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Underlying the body’s healing response is a process by which tissues inflame. Chronic inflammation, if left unchecked, can devastate the body’s tissues, especially in the vascular and nervous systems. Numerous natural products help control the inflammation switch, keeping many maladies at bay.

Blame it on a rush of blood—specifically a rush of immune cells, including proteins and various white blood cells, which flood “injured” tissues, guarding against infection and promoting healing. This is actually a good thing, when the inflammation switch is turned on and off as the injury or infection warrants.

The immune-inflammation response involves numerous cells and chemicals. Mast cells release histamine and cytokines, which signal an alarm. Small vessels release additional immune cells, while macrophages continue their front-line defense against pathogens employing chemicals such as nitric oxide (NO). Neutrophils engulf and destroy bacteria and damaged tissue, and reinforcements arrive as lymphocytes. Platelets initiate clotting and fibrin, and other substances envelope the wound. Other immune chemicals released during inflammation include nuclear factor kappa-B (NFkappaB), tumor necrosis factor alpha (TNFa) and various interleukin (IL).

As with other defense mechanisms, the immune system has a complex network of pathways through which it starts and stops inflammation, as needed. Leukotrienes and prostaglandins are inflammation mediators derived from arachidonic acid (AA) via metabolism in distinct enzymatic pathways. Leukotrienes are produced via the 5-lipoxygenase (5-LOX) pathway, while prostaglandins and thromboxanes are born from the cyclooxygenase pathway (COX). COX-1 is involved in pain and clotting; COX-2 is also involved in pain, but its mechanism is related to inflammation. This is why many pharmaceuticals were designed to disrupt the COX-2 pathway.

Unfortunately, COX-2 inhibitors pose danger to the cardiovascular system via production of vasoconstrictive thromboxanes. COX-1 produces pro-thromboxane compounds—useful in promoting clotting—while COX-2 compounds (prostacyclin) keep thromboxane in check, helping to prevent hypertension and atherothrombosis. By inhibiting COX-2, pharmaceuticals like Vioxx and Celebrex consistently throw off the balance of thromboxane’s waxing and waning. While inhibiting COX-2 pro-inflammatory activity, the drugs also put patients at a higher risk of atherothrombosis and cardiac trouble after even a short period of medication.

For a long time, many people self-treated inflammation and pain using non-steroidal anti-inflammatory drugs (NSAIDs), which act along the COX pathways. “NSAIDs are linked to further joint destruction and also both kidney damage and increased risk of gastric bleeding,” said Chris Meletis, N.D., director of science and research with Trace Minerals Research.

Joelle Lynchuk, new product development specialist with Bioriginal Food & Science Corp., added, “With NSAIDs, for example, gastrointestinal complications have been identified in some people.”

Similar to AA’s activity, EFAs produce eicosanoids (signaling compounds) via various LOX and COX enzymes. The omega-3 chain starts with linolenic acid (LNA), which competes with the omega-6 alpha linoleic acid (ALA) for a certain desaturase enzyme for further metabolism. Downstream, LNA converts to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which tend to generate anti-inflammatory eicosanoids; on the other hand, ALA converts to gamma linoleic acid (GLA) and then primarily AA, which produces eicosanoids that tend to act in a pro-inflammatory manner.

Eicosanoids control functions such as inflammation and immune response, in addition to serving as messengers for the nervous system. Eicosanoids produced by EPA, DHA and AA include various prostaglandins, prostacyclins, leukotrienes and thromboxanes.

Ingredients rich in LNA, such as flaxseed, can help by supplying raw materials to produce the longer-chain EPA and DHA and the resulting anti-inflammatory eicosanoids; but, much attention has turned to fish oil, which inherently supplies rich amounts of EPA and DHA.

In fact, EPA and DHA have proven themselves worthy adversaries of AA-derived pro-inflammatory eicosanoids.¹ EPA and even GLA-derived DGLA compete with AA for LOX and COX enzymes, often resulting in decreased AA eicosanoids. Specifically, EPA inhibits prostaglandin-2 (PG2) and thromboxane.² Douglas MacKay, N.D., research advisor to Nordic Naturals, explained PGE³ is derived from EPA, and higher levels of PGE3 reduce sensitivity to pain, relax blood vessels, increase blood flow, and support the body’s natural anti-inflammatory response. “It is important to remember that both PGE2 and PGE3 are necessary,” he noted. “It is the relative amounts of these competing messenger molecules that will either contribute to, or mitigate, chronic pain and inflammatory syndromes.”

