Phytochemicals as Modulators of Signaling in Inflammation |
239 |
N
O
O
O
Figure 12.6 Piperine.
O OH
HO
O
Figure 12.7 Gingerol.
12.5.6Gingerol
Gingerol is another phytochemical, known to inhibit NF-kB-mediated inflammation (Figure 12.7). It is the pungent constituent of ginger. Gingerol has also been found to inhibit IkB kinase activity.32 In this study, macrophages (RAW 264 cells) were stimulated by LPS, which activated the cells and initiated an inflammatory cascade with NF-kB stimulation. It was found that an 80-mM concentration of gingerol can inhibit 70% of the NF-kB activation by LPS. The bioavailability of gingerol is not high, with peak concentrations of metabolites being 0.1 mg/ml to 1.7 mg/ml in human plasma after a 1 g dose.33
12.5.7Curcumin
Curcumin is the main ingredient found in the curry spice tumeric (Figure 12.8). Curcumin has been found to inhibit NF-kB. One study found that 10–20 mM amounts of curcumin can inhibit NF-kB in MyD88 and RAW264.7 cells activated by LPS.34 This was shown to occur through blocking the dimerization of TLR-4 and by inhibiting IkB kinase. Curcumin inhibits numerous inflammatory pathways upstream and downstream of NF-kB, such as mitogenic pathways, AP-1
transcription and expression of COX-2, anti-apoptotic proteins and growth factors.35,36 Curcumin was confirmed to inhibit IkB kinase activity.36 The con-
centration needed to inhibit NF-kB from IL-1 activation in U937 cells was 50 mM. However, curcumin has very poor bioavailability. The concentrations found in human plasma were 0.4–3.6 mM after the ingestion of 4–8 g of
240 Chapter 12
curcumin.37 The bioavailability is greatly improved with the addition of piperine.
12.5.8Guggulsterone
Guggulsterone has been used for centuries in Ayurvedic medicine for its anti-inflammatory activity in arthritis, cardiovascular disease, obesity and bone fractures38 (Figure 12.9). It is found in the guggul plant in northern India. Guggulsterone has been found to inhibit NF-kB activation by RANKL (TNFa cytokine family) in RAW-269.7 cells.38 This study demonstrated that guggulsterone was a direct inhibitor of IkB kinase. The doses found to inhibit NF-kB entirely were 10 mM in this cell system. Another study similarly found that NF-kB activation by IL- 1b could also be abolished at 10 mM concentrations of guggulsterone in fibroblastlike synoviocytes, a cell model for arthritis,39 by blocking the degradation of IkBa.
It is known that mM amounts of guggulsterone inhibit inflammation in vivo, and guggulsterone has numerous beneficial e ects in vivo,40 such as in the cardiovascular system in humans. However, there are few data as to the bioavailability of this agent.
O |
OH |
O |
O |
HO |
OH |
Figure 12.8 Curcumin.
H 
O
H H
O
H 
O
H H
O
Figure 12.9 E- and Z-Guggulsterone.
Phytochemicals as Modulators of Signaling in Inflammation |
241 |
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.