ABSTRACT
The relationship between poor in vivo bioavailability and effective pharmacological activity are not yet fully clarified for many flavonoids. The analysis of flavonoids-induced alterations in the gut microbiota represents a promising approach to provide useful clues to elucidate the mechanism of action. Here, we investigate the effect of myricetin supplementation on high-fat-diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) in rats and explore the associations with the gut microbiota through high-throughput analyses. The 12-week myricetin supplementation and fecal microbiota transplantation outcomes suggest that myricetin significantly slows the development of NAFLD. Meanwhile, the anti-NAFLD effects of myricetin are associated with the modulation of the gut microbiota composition. Myricetin reduces hepatic lipid synthesis and inflammation through modulations in fecal butyric-acid-related gut microbiota and protection of the gut barrier function. This study may facilitate the elucidation of the action mechanism of flavonoids with low bioavailability.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Bacteria/drug effects , Flavonoids/pharmacology , Gastrointestinal Microbiome/drug effects , Hepatitis/prevention & control , Lipogenesis/drug effects , Liver/drug effects , Non-alcoholic Fatty Liver Disease/prevention & control , Animals , Bacteria/growth & development , Bacteria/metabolism , Biomarkers/blood , Butyrates/metabolism , Diet, High-Fat , Disease Models, Animal , Dysbiosis , Fecal Microbiota Transplantation , Hep G2 Cells , Hepatitis/metabolism , Hepatitis/microbiology , Humans , Inflammation Mediators/blood , Lipids/blood , Liver/metabolism , Male , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/microbiology , Rats, WistarABSTRACT
AIMS: Epithelial-mesenchymal transition (EMT) is one of the important regulators of metastasis in advanced hepatocellular carcinoma (HCC). Blocking the Notch signaling pathway and then reversing the EMT process is a hot spot in clinical tumor research. Here, we aimed to investigate the effect and underlying mechanisms of ADAM-17 (a key cleavage enzyme of Notch pathway) inhibitor ZLDI-8 we found before on the metastasis of hepatocellular carcinoma in vitro and in vivo. MAIN METHODS: The cell viability of HCC cells was evaluated by MTT and colony formation assays. Migration and invasion were assessed respectively with wound healing and transwell assays. The expression and location of proteins were detected by western blot and immunofluorescence, respectively. The effects of ZLDI-8 on metastasis of liver cancer in vivo were investigated in a tail vein injection model. KEY FINDINGS: In the present work, ZLDI-8 significantly inhibited proliferation, migration, invasion and EMT phenotype of highly aggressive MHCC97-H and LM3 cells. Moreover, ZLDI-8 could inhibit the migration and invasion of HepG2 and Bel7402 cells induced by TGF-ß1. ZLDI-8 suppressed the protein expression of interstitial markers and increased that of epithelial markers. Meanwhile, ZLDI-8 decreased the expression of proteins in the Notch signaling pathway. Finally, ZLDI-8 blocks metastasis in the lung metastasis model in vivo. SIGNIFICANCE: ZLDI-8 suppressed the metastasis of hepatocellular carcinoma, which was associated with reversing the EMT process and regulating Notch signaling pathway. The study laid the foundation for the discovery of drugs that reverse EMT to inhibit advanced HCC metastasis.
Subject(s)
ADAM17 Protein/antagonists & inhibitors , Carcinoma, Hepatocellular/drug therapy , Enzyme Inhibitors/pharmacology , Epithelial-Mesenchymal Transition/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Animals , Apoptosis , Carcinoma, Hepatocellular/enzymology , Carcinoma, Hepatocellular/pathology , Cell Proliferation , Humans , In Vitro Techniques , Liver Neoplasms/enzymology , Liver Neoplasms/pathology , Lung Neoplasms/enzymology , Lung Neoplasms/secondary , Mice , Mice, Nude , Signal Transduction , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Advanced treatment of mature landfill leachate from a municipal landfill located in southern China (Jiangmen) was carried out in a full-scale plant using a new process. The combined process has a sequencing batch reactor (SBR) serving as the primary treatment, with polyferric sulfate (PFS) coagulation coupled with a Fenton system as secondary treatment, and a pair of upflow biological aerated filters (UBAFs) in parallel as tertiary treatment. The overall removal efficiency of chemical oxygen demand (COD) in this process was 97.3%, with an effluent COD less than 100 mg/L. Up to 99% ammonia (N-NH3) removal efficiency was achieved in the SBR, with an effluent of less than 3 mg/L, which meets the discharge standard (< or =25 mg/L) with only primary treatment. The total phosphorus (TP) and suspended solids (SS) in the final effluent were reduced to less than 1 mg/L and 10 mg/L, respectively. The experience gained in the operation and maintenance will lead to a more stable performance of this combined process. An economic analysis shows that the overall operating cost of the advanced treatment was $2.70/m(3). This new combination process was proved to be highly compatible and efficient in a small-scale landfill leachate treatment plant and is recommended for small-scale landfill leachate treatment plants.
