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Farnesoid X Receptor Regulation of the NLRP3 Inflammasome Underlies Cholestasis-Associated Sepsis.

Cell Metab. 2017; 
Hao H, Cao L, Jiang C, Che Y, Zhang S, Takahashi S, Wang G, Gonzalez FJ.
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Peptide Synthesis , 2009) N/A Chemicals, Peptides, and Recombinant Proteins Lipopolysaccharides from Escherichia coli 0111:B4 Sigma-Aldrich Cat#L2630 Phorbol 12-myristate 13-acetate Sigma-Aldrich Cat#P8139; CAS:16561-29-8 Protease inhibitor cocktail Sigma-Aldrich Cat#P8340 Protein A Agarose Novex Cat#15918-014 U-13C6-Glucose Cambridge Isotope Laboratories Cat#CLM-1396-1; CAS:110187-42-3 Deoxycholic acid Sigma-Aldrich Cat#D2510; CAS:83-44-3 Chenodeoxycholic acid Sigma-Aldrich Cat#C9377; CAS:474-25-9 Sodium taurodeoxycholate hydrate Sigma-Aldrich Cat#T0875; CAS:207737-97-1 Sodium taurochenodeoxycholate Sigma-Aldrich Cat#T6260; CAS:6009-98-9 2 0 ,7’-Dichlorofluorescin diacetate Sigma-Aldrich Cat#D6883; CAS:4091-99-0 Pluronic F-127 Sigma-Aldrich Cat#P2443; CAS:9003-11-6 BAPTA-AM Sigma-Aldrich Cat#A1076; CAS:126150-97-8 Cholestyramine resin Sigma-Aldrich Cat#C4650; CAS:11041-12-6 Cholic acid Sigma-Aldrich Cat#C1129; CAS:81-25-4 Obeticholic acid Selleck Cat#S7660; CAS:459789-99-2 GW4064 Selleck Cat#S2782; CAS:278779-30-9 Taurocholic acid sodium salt hydrate Sigma-Aldrich Cat#T4009; CAS:345909-26-4 Adenosine 5 hydrate 0 -triphosphate disodium salt Sigma-Aldrich Cat#A7699; CAS:34369-07-8 Ionomycin, Free Acid Merck Millipore Cat#407950; CAS:56092-81-0 Tauro b-muricholic acid sodium salt Steraloids Cat#C1899-000 Recombinant Human M-CSF GenScript Cat#Z02914-100 Sodium deoxycholate Sigma-Aldrich Cat#30970; CAS:302-95-4 TAK-242 (Resatorvid) Chemleader Biomedical CAS:243984-11-4 Thioglycollate Medium, Brewer Modified BD, Difco Cat#211716 Mitotracker Red CMXRos Cell Signaling Technology Cat#9082P Normal rabbit IgG Santa Cruz Cat#SC-2027 Critical Commercial Assays Fluo-4 NW Calcium Assay Kit Molecular Probes Cat#F36206 Human IL-1b ELISA Kit ExCell Bio Cat#EH001-96 (Continued on next page) e1 Cell Metabolism 25, 856–867.... Cells were differentiated into macrophages by 100 U/ml recombinant human M-CSF (Z02914-100, GenScript) for 7 days. Get A Quote

摘要

Cholestasis is a common complication of sepsis, and the increased plasma levels of bile acids are predictive of sepsis-associated mortality. However, the exact mechanism by which cholestasis aggravates sepsis development remains elusive. Here, we show that bile acids are danger-associated molecular patterns (DAMPs) that can activate both signal 1 and 2 of the NLRP3 inflammasome in inflammatory macrophages. Mechanistically, bile acids induce a prolonged calcium influx and activate the NLRP3 inflammasome synergistically with ATP. Experimental cholestasis sensitizes, while cholestyramine, a bile acid sequestrant, protects mice from LPS-induced sepsis. FXR negatively regulates the NLRP3 inflammasome via physical i... More

关键词

NLRP3 inflammasome; bile acids; cholestasis; damage-associated molecular patterns; farnesoid X receptor; protein-protein interaction; sepsis