Inflammation-Modulating Supplements

James South, M.A.

As I reported in the last issue of Vitamin Research News, chronic, often "silent" inflammation is the new plague of the 21st century.[1] This inflammation is triggered by aging and a host of lifestyle factors, including obesity/overweight, too little exercise, too much high sugar/high starch and overcooked foods, trans fatty acids, high vegetable oil intake, stress and sleep deprivation.[1]

This chronic inflammation plays a major role in a variety of diseases, including cancer, heart disease, Alzheimer's disease, diabetes, obesity, periodontal disease, allergies, asthma, depression and osteoporosis, to name just a few.[1]

In my article on inflammation I detailed a series of diet and lifestyle changes to reduce inflammation.[1] This month I report on some herbal extracts and nutrients that can effectively reduce various inflammatory mediators, including interleukin-6 (IL-6), IL-1 beta, TNF-alpha, prostaglandin E2 and leukotrienes.

Stephania tetrandra
Stephania tetrandra is an herb used in China and Korea to treat various inflammatory conditions, including rheumatoid arthritis, lung silicosis and hypertension.[2,3] Its main anti-inflammatory components have been found to be tetrandrine (Tet) and fangchinoline (Fang).[4] Stephania extracts concentrate these two ingredients so that their combined level represents 10 to 20 percent of the extract. A Stephania preparation has shown significant effect in reducing the neutrophil-induced inflammation in rheumatoid arthritis.[5]

Tet and Fang have been shown to suppress multiple inflammatory cytokines and mediators. Tet powerfully suppressed nuclear factor kappa Beta (NFkB) activation in human T cells (immune cells).[6]

NFkB is a multimodal inflammation factor that promotes production of powerful inflammatory cytokines including IL-1, IL-6, IL-8 and tumor necrosis factor-alpha.[7] Tet effectively reduced conjunctivitis in mice exposed to ragweed pollen, reducing inflammatory cytokines IL-1 beta and IL-5, while also reducing mast cell degranulation (source of histamine).[8]

All of these are part of the cause of allergen-triggered red, itchy, irritated eyes. Tet and Fang powerfully suppressed formation of thromboxane B2 by human platelets, reducing their tendency to form unnecessary clots.[9] Tet and Fang reduced by 90 percent the production of IL-1 and tumor necrosis factor-alpha when human monocytes (white blood cells) were activated by germs.[10]

Tet showed potent inhibitory effect on leukotriene and prostaglandin (PG) generation by human monocytes and neutrophils.[11] Tet did not directly inhibit the cyclooxygenase (COX) enzyme that makes inflammatory PGs, but rather acted like a corticosteroid to inhibit arachidonic acid release from cell membranes, thereby depriving the COX enzyme of the raw material needed to make PGs.[11]

Perhaps most importantly, both Tet and Fang have shown powerful (63 to 86 percent) suppression of IL-6 activity, even at very low concentrations. IL-6 becomes especially problematic with aging, obesity, stress and sleep deprivation.[1] IL-6 is the main cause of elevated blood C-reactive protein, a major risk factor for heart disease.[1]

5-Loxin® is a special extract of boswellic acids from the traditional East Indian herb frankincense (Boswellia serrata). 5-Loxin contains approximately 30 percent AKBA (acetyl-II-keto-beta-boswellic acid), due to a patented process that converts other beta-boswellic acids to AKBA. AKBA is a selective inhibitor of 5-lipoxygenase (5-Lox).[12]

5-Lox converts arachidonic acid (made within the body from linoleic acid in vegetable oils) to the highly inflammatory leukotrienes.[13] Leukotrienes promote cancer,[14] damage the brain,[13] and promote asthma, arthritis, psoriasis and colitis.[14] They may also promote atherosclerosis.[15] 5-Lox is activated by stress-released cortisol.[16] Boswellia extracts have been used successfully to treat ulcerative colitis,[17] asthma,[18] ileitis[19] and osteoarthritis.[20]

Traditional Boswellia extracts typically contain 2 percent or less AKBA.[20] Other boswellic acids show little or no 5-Lox inhibition, and some may even counteract AKBA's inhibition of 5-Lox.[12] Thus 5-Loxin represents a superior form of Boswellia extract, which works at much lower potencies than traditional Boswellia extracts.