EPA also lowers series-4 leukotrienes from AA, instead raising less active series-5 leukotrienes.³ For its part, DHA does not produce active eicosanoids, but has been shown to decrease AA’s production of inflammatory prostanoids.4 Further, GLA-derived DGLA produces PGE-1 to counteract AA’s PGE2, while EPA offers leukotriene B-5 (LTB5) to counter AA’s LTB⁴, a more inflammatory compound.⁵ EPA- and DHA-rich fish oil has demonstrated similar effects on inflammatory compounds, such as IL-6, C-reactive protein (CRP), TNFa and transforming growth factor beta (TGF-beta).^6,7,8

Such mechanisms by fish oil EFAs have been investigated relative to various inflammatory health problems affecting the skin, eyes, heart and joints. In fact, researchers have credited fish oil supplementation with producing increased amounts of anti-inflammatory cytokines, such as IL-10, as well as regulating gene expression, which suggests the supplement can address dermatitis concerns.⁹

Recently, researchers reported DHA, the principal EFA in the retina, inhibits cytokine-induced adhesion molecule expression in human retinal cells affected by diabetic retinopathy.¹⁰ In subsequent work, these Michigan State University researchers found DHA incorporated into retinal caveolae/lipid rafts—discrete regions within the plasma membrane that coordinate and regulate a variety of signaling processes—affects cholesterol levels and, in turn, cytokine-induced signaling.¹¹

In other areas of eye inflammation, higher omega-3 intake was found to improve age-related macular degeneration (AMD) by increasing DHA levels in rod outer segment membranes, while reducing pro-inflammatory omega-6 activity.¹² University of Michigan researchers linked fish oils to a possible decrease in risk of AMD.¹³

One of the places inflammation has reared its ugly head of late has been in cardiovascular disease (CVD).

“Epidemiological studies have demonstrated increased CVD risk in individuals with elevated serum levels of cytokines such as IL-6 and TNFa; cell adhesion molecules such as intercellular adhesion molecule-1 and P-selectin; and acute-phase proteins such as CRP, fibrinogen and serum amyloid, as well as uric acid and homocysteine,” reported Vladimir Badmaev, Ph.D., vice president of scientific and medical affairs with Sabinsa Corp. “Of the listed serum markers, high-sensitivity CRP measurement has the most potential for clinical use because high levels of hsCRP are associated with a two-fold to threefold increase in the prevalence of myocardial infarction, stroke and peripheral vascular disease, and it predicts incident cardiovascular events in those with and without preexisting CVD.”

Omega-3s and fish oil have been extensively studied for actions in cases of fatal arrhythmias and vascular dysfunction. Italian scientists noted omega-3s have been shown to decrease activation of adhesion molecules and inflammatory cytokines involved in endothelial function and inflammation; they added this gene regulation is related to decreased activation of NFkappaB transcription factors, further suggesting the high number of double bonds in the long chain EFAs may be key to the benefit.¹⁴ They also pointed to the ability of omega-3s to reduce COX-2 gene expression, which affects plaque angiogenesis and rupture.

According to Lynchuk, omega-3 eicosanoids are particularly adept at vascular improvements. “GLA is known to produce prostaglandins series 1, while EPA produces prostaglandins series 3,” she said. “These particular prostaglandin types are known to have anti-inflammatory effects in the body and aid in the dilation of blood vessels as well as the dis-aggregation of platelets.”

