Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Apoptosis / drug effects
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Blotting, Western
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Cell Line
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Cell Survival / drug effects
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Diterpenes / chemistry
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Diterpenes / pharmacology*
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Diterpenes / therapeutic use
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Dose-Response Relationship, Drug
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Flow Cytometry
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Humans
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Inflammation / metabolism
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Inflammation / pathology
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Inflammation / prevention & control*
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Liver X Receptors
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MAP Kinase Kinase Kinases / metabolism
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Macrophages / cytology
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Macrophages / drug effects*
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Macrophages / metabolism
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Mice
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Molecular Structure
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Nitric Oxide / biosynthesis
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Orphan Nuclear Receptors
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Phosphorylation / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factor RelA / metabolism
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Transfection
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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DNA-Binding Proteins
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Diterpenes
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Liver X Receptors
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Orphan Nuclear Receptors
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Transcription Factor RelA
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labdane
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Nitric Oxide
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Nitric Oxide Synthase Type II
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Cyclooxygenase 2
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MAP Kinase Kinase Kinases