Hyperuricemia (HUA) and its associated metabolic diseases seriously threaten human health, and commensal microbiota has been identified as one of the environmental triggers of HUA. The role of berberine (BBR) in the treatment of HUA has begun to receive attention in recent years. However, how BBR modulates the microbiota to slow HUA progression is unclear. In this study, we showed that BBR alleviated potassium oxonate (PO)-induced HUA in mice by suppressing the expression of xanthine oxidase (XOD) in the liver and urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidney. The BBR also improved renal inflammation by inhibiting the expression of TNF-[Formula: see text], IL-1[Formula: see text], and caspase-1. Subsequently, we evaluated whether the observed anti-HUA effects of BBR were associated with changes in gut microbial structure in mice. 16S rRNA sequencing data showed that BBR significantly altered the community compositional structure of the gut microbiota. Specifically, BBR enriched the abundance of Coprococcus, Bacteroides, Akkermansia, and Prevotella. Antibiotic treatment can reverse the anti-HUA effects of BBR that further supports the role of the gut microbiota. In conclusion, our study provides evidence that BBR ameliorates PO-induced HUA by modulating the gut microbiota.

Tanshinone IIA (Tan-IIA) is a major component extracted from the traditional herbal medicine Danshen, which has shown antipulmonary fibrosis by suppress reactive oxygen species-mediated activation of myofibroblast. However, the exact mechanism of Tan-IIA against pulmonary fibrosis (PF) remains unclear. This work aimed to explore the underlying mechanism of the protective effects of Tan-IIA on PF. By using high-throughput RNA-Seq analysis, we have compared the genome-wide gene expression profiles and pathway enrichment of Tan-IIA-treated NIH-3T3 cells with or without transforming growth factor beta 1 (TGF-[Formula: see text]1) induction. In normal NIH-3T3 cells, Tan-IIA treatment up-regulated 181 differential expression genes (DEGs) and down-regulated 137 DEGs. In TGF-[Formula: see text]1-induced NIH-3T3 cells, Tan-IIA treatment up-regulated 709 DEGs and down-regulated 1075 DEGs, and these DEGs were enriched in extracellular matrix organization, collagen fibril organization, cell adhesion, ECM–receptor interaction, PI3K-Akt signaling pathway and P53 signaling pathway. Moreover, there were 207 co-expressed DEGs between Tan-IIA treatment vs. the Control and TGF-[Formula: see text]1 plus Tan-IIA treatment vs. TGF-[Formula: see text]1 alone treatment, some of which were related to anti-oxidative stress. In both normal and TGF-[Formula: see text]1-induced NIH-3T3 cells, protein–protein interaction network analysis indicated that Tan-IIA can regulate the expression of several common anti-oxidant genes including Heme oxygenase 1 (Ho-1, also known as Homx1), Sestrin2 (Sesn2), GCL modifier subunit (Gclm), GCL catalytic subunit (Gclc) and Sequestosome-1 (Sqstm1). Quantitative Real-time polymerase chain reaction analysis confirmed some DEGs specifically expressing on Tan-IIA treated cells, which provided new candidates for further functional studies of Tan-IIA. In both in vitro and in vivo PF models, the protein expression of Sesn2 was significantly enhanced by Tan-IIA treatment. Overexpression and knockdown experiments showed that Sesn2 is required for Tan-IIA against TGF-[Formula: see text]1-induced myofibroblast activation by reinforcing nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated anti-oxidant response via downregulation of kelch-like ECH-associated protein 1 (Keap1). These results suggest Tan-IIA inhibits myofibroblast activation by activating Sesn2-Nrf2 signaling pathway, and provide a new insight into the essential role of Sesn2 in PF.