Abstract
Inotilone was isolated from Phellinus linteus. The anti-inflammatory effects of inotilone were studied by using lipopolysaccharide (LPS)-stimulated mouse macrophage RAW264.7 cells and λ-carrageenan (Carr)-induced hind mouse paw edema model. Inotilone was tested for its ability to reduce nitric oxide (NO) production, and the inducible nitric oxide synthase (iNOS) expression. Inotilone was tested in the inhibitor of mitogen-activated protein kinase (MAPK) [extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal kinase (JNK), p38], and nuclear factor-κB (NF-κB), matrix-metalloproteinase (MMP)-9 protein expressions in LPS-stimulated RAW264.7 cells. When RAW264.7 macrophages were treated with inotilone together with LPS, a significant concentration-dependent inhibition of NO production was detected. Western blotting revealed that inotilone blocked the protein expression of iNOS, NF-κB, and MMP-9 in LPS-stimulated RAW264.7 macrophages, significantly. Inotilone also inhibited LPS-induced ERK, JNK, and p38 phosphorylation. In in vivo tests, inotilone decreased the paw edema at the 4th and the 5th h after Carr administration, and it increased the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx). We also demonstrated that inotilone significantly attenuated the malondialdehyde (MDA) level in the edema paw at the 5th h after Carr injection. Inotilone decreased the NO and tumor necrosis factor (TNF-α) levels on serum at the 5th h after Carr injection. Western blotting revealed that inotilone decreased Carr-induced iNOS, cyclooxygenase-2 (COX-2), NF-κB, and MMP-9 expressions at the 5th h in the edema paw. An intraperitoneal (i.p.) injection treatment with inotilone diminished neutrophil infiltration into sites of inflammation, as did indomethacin (Indo). The anti-inflammatory activities of inotilone might be related to decrease the levels of MDA, iNOS, COX-2, NF-κB, and MMP-9 and increase the activities of CAT, SOD, and GPx in the paw edema through the suppression of TNF-α and NO. This study presents the potential utilization of inotilone, as a lead for the development of anti-inflammatory drugs.
Highlights
Inflammation, a physiological response to infection or injury, plays a critical role in chronic diseases, including asthma, rheumatoid arthritis, atherosclerosis, and Alzheimer’s disease, and it plays a role in various human cancers [1]
The chemical structure of the purified yellow powder was elucidated by NMR spectroscopy and mass spectrometry studies and it was identified as inotilone (Fig. 1A) [9]
There was either a significant decrease in the nitrite production of group treated with 3.12 mM inotilone (p,0.05) or very or highly significant decrease of groups treated respectively with 6.25, 12.5 and 25 mM of inotilone when compared with the LPS-alone group (p,0.01 or p,0.001)
Summary
Inflammation, a physiological response to infection or injury, plays a critical role in chronic diseases, including asthma, rheumatoid arthritis, atherosclerosis, and Alzheimer’s disease, and it plays a role in various human cancers [1]. One of the major factors involved in the inflammation response is induced by lipopolysaccharide (LPS) and various inflammatory mediator cytokines such as interferon, interleukins, and tumor necrosis factor (TNF)-a [3]. Many researchers reported that inflammatory effect induced by lcarrageenan (Carr) could be associated with free radical formation. Prostaglandin and NO will be released when administrating with Carr for 1–5 h. The edema effect was raised to maximum at the 3th h and its malondialdehyde (MDA) production was due to free radical attack plasma membrane [4]
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