Jan Breslow, M.D., head of the Laboratory of Biochemical Genetics and Metabolism at Rockefeller University, New York, reported the evidence from randomized control trials (RCTs) suggests the benefits of EPA and DHA in heart health are due to suppression of fatal arrhythmias, rather than stabilization of atherosclerotic plaques.¹⁵ British scientists from City Hospital Birmingham University of Medicine noted atrial biopsies from patients with arrhythmia have confirmed the presence of inflammation, and indicated fish oil might help by modulating inflammatory pathways.¹⁶

Omega-3s and fish oil have also proven useful in various autoimmune conditions, which are based in inflammation. Fish oil’s modulation of inflammatory compounds provides positive results against juvenile diabetes and psoriasis (defined by the existence of plaques)—both of which feature altered eicosanoid metabolism—as well as by increased AA and its pro-inflammatory metabolites.^17,18 And, fish oil supplementation helped control pro-inflammatory prostaglandins, cytokines and chemokines in rheumatoid arthritis (RA) patients.¹⁹ Crohn’s and lupus patients have also benefited from EPA and DHA trials, which have resulted in mediation of inflammatory cytokines.^20,21

Omega-3 management of eicosanoids is also a benefit for people with cancer, especially as an adjunctive to conventional cancer treatment. Texas A&M researchers studied the connection between chronic inflammation and colorectal cancer, finding fish oil EFAs directly suppress Th1 cell development, favorably altering the balance between Th1 and Th2 cells.²²

Even GLA, with its confusing mechanisms of action in the COX/LOX pathways—it can covert to but also competes with/inhibits AA—has demonstrated benefits to inflammatory diseases, especially in joint health issues. In vivo and in vitro examination of GLA in RA cells resulted in suppressed pro-inflammatory IL-1 and TNFa, suggesting GLA suppresses synovitis in RA patients.²³ GLA is abundant in evening primrose oil and borage oil, both of which have demonstrated activities against inflammatory prostaglandins and leukotrienes, as well as reduction of AA oxygenation byproducts.^24,25 A 2004 trial looked at evening primrose oil, as well as virgin olive oil (omega-9 EFA) and fish oil, relative to stimulating production of inflammatory mediators by leukocytes.²⁶ All three EFA oils reduced pesky inflammatory PGE2.

Inflammation can be a silent marauder in health issues such as heart disease and cancer, but many people with chronic joint pain hear inflammation’s roar. When the immune system thinks cartilage and other joint tissues are foreign or infected, it attacks with the full heat of its inflammatory arsenal, causing heat, pain and pressure. RA is the most common manifestation of this joint misfortune.

The king of joint health supplements, glucosamine alone has eased the pain of RA by way of inhibiting inflammatory compounds and their activities, including iNOS expression.^27,28,29 In a common tandem, glucosamine and chondroitin have decreased inflammation, IL-1 and MMP-9 to a greater degree than chondroitin alone.³⁰

The word arthritis means joint inflammation, and all forms of the disease end up involving some degree of swelling and pain in the joint. Inflammation may not be the chief culprit in osteoarthritis (OA), but European researchers comparing synovial tissue in early- and late-stage OA patients recently reported increased mononuclear cell infiltration and over-expression of mediators of inflammation were seen in early OA, compared to late OA.³¹

Synovial inflammation can be addressed with hyaluronic acid (HA), a primary component of the synovial fluid lubricant found between bones. While injected HA is more studied for decreasing synovial levels of certain inflammatory factors, including VCAM-1 and ICAM-1,³² oral HA supplementation has slowly begun to generate similar results on inflammatory markers.³³

Inflammation in OA appears to be mediated by leukocyte and neutrophil (white blood cell) activities. Combating this, milk protein concentrate (as Microlactin™, from Humanetics Corp.) has been shown to suppress vascular neutrophil activity, while increasing the absolute serum neutrophil count.³⁴ Based on this mechanism, scientists have suggested milk-based supplements can alleviate pain, swelling and dysfunction associated with OA.³⁵

Cetylated fatty acid esters also improve chronic OA symptoms, including swelling. Experts hypothesize this family of fatty acid esters (as Celadrin®, available from Pacific Rainbow) possibly modulates COX-1 and COX-2 activity, and may even inhibit LOX. Studies suggest Celadrin topical cream can reduce pain and joint function in people with OA,³⁶ in addition to improving knee function.³⁷

Lorna Vanderhaeghe, medical journalist and author of Get a Grip on Arthritis and Other Inflammatory Disorders, said Celadrin works similar to, but much more dramatically than, EPA and DHA. “The esterified fatty acids present in Celadrin have pronounced anti-inflammatory effects, such as the inhibition of inflammation in endothelial cells and decreasing the pro-inflammatory effects of other fatty acids like arachidonic acid,” she explained.

