Metabolomics-based Exploration Of The Protective Effects Of Chiglitazar On The Improvement Of Sepsis Outcomes And Multiple Organ Injury

Sepsis is a systemic inflammatory response syndrome caused by the invasion of pathogenic microorganisms and the body’s reaction to infections that can lead to end-stage organ dysfunction and even death.It is hard to identify,cure and research sepsis because of its high mortality and individual differences.In addition to the traditional antibiotic and hormone therapy,some hypoglycemic drugs have been found to have significant prognostic improvement in the treatment of sepsis in recent years.As a kind of peroxisome proliferator-activated receptors(PPARs)agonists,thiazolidinediones exert the effects of anti-inflammation and organ protection in clinical application,and may become a new effective treatment for sepsis.Chiglitazar is a new thiazolidinedione hypoglycemic drug independently developed and possessing independent intellectual property rights in China.It is a multiple PPARs agonist,and has been clinically used for the treatment of diabetes.However,there is a lack of assessment of the effect of multiple PPARs agonists on the improvement of the prognosis of sepsis,and the analysis of its metabolic pathways and mechanisms of action is not comprehensive enough.We found the anti-inflammatory and organ protective effects of chiglitazar in sepsis by the animal and cell models,and metabolic reprogramming of sepsis by ways of metabolomics.The results confirmed the improvement of chiglitazar on the prognosis of sepsis.Objective: Investigate the anti-inflammatory and organ-protective effects of a novel hypoglycemic agent,chiglitazar,in sepsis and its effect to reprogram the metabolism of sepsis.Methods: The rats were randomly divided into a sham operation group,a model group,an administration group,and a positive control group.Preventive medication was taken for five days.The rats in the administration group were given chiglitazar(10 mg/kg)by gavage,while those in the positive control group were given pioglitazone(10 mg/kg)by gavage.The rats in the sham operation group and model group were given the same amount of double distilled water.The model of sepsis was established by cecal ligation and puncture(CLP).Serum and organ samples of the rats were collected 24 h after surgery.The survival condition of the rats during 72 h after operation was observed and the survival curve was drawn.H&E staining sections of organ samples from each group were compared.The macrophage RAW264.7 was stimulated with lipopolysaccharide(LPS)and chiglitazar was administered at concentration gradients of 2,4,8,16,32,and 64 μM.The expression of inflammatory factors in the cell supernatant was detected by ELISA kit.The serum was pretreated,and analyzed by gas chromatography-tandem mass spectrometry(GC-MS)and liquid chromatography-tandem mass spectrometry(LC-MS).The metabolites were qualitatively and quantitatively analyzed,and the differences among groups were compared and screened.Pathway enrichment analysis was performed on the target metabolites.The pathway changes of L-kynurenine—NAD+ in the analysis results were further discussed.Results: Chiglitazar significantly improves the survival rate of septic rats and reduces the organ damage in liver,kidney and lung caused by sepsis.Chiglitazar reduces the expression of inflammatory factors in the inflammation macrophage model.Chiglitazar can promote the synthesis of L-kynurenine into NAD+,playing an anti-inflammatory and multi-organ protection role.Conclusions: As a PPARs multiple agonist,chiglitazar has good anti-inflammatory and organ protective effects by regulating the synthesis of NAD+ from L-kynurenine metabolism and can well improve the therapeutic prognosis of sepsis.