Inflammation, a complex process, involving numerous mediators of cellular and plasma origins, is considered to be a critical factor in many human diseases and conditions, including obesity, cardiovascular diseases, diabetes, aging, and cancers. Inotilone, a secondary metabolite recently found in the dietary Inonotus mushroom, has been reported as a potent inflammatory inhibitor in test tube. However, its inhibitory effect at cellular level as well as in animal model remain unclear. The anti-inflammatory effects of inotilone were investigated in vitro using lipopolysaccharide (LPS)-stimulated murine macrophage. Inotilone was shown to inhibit nitric oxide (NO) and prostaglandin E2 (PGE2) production through modulating inducible nitric oxide synthase (iNOS) expression and cyclooxygenase-2 (COX-2) enzyme activity, respectively. It is also found that inotilone can only suppressed the expression of iNOS but not COX-2. This divergence may origin from the differential effect of inotilone on transcription factors, nuclear factor-kappaB (NF-kappaB) and CCAAT enhancer-binding protein (C/EBP). However, this differential effect was not found in the in vivo study employing 12- O-tetradecanoylphorbol-13-acetate (TPA)-treated mouse skin. This finding suggested that the effects of inotilone on C/EBPbeta expression may be cell type- or stimuli-specific. The inhibitory effects of inotilone were also observed on the activation of phosphatidylinositol 3-kinase/Akt (PI3K/Akt), extracellular signal-regulated protein kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signaling pathways both in vitro and in vivo. Furthermore, the ability of inotilone to prevent inflammation-associated tumorigenesis was also evaluated using a classical two-stage mouse skin carcinogenesis model. After initiation of 7,12-dimethylbenz[a]nthracene (DMBA), applying inotilone topically before each TPA treatment was found to reduce the incidence and multiplicity of papillomas at 20th week. Taken together, the results suggest that inotilone has potential to be developed into an effective chemopreventive agent for the treatment of a variety of inflammatory diseases, especially the prevention and treatment of epithelial skin cancer.
Number Of Pages: 88
Published: 1st October 2011
Dimensions (cm): 25.4 x 20.3 x 0.6
Weight (kg): 0.191