labdane and Inflammation

The rhizomes of Hedychium coronarium have been used for the treatment of inflammation, skin diseases, headache, and sharp pain due to rheumatism in traditional medicine. From this plant, two new labdanes, 15-methoxylabda-8(17),11E,13-trien-16,15-olide (1) and 16-methoxylabda-8(17),11E,13-trien-15,16-olide (3), named hedycoronens A and B, as well as four known, labda-8(17),11,13-trien-16,15-olide (2), 16-hydroxylabda-8(17),11,13-trien-15,16-olide (4), coronarin A (5), and corronarin E (6) were isolated. Their chemical structures were elucidated by mass, 1D- and 2D-nuclear magnetic resonance (NMR) spectroscopy. They were evaluated for inhibitory effects on the lipopolysaccharide (LPS)-stimulated production of pro-inflammatory cytokines in bone marrow-derived dendritic cells. Among of them, compounds 1-3 were potent inhibitors of LPS-stimulated interleukin-6 (IL-6) and IL-12 p40, with IC(50) ranging from 4.1±0.2 to 9.1±0.3 μM. Compounds 1 and 3 showed moderate inhibitory activity on the tumor necrosis factor-α (TNF-α) production with IC(50) values of 46.0±1.3 and 12.7±0.3 μM. The remains of compounds showed inactivity. These results warrant further studies concerning the potential anti-inflammatory benefits of labdane-diterpenes from H. coronarium.

Topics: Animals; Bone Marrow Cells; Cytokines; Dendritic Cells; Diterpenes; Down-Regulation; Inflammation; Inhibitory Concentration 50; Lipopolysaccharides; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C57BL; Molecular Structure; Rhizome; Zingiberaceae

A series of 11 labdane-type diterpenoids (1-11) with various patterns of substitution were tested for potential anti-inflammatory activity. Of these compounds, 4 and 11 were selected to evaluate their influence on targets relevant to the regulation of the inflammatory response. These diterpenoids reduced the production of nitric oxide (NO), prostaglandin E2, and tumor necrosis factor-alpha in LPS-activated RAW 264.7 macrophages, with IC50 in the range 1-10 microM. Inhibition of these inflammatory mediators was related to inhibition of the expression of nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) at the transcriptional level, as determined by western-blot and RT-PCR. Examination of the effects of these diterpenoids on nuclear factor kappaB signaling showed that both compounds inhibit the phosphorylation of IkappaBalpha and IkappaBbeta, preventing their degradation and the nuclear translocation of the NF-kappaB p65 subunit. Inhibition of IKK activity was also observed. These derivatives displayed significant anti-inflammatory activity in vivo, suppressing mouse ear edema induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) and inhibiting myeloperoxidase activity, an index of neutrophil infiltration. The anti-inflammatory effects of these labdane diterpenoids, together with their low cell toxicity, suggest potential therapeutic applications in the regulation of the inflammatory response.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Blotting, Western; Cell Line; Cell Survival; Cyclooxygenase 2; Diterpenes; DNA-Binding Proteins; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Inflammation; Liver X Receptors; Macrophages; MAP Kinase Kinase Kinases; Mice; Molecular Structure; Nitric Oxide; Nitric Oxide Synthase Type II; Orphan Nuclear Receptors; Phosphorylation; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription Factor RelA; Transfection