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Phytochemicals as Modulators of Signaling in Inflammation |
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12.6Agonists of PPARc that Reciprocally Inhibit NF-jB
In general, many of the natural agonists of PPARg are analogs of fatty acids, lipid molecules, cholesterol and other terpenoids.41 Terpenoids can be found in eucalyptus, cinnamon, cloves, ginger, citral, menthol, camphor and many plants. The following are a few examples of common natural product PPARg agonists.
12.6.1Phytanic Acid
Phytanic acid is an example of a terpenoid derived from chlorophyll in plant extracts. It is a derivative of the phytol side chain of chlorophyll. In one study, phytanic acid (Figure 12.10) was able to stimulate PPARg activation in hepatocytes in a dose-dependent manner from 10–100 mM, in doses comparable to thiazolidinedione derivatives.42 Some of the original studies on phytanic acid demonstrated that human plasma contains mM levels of this compound.43
12.6.2Dehydroabietic Acid
Dehydroabietic acid is a diterpenoid found in pine tree resins. It is also a potent PPARg agonist.44 In this study, dehydroabietic acid (Figure 12.11) was found to inhibit the production of MCP-1, TNFa and NO in LPS-activated macrophages at a 40 mM concentration. However, no bioavailability data or toxicity studies are yet available for this agent.
O
OH
Figure 12.10 Phytanic acid.
H
HO O
Figure 12.11 Dehydroabietic acid.
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12.6.3Geraniol
Geraniol, farnesol and geranylgeraniol are another class of PPARg agonists that stimulate PPARg.45 The geraniols (Figure 12.12) are found in rose oil, palmarosa oil, citronella oil and in geranium, lemon and other essential oils. Geraniols have been documented to inhibit LPS-induced stimulation of COX-2, iNOS and NF-kB in mM concentrations.46 However, bioavailability data are unavailable for geraniol at this time.
12.7 Agonists of LXR that Reciprocally Inhibit NF-jB
Many of the natural product agonists of LXR resemble cholesterol-like molecules such as plant sterols. Many cholesterol intermediates are also agonists for LXR. The following are a few examples of common natural product LXR agonists. However, there are few human bioavailability data available.
12.7.1Stigmasterol
Stigmasterol is a plant-derived sterol and a potent agonist of LXR (Figure 12.13). It is found in lipid-rich areas of plants or oils of soybean, calabar bean, rape seed and Chinese herbs such as ginseng. The addition of stigmasterol to CHO-7 cells was able to increase expression of many genes downstream of LXR, such as the ATP binding cassette transporter (ABCA1), which promotes the e ux of cholesterol.47
Stigmasterol is also known for its anti-inflammatory activity.48 In osteoarthritis cell culture models stimulated by IL-1, stigmasterol in a 20 mg/ml concentration was able to inhibit NF-kB-induced expression of IL-6 and MMP-3.
OH
Figure 12.12 Geraniol.
H
H
H H
HO
Figure 12.13 Stigmasterol.
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12.7.2b-Sitosterol
b-sitosterol is another plant-derived sterol found in black cumin seed, pecans, saw palmetto, avocados, pumpkin seed, cashew, rice brain, corn oil and soybeans. It is considered to be a potent LXR agonist and anti-inflammatory agent49 (Figure 12.14). In cell culture models of osteoarthritis, b-sitosterol was able to decrease proinflammatory pathways.
12.7.3Ergosterol
Ergosterol is another LXR agonist, found in fungal membranes, and is considered to be a very potent LXR agonist. In fact, some of the ergosterol derivatives found in nature activate LXR (Figure 12.15) much more e ectively than the known cholesterol agonists.50 Ergosterol has been found to have antiinflammatory properties as well.51
12.8 Conclusion
Numerous phytochemicals and natural products can intervene in signal transduction mechanisms to attenuate NF-kB-mediated inflammatory
H
H
H H
HO
Figure 12.14 b-Sitosterol.
H
H H
HO
Figure 12.15 Ergosterol.
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pathways. However, much remains to be elucidated regarding the pharmacology, toxicology and peak concentrations of these natural products that can be achieved in human plasma. Transcriptional regulators in inflammation present a powerful strategy to target chronic inflammatory diseases. It may be that the life-long prophylactic use of these natural ligands may preempt the use of stronger synthetic derivatives later on.
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