Luteolin is a flavone (flavonoid) widespread in nature, present in foods such as celery, green pepper, perilla leaf and seed and chamomile.[21] According to Kotanidou and colleagues, "Luteolin is...among the most potent and efficacious flavonoid inhibitors of LPS [germ cell wall fragment]-induced TNF-[alpha], interleukin-6 production and inducible nitric oxide expression."[21]

Luteolin possesses strong anti-inflammatory and anti-allergic activity in vivo (living organism).[22] In mice given LPS to induce sepsis, luteolin increased the survival rate from 4 percent (untreated) to 48 percent (luteolin-treated).[21]

When compared to other flavonoids, such as quercetin, myricetin, chrysin, apigenin and taxifolin, only luteolin successfully inhibited TNF-alpha production and reduced several forms of inflammatory edema when given orally to test animals.[23]

Luteolin inhibited mast cell release of histamine in rats challenged with IgE (allergy) antibodies.[24] In studies with human colon cells, luteolin effectively suppressed TNF-alpha and IL-8 production.[25] Luteolin also inhibited the release of histamine, leukotrienes and PGD2 from cultured human mast cells sensitized with IgE antibody.[25]

Unlike many flavonoids, luteolin has been shown to be well-absorbed orally by animals and humans, and to be highly bioavailable (taken up by body cells).[21-23,27,28] Luteolin has been shown effective even at low levels.[21-23] Luteolin, along with Stephania, may be one of the most broad-spectrum anti-inflammatory "nutrients."

Stinging Nettle Leaf
Stinging Nettle (Urtica dioica) is an herb that grows throughout the temperate zones of Europe and America. It has been used as a medicine since ancient times and has been used to treat inflammatory conditions such as asthma, eczema and rheumatic conditions. In Germany a nettle leaf extract is approved as adjuvant therapy of rheumatic diseases (joint or musculoskeletal inflammatory conditions).[29]

Nettle leaf extract (NLE) has been shown to reduce IL-2 and interferon-gamma release by monocytes, which "may inhibit the inflammatory cascade in autoimmune diseases like rheumatoid arthritis."[29] NLE was shown to reduce secretion of TNF-alpha by human dendritic cells, leading to reduced T cell-mediated inflammatory response.[30] Mice suffering colitis treated with NLE exhibited fewer signs of colitis than untreated mice. The treated mice also had significantly lower levels of IL-1 beta and TNF-alpha than untreated mice.

Monocyte proliferation (which promotes inflammation) after LPS stimulation was also less in treated mice.[31] When 20 healthy humans ingested NLE for 21 days, there was an 80 percent reduction in TNF-alpha and a 99 percent reduction in IL-1 beta when blood samples were stimulated with LPS ex vivo (outside the body).[32] NLE has also been shown to inhibit NFkB activation.[33] NLE thus exhibits multimodal anti-inflammatory activity.

Holy Basil
Holy basil (Ocimum sanctum) is an East Indian herb highly esteemed in Ayurvedic medicine.[34] Newmark and Schulick report holy basil leaf extract (HBE) to be an inhibitor of both cyclooxygenase-2 (COX-2) and 5-lipoxygenase.[34] Kelm and colleagues found various compounds in holy basil leaves to be effective COX-2 inhibitors.[35] A key constituent of HBE is ursolic acid.[34] Ringbom and associates reported ursolic acid to be an effective COX-2 inhibitor.[36]

Godhwani and coworkers tested HBE in rats and found that it was about 60 percent as effective as sodium salicylate (an aspirin-related compound) in reducing inflammation in various tests.[37] HBE has also been shown to reduce corticosterone release in response to noise stress in rats.[38,39]

This is a novel anti-inflammatory property of HBE, given that noise stress is ubiquitous in the modern world, that noise stress can increase cortisol release in humans, and that cortisol activates 5-lipoxygenase, producing inflammatory leukotrienes.[16] As a COX-2 inhibitor (not as powerful, and thus safer, than the prescription COX-2 inhibitors that have made recent headlines), HBE represents an important herbal anti-inflammatory agent.

Green Tea Polyphenols
Dona and colleagues stated, "Green tea is rich in flavonoids and indeed epidemiological, in vitro, and animal-model studies have associated green tea consumption with health benefits, including decreased inflammation."[40] The researchers found both EGCG (the most important green tea polyphenol) and green tea extract (GTE) inhibited neutrophil-mediated angiogenesis in an in vivo inflammatory angiogenesis model.[40]

Inflammation-induced angiogenesis (growing new blood vessels) helps tumors create the massive blood supply they need for growth. Researchers also found that oral GTE enhanced resolution in a mouse lung inflammation model, significantly reducing subsequent fibrosis.[40]

Ahmed and associates found EGCG reduced expression and activity of COX-2 in human chondrocytes (cartilage-producing cells) from osteoarthritis cartilage.[41] They also found GTE reduced inflammatory PGE2 production when the chondrocytes were stimulated with IL-1 beta.[41]

Kundu and coworkers found that mice pretreated with oral GTE had reduced COX-2 expression when stimulated by a tumor promoter.[42] Wheeler and associates found that EGCG inhibited NFkB activation in human lung epithelial cells treated with IL-1 beta, which is a powerful activator of NFkB.[43] The same researchers had also previously shown that EGCG inhibits TNF-alpha activation of super inflammatory NFkB.[43]

Aktas and colleagues found that EGCG reduced the severity of experimental autoimmune encephalomyelitis (inflammatory brain disease) when mice were orally pretreated with EGCG.[44] They also found that EGCG significantly reduced TNF-alpha production in the mice.[44]

Hussain and coworkers found that EGCG inhibited COX-2 without inhibiting COX-1 expression (COX-1 is important for intestinal and kidney health) in several different types of human prostate cancer cells.[45]

Varilek and associates found that GTE attenuated chronic inflammation in mice suffering inflammatory bowel disease, demonstrating lower interferon-gamma and TNF-alpha levels than control mice with colitis that were not given EGCG.[46] Thus EGCG-rich green tea extract also qualifies as a broad-spectrum anti-inflammatory agent.

