ellagic acid,which reduced the inflammatory symptoms of the organism and effectively protected the lesions of liver tissue.2.Transcriptomic analysis of the effect of Rosa roxbunghii ellagic acid on glycolipid metabolism in type 2 diabetes mellitus.The effect of Rosa roxbunghii ellagic acid on improving glucolipid metabolism in type 2 diabetes was analyzed by transcriptome high-throughput sequencing(RNA-seq)of mouse liver tissues and bioinformatics techniques.It was found that under the intervention of Rosa roxbunghii ellagic acid,707 differentially expressed genes were mainly enriched in the metabolic pathways of steroid hormone biosynthesis,glycolysis/glycogenesis,HIF-1 signaling pathway,AMPK signaling pathway,MAPK signaling pathway,etc.Rosa roxbunghii ellagic acid back-regulated the expression of Pgk1,Pdha1,Eno1 b,Egf,Camk2 b,Calm2 and other genes on their related pathways.It is suggested that Rosa roxbunghii ellagic acid may regulate glucose homeostasis and lipid metabolic transport through mediating Pgk1/Pdha1/Eno1b/Egf/Camk2b/Calm2 genes.3.Multi-omics analysis of the mechanism of action of Rosa roxbunghii ellagic acid in improving type 2 diabetes mellitus.Analysis of the mechanism of action of Rosa roxbunghii ellagic acid in improving type 2 diabetes mellitus by metabolomics.It was found that there were 154 differential metabolites between the model group and the Rosa roxbunghii ellagic acid group,with palmitoleic acid undergoing the most significant changes.Suggesting that Rosa roxbunghii ellagic acid may alleviate hyperglycemia by regulating palmitoleic acid levels in the fatty acid biosynthesis pathway.Further joint analysis of transcriptome and metabolome revealed that Rosa roxbunghii ellagic acid affected the expression of genes related to metabolic processes such as glucagon signaling pathway,Wnt signaling pathway,glycolysis/gluconeogenesis,arachidonic acid metabolism,retinol metabolism,linoleic acid metabolism,steroid biosynthesis,and regulated Acetylcholine,5,6-DHET,9-cis-Retinoic acid and all-trans-Retinoic acid levels to alleviate diabetes mellitus.It indicates that the hypoglycemic mechanism of Rosa roxbunghii ellagic acid is closely related to glucose metabolism and lipid metabolism.The key target genes of Rosa roxbunghii ellagic acid in regulating diabetes were screened by correlation analysis as Calm2,Pdha1,Scd1,Dvl1,Camk2 b,Cyp2c29.Validation of key target genes and protein expression by qPCR and WB revealed that Rosa roxbunghii ellagic acid significantly decreased the expression level of Dvl and elevated the expression of Calm2,Pdha1,Scd1,Dvl1,Camk2 b and Cyp2c29,which in turn regulated glycolipid metabolism.In summary,Rosa roxbunghii ellagic acid mediates Calm2/Pdha1/Scd1/Dvl1/Camk2b/Cyp2c29 genes to improve metabolic disorders in diabetes and increase insulin by affecting PPAR signaling pathway,Wnt signaling pathway,glycolysis/gluconeogenesis,arachidonic acid metabolism,retinol metabolism,linoleic acid metabolism,steroid biosynthesis and other metabolic pathways.sensitivity,which in turn reduces blood glucose levels. |
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