The natural ingredients industry is delivering a range of natural anti-inflammatory bioactives to address the underlying cause of most degenerative disease states. Todd Runestad assesses the state of the science
Coronary heart disease, major depression, ageing and cancer are just some of the conditions characterised by an increased level of pro-inflammatory markers and mediators such as cytokines and eicosanoids. With pharmaceutical cox-2 inhibitors down for the count from their side effects, natural bioactives are just now coming into their own. Additional research will continue to tease out the mechanism of action for many natural ingredients, and may well find anti-inflammatory effects at their core.
From commodity ingredients such as vitamins C and E and dietary fibre to proprietary ones like LitoZin rose hip extract or Celadrin, the arsenal of natural products to address the many conditions with inflammation at their core will continue to expand. Consumers will be the better for it. Here is the state of the science behind six leading natural anti-inflammatory ingredients.
About twenty years ago researchers began looking at eicosanoid precursors as contributing mightily toward chronic inflammatory disorders. Prostaglandins, leukotrienes and other eicosanoids are synthesised from the PUFA arachidonic acid. It was suggested that alteration of cellular fatty acids may be a worthwhile approach to controlling inflammation.
Two decades and hundreds of research studies later, it is now known that omega-3 PUFAs, in particular EPA and DHA, modulate the amount and types of eicosanoids such as prostaglandin E2 and leukotriene B4 that are made. In addition, mechanisms to control inflammation other than eicosanoid effects are now seen, including actions on intracellular signalling pathways and gene expression. 1 EPA and DHA are metabolised into anti-inflammatory prostaglandin E1. 2
This is in addition to the relatively simple arithmetic of omega-3s competing against pro-inflammatory omega-6 fatty acids, in particular EPA against arachidonic acid. Increasing the intake of omega-3 fatty acids while decreasing the omega-6 fatty acids in the diet has led to a decrease of nonsteroidal anti-inflammatory drugs used by people with rheumatoid arthritis and asthma.3,4
In short, omega-3 PUFAs have anti-inflammatory effects, and high dietary levels are associated with a lower incidence of inflammatory diseases. As R&D and product developers work closer with brand managers and marketers, this health message — of cutting back on foods and oils laden with omega-6s — ought to resonate throughout the food chain.
The carotenoid pigment astaxanthin has applications in a number of industries, ranging from its biggest use as aquaculture feed to the most lucrative in the nutraceutical and cosmetics fields. The micro-algae Haematococcus pluvialis is the richest source of natural astaxanthin. Carotenoids are known to take part in protecting marine animals against damage from free radicals.5
The cascade of inflammation begins with the release of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha), interleukin-1B (IL-1B), and interleukin-6 (IL-6), as well as inflammatory mediators like nitric oxide and prostaglandin E2, which are synthesized by nitric oxide synthase and the cox enzymes.6
Beyond its pronounced effects as an antioxidant — one study showed astaxanthin to be 550 times stronger than vitamin E in singlet oxygen quenching — astaxanthin is showing benefits as an anti-inflammatory. 7 It appears to work through multiple pathways to combat inflammation throughout the entire body. It does act as a mild cox-1 and cox-2 inhibitor. It also suppresses the other inflammatory agents in the body such as prostaglandin E2, nitric oxide, IL-1B, TNF-alpha and C-reactive protein (CRP).
In one eight-week, double-blind, placebo-controlled human clinical trial, 15 subjects took 12mg/day BioAstin brand astaxanthin and eight took a placebo. CRP levels dropped a significant 20 per cent compared to placebo.8 CRP is one of the acute-phase proteins that increases during systemic inflammation.
A 2003 rat study found that astaxanthin inhibits iNOS enzyme activity, which decreases production of nitric oxide as well as prostaglandin E2 and TNF-alpha.9
Other research shows astaxanthin's utility with a range of inflammatory conditions including rheumatoid arthritis, carpal tunnel syndrome, tendonitis, joint and muscle soreness after exercise, and as an internal sunblock — another inflammatory condition because sunburn is an inflammation of the body's largest organ, the skin. Its effects are typically seen in two to four weeks.
Researchers in one study said astaxanthin's pronounced and widespread effects on inflammation were due to its potent antioxidant effects.6
The standardised extract of the bark of the French maritime pine (Pinus pinaster), Pycnogenol is one of those rare natural bioactives that works on a seemingly endless number of health conditions, from cardiovascular conditions to skin care, diabetes, asthma, allergies, menstrual disorders, varicose veins, cancer and inflammation.
Even more curious is the precise mechanism of action. Some studies show its utility as an antioxidant free radical scavenger. It binds to collagen and elastin. And it helps to vasodilate blood vessels.
What has been demonstrated is that Pycnogenol inhibits key triggers of inflammation. In a 2006 study on seven healthy human volunteers, 200mg/day exerted anti-inflammatory effects, apparently by inhibiting pro-inflammatory gene expression.10 This confirmed an earlier lab study that first postulated Pycnogenol works on a genetic level by suppressing TNF-alpha-induced activation of nuclear factor-kappa B (NF-kappaB) — a master switch known to regulate expression of more than 300 genes that promote an abnormal inflammatory response and can lead to disorders ranging from arthritis to cancer.11 Another small human study from 2006 found evidence that 200mg/day Pycnogenol inhibits pro-inflammatory eicosanoid-generating enzymes.12 A second arm of this study found that a single dose of 300mg significantly inhibited cox-1 and cox-2 enzymes after only 30 minutes.