Vanderhaeghe noted most people only think about inflammation in regard to arthritis, yet inflammation can be a very serious problem in other parts of the body and should be addressed long before symptoms become apparent.

The botanical joint aid Boswellia serrata works along the LOX pathway to offer anti-inflammatory benefits to people suffering from not only arthritis, but also other inflammatory ailments such as Crohn’s, asthma and colitis.^38,39 A study on boswellia (as WOKVEL, from Verdure Sciences) and the anti-inflammatory drug valdecoxib in arthritis patients found improved knee and joint function from a combination of the two treatments.⁴⁰ Results from the six-month, randomized, prospective, comparative study showed an overall decrease in WOMAC (Western Ontario and McMaster University Osteoarthritis Index) scores from both treatments; but, after treatments ceased, the benefit was far more sustained in the boswellia group, as the drug group scores elevated back to baseline levels. The researchers reported boswellic acid may act on the functional cellular processes involved in the inflammatory response.

A 2006 study also supported boswellia’s anti-inflammatory actions in arthritis, as in vivo and in vitro experiments on microvascular endothelial cells revealed pretreatment with 5-Loxin® (from P.L. Thomas and Laila Nutraceuticals) inhibited TNFa expression and various matrix metalloproteinases (MMPs), which can degrade collagen and elastin.⁴¹ Genetic research has shown 113 of the 522 genes induced by TNFa are sensitive to boswellia (as 5-Loxin), as researchers reported boswellia inhibited TNFa-induced expression of VCAM-1 and ICAM-1 genes, which recruit inflammatory chemicals to the inflamed area.⁴²

Turmeric has also proven itself particularly adept at curtailing LOX and COX-2, as well as the inflammatory activities of NFkappaB, IL-12 and iNOS.^43,44,45

Badmaev explained the yellow pigment from turmeric is essentially a mixture of three related compounds—curcumin, demethoxycurcumin and bisdemethoxycurcumin—collectively termed as curcuminoids, which are well-researched antioxidant and anti-inflammatory agents. “The curcuminoids inhibit the COX-2 enzyme, with curcumin being the strongest inhibitor; [they] are also active against the COX-1 enzyme, with demethoxycurcumin showing the highest activity against COX-1,” he noted. “All curcumins have demonstrated greater inhibition of COX-2 rather than COX-1 enzyme, with no gastrointestinal irritation and discomfort—a side effect typical of the NSAID class of drugs.”

In recent research, curcumin has been effective in quelling inflammation and oxidative damage in cases ranging from Alzheimer’s disease to cancer.^46,47 Badmaev added, “Curcumin inhibits the ‘master switch’ of the inflammatory process, NFkappaB, which in turn inhibits COX-2 and -1, as well as several cancer promoting compounds such as TNFa and inflammation promoting interleukins, e.g. IL-1b and IL-8.”

This mechanism of action is also a key to curcumin’s benefits to chronic colitis patients.48 It also explains turmeric’s results against experimental arthritis, inhibiting joint inflammation and periarticular joint destruction.⁴⁹

Herbs and spices continue to impact inflammation research. Ginger has demonstrated anti-inflammatory properties useful in various conditions. According to Badmaev, the ginger root constituents gingerols and metabolites shogaols are keys to the anti-inflammatory action, inhibiting prostaglandins and leukotrienes. The herb also contains vanillyl ketones, which have been shown to help modulate TNFa production.⁵⁰ In fact, an osteoarthritis (OA) study reported ginger inhibited production of TNFa and COX-2 expression, thereby stifling NFkappaB induction.⁵¹

Another herb found to modulate COX enzymes is French maritime pine bark extract, which curbed COX-1 and -2 in human serum research.⁵² More specifically, the extract influences cell adhesion molecule (CAM) expression in inflammatory conditions. University of California, Berkeley, scientists pretreated human keratinocyte cell lines with pine bark (as Pycnogenol®, from Natural Health Science) and found the extract significantly inhibited IFN-gamma-induced expression of ICAM-1 expression in those cells.⁵³ They concluded this mechanism has potential to help people with inflammatory skin disorders. Other scientists have found Pycnogenol is a good therapy for inflammatory components of systemic lupus and asthma.^54,55

