Author:
Xie Fengfeng,Xu Liba,Zhu Hua,Li Yinlan,Nong Lizhen,Chen Yaling,Zeng Yanfang,Cen Sijie
Abstract
Ellagic acid (EA) is a polyphenol dilactone that has been reported to have antipyretic, anti-inflammatory, anti-tumor, and antioxidant activities, but the mechanism of action has not been reported. In this study, serum metabolomics was used to explore the mechanism of EA on rat fever induced by beer yeast, and to screen out marker metabolites to provide a reference for the antipyretic effect of EA. The acute fever model of male Sprague Dawley rats involved subcutaneous injection with 20% aqueous suspension of yeast (15 mL/kg) in their back. At the same time of modeling, EA was given orally by 10 mL/kg intragastric administration for treatment. During the experiment, the temperature and its change values of rats were recorded, and Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α), Prostaglandin E2 (PGE2), Cyclic Adenosine Monophosphate (cAMP), Superoxide Dismutase (SOD) and Malondialdehyde (MDA)—six physiological and biochemical indexes of rats—were detected after the experiment. In addition, the hypothalamus of each rat was analyzed by Western blot (WB), and the levels of Phospho Nuclear Factor kappa-B (P-NF-κB P65) and IkappaB-alpha (IKB-α) were detected. Then, the serum metabolites of rats in each group were detected and analyzed by gas chromatograph mass spectrometry and the multivariate statistical analysis method. Finally, when screening for differential metabolites, the potential target metabolic pathway of drug intervention was screened for through the enrichment analysis of differential metabolites. Pearson correlation analysis was used to systematically characterize the relationship between biomarkers and pharmacodynamic indicators. EA could reduce the temperature and its change value in yeast induced fever rats after 18 h (p < 0.05). The level of IL-6, TNF-α, PGE2, cAMP, SOD and MDA of the Model group (MG) increased significantly compared to the Normal group (NG) (p < 0.001) after EA treatment, while the levels of the six indexes in the serum and cerebrospinal fluid of yeast-induced rats decreased. The administration of yeast led to a significant increase in Hypothalamus P-NF-κB P65 and IKB-α levels. Treatment with EA led to a significant decrease in P-NF-κB P65 levels. Moreover, combined with VIP > 1 and p < 0.05 as screening criteria, the corresponding retention time and characteristic mass to charge ratio were compared with the NIST library, Match score > 80%, and a total of 15 differential metabolites were screened. EA administration significantly regulated 9 of 15 metabolites in rat serum. The 15 differential metabolites involved linoleic acid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, galactose metabolism, biosynthesis of unsaturated fatty acids and glycerolipid metabolism. Pharmacodynamic correlation analysis was conducted between 15 different metabolites and six detection indexes. There was a significant correlation between 13 metabolites and six detection indexes. D-(−)-lactic acid, glycerin, phosphoric acid, 5-oxo-L-proline were negatively correlated with TNF-α, and p values were statistically significant except for L-tyrosine. In addition, glycerin was negatively correlated with IL-6, PGE2 and MDA, while phosphoric acid was negatively correlated with IL-6. In conclusion, EA may play an antipyretic anti-inflammatory role through the inhibition of the IKB-α/NF-κB signaling pathway and five metabolic pathways, which may contribute to a further understanding of the therapeutic mechanisms of the fever of EA.
Funder
the Collaborative Innovation Center of Zhuang and Yao Ethnic Medicine
Subject
Molecular Biology,Biochemistry,Endocrinology, Diabetes and Metabolism
Reference31 articles.
1. Metabolism of Human Diseases;Lammert,2014
2. Evidence of substance P autocrine circuitry that involves TNF-α, IL-6, and PGE2 in endogenous pyrogen-induced fever
3. Cytokines as Endogenous Pyrogens
4. Effects of naloxone on the contents of cAMP in hypothalamus and AVP in ventral septal area in fever rats;Zhao;J. Appl. Physiol.,2009
5. Studies on the mechanism of alpha-MSH in reducing IL-1 beta-induced fever;Hu;Acta Physiol. Sinica,1998
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献