Study On Differences In Metabolic Regulation Of Rhizoma Paridis Saponins And Curcumin In Normal And Tumor Models

Rhizoma Paridis saponins (RPS) are famous for the treatment of various cancers in modern clinical uses. Curcumin is a widely used spice and coloring agent in food and possesses anticarcinogenic pharmacological activities. The toxicity assessment of long-term use of them has been investigated. RPS can induced liver and lung injury while curcumin induced slight liver injury. However, the the mechanism has not yet been investigated. In order to explain this phenomenon, metabolites and metabolism related genes were detected.As a result, RPS inhibited the oxidation of fatty acids, glycolysis, and TCA cycle pathway,and disturbed glycine, serine, and threonine metabolism. Low expression of TG, T-CHO,and LDL-C and high levels of ALT and AST indicated that chronic exposure to RPS caused hepatocyte damage, synthesis dysfunction, and transportation failure of lipoproteins. In addition, RPS downregulated the mRNA levels of CYP1A2, CYP2E1, and UGTs.Curcumin significantly increased key mRNA levels of HK2, PKM2, LDHA, CES, Cptl,Cpt2, FASN, and ATP5b and decreased levels of GLUT2 and ACC1 to enhance glycolysis and inhibit lipid metabolism and TCA cycle. Therefore, overdose or long-term intake of curcumin could initiate the unbalanced state of bodies through metabolic disorders, which induces liver injury. RPS treatment decreased most lipid compound levels and concentration of lactic acid. Meanwhile, RPS increased concentration of glutamate and glucose. In contrast, DDP treatment increased the levels of lipids and decreased the concentration of glucose. For the metabolic enzymes related genes analysis,RPS and DDP regulated p53/mTOR-c-Myc-HIF-1? network to decrease GLUT1, HK2, PKM2 and LDHA genes. Meanwhile, the ascendent mRNA of p53 raised GLS level and suppressed ATP product. What's more,RPS treatment decreased mRNA level of FASN to repress lipogenesis. In contrast, DDP treatment increased lipogenesis to induce pulmonary metastasis. RPS significantly decreased tumor weight correlates to down-regulating lactate,acetate, N-acetyl amino acid and glutamine signals (p<0.05). For the analysis of metabolic enzyme related genes, RPS reversed the aerobic glycolysis through activating tumor suppressor p53 and PTEN, and suppressed FASN to inhibit lipogenesis. What's more, RPS repressed Myc and GLS expression and decreased glutamine level. The regulating PI3K/Akt/mTOR and HIF-1?/Myc/Ras networks also participated in these metabolic changes. Taken together, RPS suppressed ATP product made the tumor growth slow, which indicated a good anti-cancer effect and new angle for understanding the mechanism of RPS.What's more, we investigated mechanism-based chemopreventive potential of curcumin against DEN-induced liver disease in Kunming mice and the study was to embark upon the protective effect of curcumin against DEN-induced alterations on metabolic enzyme activities in mice during liver damage. Further serum marker enzymes were also analyzed. Docking study showed the curcumin presented strong affinity with key relative metabolism protein and with more number of amino acid residues involved in targeting enzymes binding with hydrogen bonds and hydrophobic interactions. Furthermore, this fact was also supported by the PCR result. So curcumin partly attenuates DEN-induced liver injury in mice via induction of AFP and key relative metabolic enzymes against DEN damage. Therefore, RPS and curcumin could influence expression of related genes and the metabolites of energy metabolism to exert anti-cancer effect. Thereby, this results is also to provide theoretical basis for the anti-cancer mechanism of RPS combind with curcumin infuture.