Antioxidants have also made their mark against inflammation. Astaxanthin, a carotenoid commonly sourced from microalgae, has inhibited inflammatory compounds such as NFkappaB, TNFa, NO, PGE2 and IL-1b in a mouse model.⁵⁶ Research has suggested a possible interaction of astaxanthin and the 5-LOX enzyme as key to its benefits in chronic inflammation, such as in CVD, asthma and cancer.⁵⁷ A Japanese animal study concluded the anti-inflammatory effect of 100 mg/kg astaxanthin was as strong as that of 10 mg/kg prednisolone, a corticosteroidal anti-inflammatory drug.⁵⁸ The researchers noted astaxanthin decreased production of NO, PGE2 and TNFa, in addition to reducing iNOS activity. Astaxanthin has also reduced gastric inflammation associated with H. pylori infection, shifting T-lymphocyte response from pro-inflammatory to homeostasis.⁵⁹

Other carotenoids have delivered similar inflammation relief. Lutein, found in high concentration in the retina, has improved inflammation in the eye, helping in AMD and various retinopathies.⁶⁰ Lutein inhibits NO synthase (NOS) and COX-2 expression in challenged retinas in a dose-dependent fashion.⁶¹ While effective and well-explored for eye health, lutein’s actions also help in reducing skin inflammation, especially relative to sun exposure and aging, by decreasing the expression of iNOS at the mRNA and protein levels.^63,64

Eating Away at Inflammation

The gut is particularly susceptible to inflammation, rearing its ugly head as inflammatory bowel diseases (IBDs), including Crohn’s and colitis. Probiotics are the frontline natural defense against IBDs, as they inhibit the expression of inflammatory cytokines in the gut.⁶⁶ Probiotic supplementation is all about the bacteria strain, as many studies have focused on specific probiotic varieties. Lactobacillus farciminis has been shown to help maintain intestinal integrity and modulate inflammatory response in rats with colitis.⁶⁷Lactobacillus GG has proven effective at managing expression of immune and inflammation genes, including TGF-beta, TNFa, cytokines, NOS and ICAM, in the small bowel mucosa of male IBD patients.⁶⁸ And L. paracasei was found to modulate mucosal inflammation in UC rats by reducing colonic cytokines.⁶⁹ In another study, a combination of lactobacilli and bifido taken by patients prior to pouchitis surgery decreased symptoms and post-operative endoscopic inflammation.⁷⁰

Similarly, digestive enzymes, proteolytic enzymes (catalyze proteins)—including papain, bromelain, pancreatin, trypsin and serrata peptidase—exert systemic effects on inflammation. Individually, the pineapple proteinase bromelain has demonstrated potent proteolytic activity in the GI tract, and scientists report bromelain supplementation may affect leukocyte migration and cytokine production.⁷¹ In other research, bromelain supplementation decreased PGE2 and substance P concentrations in rats,⁷² and deceased colonic inflammation in ulcerative colitis patients.⁷³

The anti-inflammatory benefits of enzymes are not limited to the GI tract, however, as studies also indicated benefits to arthritis sufferers,^74,75 and significant inroads to relief from inflammation in CVD.⁷⁶

Justin Marsh, president and CEO of Arthur Andrew Medical, explained circulatory disease is directly related to the purity of the blood and our body’s ability to cleanse it. He noted, “Circulatory or blood cleansing is one of the many features of systemic enzyme supplementation.”

Marsh explained systemic enzymes, specifically nattokinase and serrapeptase in clinical strength, are both proteolytic (protein digesting) and thrombolitc (blood clot digesting). When introduced to the bloodstream, these enzymes quickly digest protein-based substances such as undigested food particles, arterial plaque, scar tissue and certain prostaglandins. An advantage of these natural anti-inflammatory products is the specific electrical charge of these enzymes prevents them from digesting living tissue, according to Marsh. “Papain and bromelain reduce inflammations by digesting certain inflammatory prostaglandins,” he noted. “These enzymes only activate at just above normal body temperature, specifically at the same temperature as inflammation, since this is always higher than the rest of the body.”

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