Intervening Effects of Total Alkaloids of Corydalis saxicola Bunting on Rats With Antibiotic-Induced Gut Microbiota Dysbiosis Based on 16S rRNA Gene Sequencing and Untargeted Metabolomics Analyses

Gut microbiota dysbiosis induced by antibiotics is strongly connected with health concerns. Studying the mechanisms underlying antibiotic-induced gut microbiota dysbiosis could help to identify effective drugs and prevent many serious diseases. In this study, in rats with antibiotic-induced gut microbiota dysbiosis treated with total alkaloids of Corydalis saxicola Bunting (TACS), urinary and fecal biochemical changes and cecum microbial diversity were investigated using 16S rRNA gene sequencing analysis and untargeted metabolomics. The microbial diversity results showed that 10 genera were disturbed by the antibiotic treatment, and two of them were obviously restored by TACS. The untargeted metabolomics analysis identified 34 potential biomarkers in urine and feces that may be the metabolites that are most related to the mechanisms underlying antibiotic-induced gut microbiota dysbiosis and the therapeutic effects of TACS treatment. The biomarkers were involved in six metabolic pathways, comprising pathways related to branched-chain amino acid (BCAA), bile acid, arginine and proline, purine, aromatic amino acid, and amino sugar and nucleotide sugar metabolism. Notably, there was a strong correlation between these metabolic pathways and two gut microbiota genera (g__Blautia and g__Intestinibacter). The correlation analysis suggested that TACS might synergistically affect four of these metabolic pathways (BCAA, bile acid, arginine and proline, and purine metabolism), thereby modulating gut microbiota dysbiosis. Furthermore, we performed a molecular docking analysis involving simulating high-precision docking and using molecular pathway maps to illuminate the way that ligands (the five main alkaloid components of TACS) act on a complex molecular network, using CYP27A1 (a key enzyme in the bile acid synthesis pathway) as the target protein. This study provides a comprehensive overview of the intervening effects of TACS on the host metabolic phenotype and gut microbiome in rats with gut microbiota dysbiosis, and it presents new insights for the discovery of effective drugs and the best therapeutic approaches

Design, Synthesis and Biological Evaluation of Nitrate Derivatives of Sauropunol A and B as Potent Vasodilatory Agents

A group of nitrate derivatives of naturally occurring sauropunol A and B were designed and synthesized. Nitric oxide (NO) releasing capacity and vasodilatory capacity studies were performed to explore the structure-activity relationship of resulted nitrates. Biological evaluation of these compounds revealed that most of the synthesized mononitrate derivatives demonstrated superior releasing capacity than isosorbide mononitrate (ISMN), and 2MNS-6 even demonstrated stronger NO releasing capacity than isosorbide dinitrate (ISDN). Two dinitrates, DNS-1 and DNS-2, showed higher NO releasing capacity than ISDN. Evaluation of inhibitory activities to the contractions in mesenteric artery rings revealed that 2MNS-8 and DNS-2 showed stronger vasorelaxation activities than ISDN. High level of NO and soluble guanylyl cyclase (sGC) may be essential for the potent vasodilatory effect of DNS-2. The vasodilatory effects of DNS-2 may result from cellular signal transduction of NO-sGC-cGMP. DNS-2 was found to be the most potent sauropunol-derived nitrate vasodilatory agent for further pharmaceutical investigation against cardiovascular diseases