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Comparison of Anti‐inflammatory Activity of Two Selective Kinase Response Modulators (SKRMs), Rho‐iso‐alpha Acids (RIAA) and Tetrahydro‐iso‐alpha acids (THIAA), in Lipopolysaccharide (LPS) Mediated Inflammation in RAW 264.7 Macrophages
Author(s) -
Desai Anuradha,
Konda Veera Reddy,
Hall Amy,
Bland Jeff,
Tripp Matthew
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a735-d
Subject(s) - kinase , biology , signal transduction , microbiology and biotechnology , pharmacology
Prostaglandin E 2 (PGE 2 ) has been implicated in many inflammatory conditions including osteoarthritis, rheumatoid arthritis, angiogenesis and cancer. Previously we showed that RIAA, a modified hop extract, inhibited NFκB driven COX‐2 expression and PGE 2 formation in LPS stimulated RAW 264.7 macrophages. Consistent with these results, we found RIAA inhibited multiple protein kinases involved in LPS induced inflammation. We coined the term S elective K inase R esponse M odulators ( SKRM) to describe molecules that cooperatively modulate multiple kinases of a given pathway. Shown here, a close analog of RIAA, THIAA was also a potent PGE 2 inhibitor with an IC50 2.5x lower. RIAA and THIAA were analyzed in cell free enzyme assays against select protein kinases. Both analogs inhibited multiple kinases in the MAP kinase and B cell receptor (BCR) inflammatory signal transduction pathways; THIAA showed substantially greater inhibition than RIAA. Combinational experiments revealed that THIAA, like RIAA, synergize with rosemary and oleanolic acid to inhibit PGE 2 formation in LPS stimulated RAW 264.7 cells. Replacing RIAA with THIAA in a proprietary formula with rosemary and oleanolic acid also showed better inhibition of COX‐2, TNFα and nitric oxide production. These results suggest that THIAA based formulas may have significant therapeutic potential for inflammatory conditions (Supported by MetaProteomics, LLC).