Hyperuricemic nephropathy (HN) is characterized by increased serum uric acid levels that incite renal inflammation. While omega-3 polyunsaturated fatty acids (PUFAs) are known for their anti-inflammatory properties, their impact on HN remains unclear. This study explored the effects of omega-3 PUFAs, specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), on HN. Using a mouse model induced by adenine and potassium oxonate, we treated HN mice with DHA, EPA, or both for four weeks. The results showed that omega-3 PUFAs significantly reduced serum uric acid levels and improved kidney function, with DHA, EPA, and their combination showing similar efficacy. Transcriptome sequencing and further analysis revealed that these fatty acids alleviate renal pyroptosis by reducing key markers such as NOD-like receptor pyrin containing 3 (NLRP3), cleaved gasdermin-D, caspase-1, and interleukin-1β. To further investigate the underlying mechanism, we focused on G-protein coupled receptor 120 (GPR120), a receptor activated by DHA. The use of a GPR120 antagonist (AH7614) partially blocked DHA's effects, while the agonist (TUG891) mimicked its anti-pyroptotic actions. Co-immunoprecipitation assays showed that DHA activates GPR120, leading to its internalization and interaction with β-arrestin2, ultimately inhibiting NLRP3 inflammasome formation and reducing inflammation. Overall, omega-3 PUFAs, particularly through GPR120 activation, appear to protect against renal inflammation in HN by modulating the NLRP3/caspase-1/GSDMD pathway.

2024-10-01·Biochemical and Biophysical Research Communications

FFAR-mediated signaling drives migration of pancreatic cancer cells in hypoxic fibroblast co-cultures

Article

作者: Yashiro, Narumi ; Kusumoto, Yuka ; Yamamoto, Mao ; Takai, Miwa ; Tsujiuchi, Toshifumi ; Tamura, Moemi ; Taniguchi, Anri ; Nagano, Shion

The tumor microenvironment (TME) comprises cancer and non-cancerous stromal cells, including fibroblasts. Free fatty acids (FFAs) regulate various biological responses by binding to G protein-coupled FFA receptors (FFARs). In this study, we examined the impact of FFAR1 and FFAR4 on the cell migration of pancreatic cancer PANC-1 cells co-cultured with 3T3 fibroblast cells under hypoxic conditions. PANC-1 cells cultured at 1 % O₂ exhibited elevated FFAR1 expression and decreased FFAR4 expression compared to those at 21 % O₂. Cell migration of PANC-1 cells was reduced under 1 % O₂ conditions. FFAR1 knockdown enhanced PANC-1 cell migration, whereas FFAR4 knockdown inhibited it. Co-culture of PANC-1 cells with 3T3 cells at 1 % O₂ significantly increased FFAR4 expression, while FFAR1 expression remained unchanged. To evaluate the effects of FFAR1 and FFAR4 on PANC-1 cell migration in co-culture with 3T3 cells, we conducted a wound healing assay using the Culture-Insert 2 Well. PANC-1 and 3T3 cells were individually seeded into the two wells and incubated at both 21 % and 1 % O₂ for 13 h. The cell migration of PANC-1 cells co-cultured with 3T3 cells at 1 % O₂ was notably higher compared to 21 % O₂. TUG-770 reduced and TUG-891 enhanced the cell migration of PANC-1 cells co-cultured with 3T3 cells under both 21 % and 1 % O₂ conditions. These findings suggest that FFAR1 and FFAR4 play important roles in regulating the cell migration of PANC-1 cells co-cultured with 3T3 cells under hypoxic conditions.

2024-08-01·Cardiovascular Drugs and Therapy

The Influence of the FFAR4 Agonist TUG-891 on Liver Steatosis in ApoE-Knockout Mice

Article

作者: Wiśniewska, Anna ; Ulatowska-Białas, Magdalena ; Olszanecki, Rafał ; Kuś, Katarzyna ; Czepiel, Klaudia ; Stachyra, Kamila ; Kiepura, Anna ; Suski, Maciej

AbstractBackgroundNonalcoholic fatty liver disease (NAFLD) constitutes an independent risk factor for the development of coronary heart disease. Low-grade inflammation has been shown to play an important role in the development of atherosclerosis and NAFLD. Free fatty acid receptor 4 (FFAR4/GPR120), which is involved in damping inflammatory reactions, may represent a promising target for the treatment of inflammatory diseases. Our objective was to evaluate the effect of TUG-891, the synthetic agonist of FFAR4/GPR120, on fatty liver in vivo.MethodsThe effect of TUG-891 on fatty liver was investigated in apoE−/− mice fed a high-fat diet (HFD), using microscopic, biochemical, molecular, and proteomic methods.ResultsTreatment with TUG-891 inhibited the progression of liver steatosis in apoE−/− mice, as evidenced by histological analysis, and reduced the accumulation of TG in the liver. This action was associated with a decrease in plasma AST levels. TUG-891 decreased the expression of liver genes and proteins involved in de novo lipogenesis (Srebp-1c, Fasn and Scd1) and decreased the expression of genes related to oxidation and uptake (Acox1, Ehhadh, Cd36, Fabp1). Furthermore, TUG-891 modified the levels of selected factors related to glucose metabolism (decreased Glut2, Pdk4 and Pklr, and increased G6pdx).ConclusionPharmacological stimulation of FFAR4 may represent a promising lead in the search for drugs that inhibit NAFLD.Graphical abstract

100 项与 TUG-891 相关的药物交易

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