NMR-based Metabolomics Approach To Study The Biological Effects Of Three Drugs

Metabolomics combined with traditional biological techniques was used to explore the pharmacological mechanisms of traditional Chinese medicine and toxic effects of contaminants.The main contents are as following:First,the prevention effect of camellia nitidissima chi on colitis-associated carcinogenesis was evaluated.Colorectal cancer(CRC)is one of the most common malignant tumors worldwide,occurring in the colon or rectum portion of large intestine.With marked antioxidant,anti-inflammation and anti-tumor activities,Camellia nitidissima Chi has been used as an effective treatment of cancer.The azoxymethane/dextran sodium sulfate(AOM/DSS)induced CRC mice model was established and prevention of C.nitidissima Chi extracts on CRC was evaluated by gross examination,histopathological inspection,serum biochemistry,combined with nuclear magnetic resonance(NMR)-based metabolomics and correlation network analysis.C.nitidissima Chi extracts could significantly inhibit AOM/DSS induced CRC,relieve the colonic pathology of inflammation and ameliorate the serum biochemistry,and reverse the disturbed metabolic profiling toward the normal state.Moreover,the butanol fraction showed a better efficacy than the water-soluble fraction of C.nitidissima Chi.Further development of C.nitidissima Chi extracts as a potent CRC inhibitor was warranted.Second,protection of polygonum multiflorum on cerebral ischemia reperfusion injury in rat and underlying mechanisms were studied.Stroke is the third most common cause of death worldwide.Polygonum multiflorum(He-Shou-Wu,HSW)is one of the traditional Chinese medicines with multiple pharmacological activities which was widely used in Chinese recipe.In this part,the mortality rate,neurological deficit,cerebral infarct size,histopathology,immunohistochemistry,biochemical parameters,quantitative real-time polymerase chain reaction and western blotting were used to access the treatment effects of HSW on ischemic stroke.NMR based metabolomics analysis disclosed that HSW could relieve stroke rats suffering from the ischemia/reperfusion injury by ameliorating the disturbed energy and amino acids metabolisms,alleviating the oxidative stress from reactive oxygen species and reducing inflammation.HSW increased levels of cellular antioxidants that scavenged reactive oxygen species during ischemia-reperfusion via the nuclear erythroid 2-related factor 2 signaling pathway,and exert anti-inflammatory effect by decreasing the levels of inflammatory factors such as cyclooxygenase-2,interleukin-1?,interleukin-6 and tumor necrosis factor-?.The integrated metabolomics approach showed its potential in understanding mechanisms of HSW in relieving ischemic stroke.Further study to develop HSW as an effective therapeutic agent to treat stroke is warranted.Third,multi-tissue metabolic responses of goldfish(Carassius auratus)after acute and long-term glyphosate-based herbicide exposure.Glyphosate is an efficient herbicide widely used worldwide.However,its toxicity to non-targeted organisms has not been fully elucidated.In this study,the toxicity of glyphosate-based herbicide was evaluated on goldfish after acute and long-term exposure.Acute glyphosate exposure produced increased levels of BUN and CRE and dose-dependent injuries of tissues,and significant perturbations in neurotransmitter equilibrium,energy metabolism and amino acid metabolism,which enlighten the potential of glutamine as an early marker of glyphosate induced neurotoxicity.Long-term glyphosate exposure caused disorders of blood biochemical indexes and renal tissue injury,and significant perturbations in oxidative stress,energy metabolism,amino acids metabolism and nucleosides metabolism uncovered by correlation network analysis,which enlighten the potential of NAD,hypoxanthine and inosine as an early marker of glyphosate induced genotoxicity.The integrated metabolomics approach showed its applicability in discovering the toxic mechanisms of pesticides,which provided new strategy for the assessment of the environmental risk of herbicides to non-target organisms.