ABSTRACT
Artemether (ATM) is a natural antimalarial drug that can also regulate glucose and lipid metabolism. However, little is known regarding its pharmacological action in metabolic dysfunction-associated fatty liver disease (MAFLD), and the underlying mechanisms remain undetermined. The aim of this study was to explore the therapeutic effects of ATM against hepatic steatosis and the possible mechanisms. ATM significantly decreased blood glucose levels, improved glucose tolerance, reduced inflammatory response, and alleviated hepatic steatosis in the ob/ob mouse model as well as the high-fat diet-fed mice. ATM also inhibited lipid accumulation in murine hepatocytes in vitro. Using RNA sequencing, miR-34a-5p and peroxisome proliferator-activated receptor-α (PPARα) were identified as important regulators during ATM treatment. ATM administration downregulated miR-34a-5p expression and miR-34a-5p abrogated the inhibitory effects of ATM on PO (palmitate + oleate)-induced lipid accumulation as well as triglycerides levels in murine hepatocytes. Furthermore, the expression of PPARα, a target gene of miR-34a-5p, was upregulated by ATM and PPARα inhibitor MK-886 abolished the positive effect of ATM. Consequently, PPARα agonist fenofibrate reversed the decreased mitochondrial fatty acid ß-oxidation induced by miR-34a-5p mimics after ATM treatment, thereby leading to attenuation of intracellular lipid accumulation. Taken together, ATM is a promising therapeutic agent against MAFLD that reduces lipid deposition by suppressing miR-34a-5p and upregulating PPARα.
Subject(s)
MicroRNAs , Non-alcoholic Fatty Liver Disease , Mice , Animals , PPAR alpha/genetics , PPAR alpha/metabolism , Artemether/pharmacology , Artemether/metabolism , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Lipid Metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Lipids , Glucose/metabolism , Liver , Mice, Inbred C57BLABSTRACT
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) have become increasingly recognized as facilitators of tumor development. However, the role of MDSCs in papillary thyroid carcinoma (PTC) progression has not been clearly explored. OBJECTIVE: We aimed to evaluate the levels and function of circulating MDSCs in PTC. METHODS: The proportion of circulating polymorphonuclear (PMN)-MDSCs and mononuclear-MDSCs from patients with PTC or benign thyroid nodules and healthy controls was measured using flow cytometry. For immunosuppressive activity analysis, sorted circulating MDSCs were cocultured with CD3/CD28-costimulated T lymphocytes and the proliferation of T cells was determined. PTC cell lines (TPC-1 and BC-PAP) were cocultured with PMN-MDSCs, and the effects on cell migration, invasion, proliferation, and apoptosis were evaluated. The differential expressed microribonucleic acids (RNAs) and messenger RNAs and their function were also explored in TPC-1 cells cocultured with or without PMN-MDSCs. RESULTS: PMN-MDSCs were increased in peripheral blood mononuclear cells of patients with PTC. Circulating PMN-MDSCs displayed strong T cell suppressive activity. PTC cells demonstrated enhanced invasive capabilities in vitro and in vivo when cocultured with sorted PMN-MDSCs. PMN-MDSCs decreased expression of miR-486-3p and activated nuclear factor kappa B2 (NF-κB2), a direct target of miR-486-3p. Rescue of miR-486-3p diminished the cell migration and invasion induced by PMN-MDSCs. CONCLUSION: Collectively, our work indicates that circulating PMN-MDSCs promote PTC progression. By suppressing miR-486-3p, PMN-MDSCs promote the activity of the NF-κB2 signaling pathway, resulting in accelerated invasion of PTC cells, which may provide new therapeutic strategies for treatment of thyroid cancer.