Even the active principles are a matter of some debate, though chemical identification studies show that Pycnogenol is primarily composed of procyanidins and phenolic acids.13
The pungent yellow spice ground from the root of the Curcuma longa plant, curcumin is found in both turmeric and curry powders. Curcumin shuts down NF-kappaB.
When NF-kappaB is signaled, it releases pro-inflammatory cytokines such as TNF-alpha and IL-6.14 Numerous recent studies, working in a variety of experimental models, demonstrate that curcumin effectively targets NF-kappaB gene products.15
In addition, recent work suggests another anti-inflammatory mechanism of curcumin is that it inhibits prostaglandin E2 formation. It does this by targeting its precursor, IL-1B, as well as the cox-2 enzyme.16
This gene-receptor association was confirmed in another 2005 study, which found that curcumin can block the earliest events in the inflammation cascade by modifying the protein thiols, thereby altering the activity of the affected proteins.17
Dried extracts of the resin of the Boswellia serrata tree have been used since antiquity in India to treat inflammatory conditions. Boswellia contains anti-inflammatory triterpenoids called boswellic acids, or total organic acids.
The boswellic acids reduce inflammation by inhibiting production of pro-inflammatory 5-lipoxygenase (5-LO) chemicals and blocking leukotriene synthesis.18 Leukotrienes are important mediators in inflammatory and allergic processes that are produced from arachidonic acid, an essential fatty acid synthesised in the body via 5-LO.19,20 It has been suggested that the boswellic acids inhibit 5-LO by either directly interacting with 5-LO or by interacting with the 5-LO-activating protein.18 It appears the boswellic acids are unique in their inhibition of 5-LO as well as another pro-inflammatory enzyme, human leukocyte elastase.21
In one study of 30 patients with inflammatory bowel disease (chronic colitis), 20 were given boswellia extract 300mg three times a week for six weeks, and the other 10 were given boswellia, 1g three times a day. Of the 20 treated with 300mg boswellia, 14 went into remission, as did four of the 10 treated with 1g boswellia. The inflammatory process in colitis is associated with increased formation of leukotrienes. The key enzyme for leukotriene biosynthesis is 5-LO, which was found to be inhibited by boswellia. 22 A randomised, double-blind, placebo-controlled crossover study was conducted to assess the efficacy, safety and tolerability of Boswellia serrata extract in 30 patients with osteoarthritis of the knee for eight weeks. All patients receiving boswellia reported decreased knee pain, increased knee flexion and increased walking distance. The frequency of swelling in the knee joint was decreased. Boswellia serrata extract was well tolerated by the subjects except for minor gastrointestinal symptoms. 23
When the body's immune system gets stimulated into action, NF-kappaB activates genes that turn on production of the cox-2 enzyme, one of the body's inflammatory agents. In 2000, when conjugated linoleic acid (CLA) was still not often discussed in the functional ingredients world, researchers at the American Chemical Society's national meeting presented a unique animal study. They found that the more CLA they fed to lab animals or in vitro, the more resistant they became at producing cox-2 and other inflammatory agents. What's more, the CLA not only decreased the production of cox-2 but it also decreased the activity of the cox-2 that was produced.24
In a 2004 cell study, other researchers found that CLA reduced the ability of NF-kappaB to attach to DNA, which in turn reduced gene activity related to inflammation. By reducing NF-kappaB activity, CLA decreased the pro-inflammatory activity of the cox-2 enzyme and prostaglandin E2. CLA also reduced activity of nitric oxide, which also can have pro-inflammatory effects. The 2004 study was the first report to show that CLA has anti-inflammatory properties by reducing the activity of NF-kappaB.25
The Chemical Society researchers in 2005 followed up with an animal study that confirmed their earlier work. They examined the effects of 10t,12c-CLA and 9c,11t-CLA on cox-2 expression and prostaglandin E2 (PGE2) production. The cox-2 expression level was inhibited 80 per cent by 10t, 12c-CLA compared to only 26 per cent by 9c,11t-CLA in vitro. PGE2 production was decreased from 5.39 to 1.12 by 10t,12c-CLA and from 5.7 to 4.5 by 9c,11t-CLA. In a separate arm, mice fed 10t,12c-CLA but not 9c,11t-CLA were found to have a 34 per cent decrease in cox-2 and a 43 per cent reduction of PGE2 release in the lung. They concluded that reduced cox-2 levels were attributable to the CLA inhibiting the NF-kappaB pathway.26
An important note is that the CLA researched and marketed for weight management is generally a 50:50 mixture of cis-9, trans-11 with trans-10, cis-12, whereas the isomer found to have better efficacy against inflammation is trans-10, cis-12. However, trans-10, cis-12 has shown to increase insulin resistance in susceptible people, whereas the combination does not appear to have that effect.27,28
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