Journal
PHARMACOLOGICAL RESEARCH
Volume 152, Issue -, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2019.104581
Keywords
c-Myc; HIF-1a; Inflammation; Rheumatoid arthritis; Tylophorine; Warburg effect
Categories
Funding
- National Health Research Institutes, Taiwan, R.O.C.
- Ministry of Science and Technology, Taiwan, R.O.C. [MOST 106-2320-B-400-009-MY3, MOST 108-2811-B-400-511]
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Interruption of the Warburg effect-the observation that un-stimulated macrophages reprogram their core metabolism from oxidative phosphorylation toward aerobic glycolysis to become pro-inflammatory M1 macrophages upon stimulation-is an emerging strategy for the treatment of cancer and anti-inflammatory diseases such as rheumatoid arthritis. We studied this process with view to the discovery of novel therapeutics, and found that tylophorine-based compounds targeted a ribonucleoprotein complex containing caprin-1 and mRNAs of c-Myc and HIF-1 alpha in LPS/IFN-gamma stimulated Raw264.7 cells, diminished the protein levels of c-Myc and HIF-1 alpha, and consequently downregulated their targeted genes that are associated with the Warburg effect, as well as the pro-inflammatory iNOS and COX2. The tylophorine-based compound DBQ 33b significantly meliorated the severity and incidence of type II collagen-monoclonal antibody-induced rheumatoid arthritis and diminished gene expressions of c-Myc, HIF-1 alpha, iNOS, COX2, TNF alpha, and IL-17A in vivo. Moreover, pharmacological inhibition of either c-Myc or HIF-1 alpha exhibited similar effects as the tylophorine-based compound DBQ 33b, even though inhibition of c-Myc reversed the induction of iNOS and COX2 in LPS/IFN-gamma stimulated Raw264.7 cells to a lesser degree. Therefore, simultaneous inhibition of both c-Myc and HIF-1 alpha is efficacious for anti-inflammation in vitro and in vivo and merits further study.
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