Cytidine Alleviates Dyslipidemia and Modulates the Gut Microbiota Composition in ob/ob Mice.

Cytidine and uridine are endogenous metabolites in the pyrimidine metabolism pathway, and cytidine is a substrate that can be metabolized into uridine via cytidine deaminase. Uridine has been widely reported to be effective in regulating lipid metabolism. However, whether cytidine could ameliorate lipid metabolism disorder has not yet been investigated. In this research, ob/ob mice were used, and the effect of cytidine (0.4 mg/mL in drinking water for five weeks) on lipid metabolism disorder was evaluated in terms of an oral glucose tolerance test, serum lipid levels, liver histopathological analysis and gut microbiome analysis. Uridine was used as a positive control. Our findings reveal that cytidine could alleviate certain aspects of dyslipidemia and improve hepatic steatosis via modulating the gut microbiota composition in ob/ob mice, especially increasing the abundance of short-chain fatty acids-producing microbiota. These results suggest that cytidine supplementation could be a potential therapeutic approach for dyslipidemia.

Asiatic acid alleviates metabolism disorders in ob/ob mice: mechanistic insights.

Glucolipid metabolism disorders pose a serious and global health problem, and more effective prevention and treatment methods are urgently needed. In this study, ob/ob mice were used to explore the potential mechanism explaining how asiatic acid (AA) regulates glucolipid metabolism disorders. Five-week AA treatment (30 mg kg-1) significantly improved a host of metabolic factors in ob/ob mice, including hyperglycemia, hyperlipidemia, insulin resistance, and liver histopathology. Combined analysis of untargeted liver metabolomics, liver transcriptomics, and the gut microbiome was conducted, and the results showed that AA alleviates metabolic disorders in ob/ob mice through regulating pyrimidine metabolism, activating PPAR-γ, and modulating gut microbiota. AA treatment remarkedly increased the levels of cytosine and cytidine, two crucial endogenous metabolites related to pyrimidine metabolism, which were significantly decreased in ob/ob mice. AA treatment also affected the levels of 13-S-hydroxyoctadecadienoic acid, an endogenous PPAR-γ agonist. The abundances of Lachnospiraceae_NK4A136_group and norank_f__norank_o__Clostridia_UCG-014 were increased after AA treatment. Meanwhile, correlation analysis showed that endogenous metabolites and gut microbiota were strongly correlated. These findings indicated that AA supplements might be beneficial for the prevention of metabolic disorders.

Application of 2H stable isotope labelling methodology and ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry for the metabolite identification of dehydroandrographolide in rats.

Dehydroandrographolide (DA), one of the crucial diterpenoids of Andrographis paniculata (Burm.F.) Nees, which has been widely used clinically due to its excellent biological activities and pharmacological safety. Until now, various investigations about the biological activities, pharmacokinetic profiles, and in vitro metabolism of DA have been conducted. However, information about the in vivo biotransformation of DA was still not available. In this study, a rapid and reliable approach based on stable isotope labeling and UPLC-Q/TOF-MS was developed and applied for the first systematic research about the in vivo metabolism of DA. As a result, a total of 35 metabolites were identified in rat urine, bile, plasma, and feces samples after DA was orally administered at the dose of 95 mg/kg, and 33 of them were further verified based on stable isotope labeling. The major metabolic pathways for DA were hydroxylation, hydration, sulfonation, sulfate conjugation, and glucuronidation. Meanwhile, sulfonation, sulfate conjugation, and amino acids conjugation of DA were reported for the first time. This is the first systematic investigation of the in vivo metabolism of DA in rats, and the identification of these metabolites might provide scientific and reliable support for a full understanding of the metabolism of DA.