Liver fibrosis is a progressive liver damage condition caused by various factors and may progress toward liver cirrhosis, and even hepatocellular carcinoma. Many studies have found that the disfunction in metabolism could contribute to the development of liver fibrosis. Geniposide, derived from Gardenia jasminoides J. Ellis, has been demonstrated with therapeutic effects on liver fibrosis. However, the exact molecular mechanisms of such liver-protection remain largely unknown. The aim of this study was to explored the effect of geniposide on metabolic regulations in liver fibrosis. We used carbon tetrachloride (CCl₄) to construct a mouse model of liver fibrosis and subsequently administered geniposide treatment. Therapeutic effects of geniposide on liver fibrosis were accessed through measuring the levels of hepatic enzymes in serum and the pathological changes in liver. We also investigated the effects of geniposide on inflammatory response, oxidative stress and apoptosis in liver. Furthermore, serum untargeted metabolomics were used to explore the metabolic regulatory mechanisms behind geniposide on liver fibrosis. Our results demonstrated that geniposide could reduce the levels of hepatic enzymes in serum and ameliorate the pathological changes in liver fibrosis mice. Geniposide enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased methane dicarboxylic aldehyde (MDA) levels in liver. Geniposide treatment also decreased the levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-a) in liver tissue homogenate. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining demonstrated that geniposide could reduce the apoptosis of hepatocytes. Geniposide increased the protein expression of B-cell lymphoma-2 (Bcl-2) and downregulated the protein expression of Bcl-2 Associated X (Bax), cleaved-Caspase 3, and cleaved-Caspase 9. Serum untargeted metabolomics analysis demonstrated that geniposide treatment improved the metabolic disorders including glycerophospholipid metabolism, arginine and proline metabolism, and arachidonic acid (AA) metabolism. In conclusion, our study demonstrated the protective effects of geniposide on liver fibrosis. We found that geniposide could treat liver fibrosis by inhibiting oxidative stress, reducing inflammatory response and apoptosis in the liver, and modulating glycerophospholipid, and arginine, proline, and AA metabolism processes.

Sepsis‐induced acute lung injury (SALI) is characterized by a high incidence and mortality rate, which has caused a serious medical burden. The pharmacological effects of esculetin (ELT), such as antibacterial and anti‐inflammatory actions, have been widely confirmed. However, the therapeutic effects and mechanisms of ELT on SALI still need to be further clarified. In this study, we first evaluated the therapeutic potential of ELT on a caecal ligation and puncture (CLP) induced septic rat model, particularly in the treatment of acute lung injury. Afterwards, we explored the effect of ELT on macrophage polarization in vivo and in vitro. Then, we investigated the anti‐inflammatory mechanism of ELT based on modulating the metabolic reprogramming of macrophage (the effect on glycolysis in M1, and the effect on fatty acid β‐oxidation in M2). In addition, macrophage metabolic inhibitors (glycolysis inhibitor: 2‐DG, and fatty acid β‐oxidation inhibitor: etomoxir) were used to verify the regulatory effect of ELT on macrophage metabolic reprogramming. Our results proved that ELT intervention could effectively improve the survival rate of SALI rats and ameliorate pathological injury. Next, we found that ELT intervention inhibited M1 polarization and promoted M2 polarization of macrophages in vivo and in vitro, including the downregulation of M1‐related markers (CD86, iNOS), the decrease of pro‐inflammatory factors (nitric oxide, IL‐1β, IL‐6, and TNF‐α), the upregulation of M2‐related markers (CD206, ARG‐1), the increase of immunomodulatory factors (IL‐4 and IL‐10). Subsequently, seahorse analysis showed that ELT intervention inhibited the glycolytic capacity in M1, and promoted the ability of fatty acid β‐oxidation in M2. Besides, ELT intervention inhibited the level of glycolysis product (lactic acid), and the expression of glycolysis‐related genes (Glut1, Hk2, Pfkfb1, Pkm and Ldha) and promoted the expression of fatty acid β‐oxidation related genes (Cpt1a, Cpt2, Acox1). In addition, we found that the inhibitory effect of ELT on M1 polarization was comparable to that of 2‐DG, while intervention with etomoxir abolished the promoting effect of ELT on M2 polarization. ELT inhibited the inflammatory response in SALI by correcting macrophage polarization (inhibiting M1 and promoting M2). The mechanism of ELT on macrophage polarization was associated with regulating metabolic reprogramming (inhibiting glycolysis in M1 and promoting fatty acid β‐oxidation in M2).

Pi-Dan-Jian-Qing decoction (PDJQ) can been used in the treatment of type 2 diabetes mellitus (T2DM) in clinic. However, the protective mechanisms of PDJQ on T2DM remain unknown. Recent studies have shown that the changes in gut microbiota could affect the host metabolism and contribute to progression of T2DM. In this study, we first investigated the therapeutic effects of PDJQ on T2DM rats. 16S rRNA sequencing and untargeted metabolomics analyses were used to investigate the mechanisms of action of PDJQ in the treatment of T2DM. Our results showed that PDJQ treatment could improve the hyperglycemia, hyperlipidemia, insulin resistance (IR) and pathological changes of liver, pancreas, kidney, and colon in T2DM rats. PDJQ could also decrease the levels of pro-inflammatory cytokines and inhibit the oxidative stress. 16S rRNA sequencing showed that PDJQ could decrease the Firmicutes/Bacteroidetes (F to B) ratio at the phylum level. At the genus level, PDJQ could increase the relative abundances of Lactobacillus, Blautia, Bacteroides, Desulfovibrio and Akkermansia and decrease the relative abundance of Prevotella. Serum untargeted metabolomics analysis showed that PDJQ could regulate tryptophan metabolism, histidine metabolism, tricarboxylic acid (TCA) cycle, phenylalanine, tyrosine and tryptophan biosynthesis and tyrosine metabolism pathways. Correlation analysis indicated that the modulatory effects of PDJQ on the tryptophan metabolism, histidine metabolism and TCA cycle pathways were related to alterations in the abundance of Lactobacillus, Bacteroides and Akkermansia. In conclusion, our study revealed the various ameliorative effects of PDJQ on T2DM, including improving the liver and kidney functions and alleviating the hyperglycemia, hyperlipidemia, IR, pathological changes, oxidative stress and inflammatory response. The mechanisms of PDJQ on T2DM are likely linked to an improvement in the dysbiosis of gut microbiota and modulation of tryptophan metabolism, histamine metabolism, and the TCA cycle.