Ginger root
Ginger (Zingiber officinalis) has been used throughout the world for thousands of years as a medicine. It is called the "universal medicine" in East Indian Ayurvedic medicine. Ginger root contains a veritable cornucopia of natural anti-inflammatory compounds.[47] The USDA Phytochemical Database reported as of 1999 that ginger has more 5-lipoxygenase inhibitors than any other botanical source.[47]

Dr. Srivastava reported excellent results with ginger root in 56 patients with various rheumatic complaints, with over 75 percent getting relief in pain and swelling. He suggested that ginger inhibits both inflammatory prostaglandin (COX-2) synthesis and leukotriene (5-lipoxygenase) synthesis.[48]

Newmark and Schulick note: "Ginger has multiple constituents that inhibit COX-2 and inhibit the 5-lipoxygenase metabolism of arachidonic acid...Ginger inhibits the creation of prostaglandin PGE2, which [gives ginger] strong anti-pyretic (or anti-heat) producing effects. It balances production of inflammatory prostaglandins [PGE2] and PGI2, which also regulates the production of compounds that dilate the arteries. Ginger's constituents safely restore healthy platelet function by inhibiting the formation of...thromboxanes.... Ginger reduces prostaglandins that sensitize pain receptors at nerve endings...; [and] has significant anti-ulcer effects [which shows that ginger does not suppress intestine-essential COX-1 while suppressing COX-2]...."[47]

Jalad and colleagues reported that "Most of the [ginger root] fractions containing gingerols and/or gingerol derivatives showed excellent inhibition of LPS-induced PGE2 production."[49] Park and associates found that topical gingerol "suppressed TPA-induced...[skin] inflammation" in mice.[50]

Given its balanced anti-COX-2 and anti-5-lipoxygenase activity, ginger root extract provides useful, yet safe anti-inflammatory activity.

Inflammation Control

To help support those who struggle with long-term chronic inflammation, we have developed two products, Inflammation Control and Advanced Inflammation Control.

Advanced Inflammation Control is a four-capsule-daily formula, containing Stephania tetrandra extract; 5-Loxin, luteolin, stinging nettle leaf extract, green tea extract and ginger extract. It is a synergistic, state-of-the-art, inflammation-modulating formula.

For those desiring a more basic formula, we also offer Inflammation Control, a combination of Stephania and luteolin.

Chronic silent inflammation is probably the most insidious yet pervasive health problem in America today. Now, well-researched, high-tech herbal nutrition can be used to douse the hidden fires of inflammation.

Alpha-lipoic Highly recommended source of nutrients and supplements. vitamins antioxidants supplements

How did we qualify them ?

1. South J. America's Inflammation Epidemic. The new "plague" of our times. Vit Res News. November 2006;20(11).
2. Choi H, et al. Anti-inflammatory effects of fangchinoline and tetrandrine. J Ethnopharmacol. 2000;69:173-79.
3. Ho L, et al. Plant alkaloid tetrandrine downregulates Ikappa B alpha kinases-Ikappa Balpha-NF-kappaB signaling pathway in human peripheral blood T cell. Br J Pharmacol. 2004;143:919-27.
4. Shen Y-C, et al. Anti-inflammatory effects of the partially purified extract of radix Stephania tetrandrae: comparative studies of its active principles tetrandrine and fangchinoline or human polymorphonuclear leukocyte functions. Mol Pharmacol. 2001;60:1083-90.
5. Sekiya N, et al. Suppressive effects of Stephania tetrandra of the neutrophil functions in patients with rheumatoid arthritis. Phytother Res. 2004;18:247-49.
6. Ye J, et al. On the role of hydroxyl radical and the effect of tetrandrine on nuclear factor-kappa B activation by phorbol 12-myristate 13-acetate. Ann Clin Lab Sci. 2000;30:65-71.
7. Tak P, Firestein G. NF-kB: a key role in inflammatory disease. J Clin Invest. 2001;107:7-11.
8. Hu S, et al. Potent inhibitory effect of tetrandrine on experimental allergic conjunctivitis in mice. J Ocul Pharmacol Ther. 1997;13:435-44.
9. Kim H, et al. Effects of tetrandrine and fangchinoline on human platelet aggregation and thromboxane B2 formation. J Ethnopharmacol. 1999;66:241-46.
10. Onai N, et al. Inhibiting effects of bisbenzylisoquinoline alkaloids on induction of proinflammatory cytokines, interleukin-1 and tumor necrosis factor-alpha. Planta Med. 1995;61:497-501.
11. Teh, et al. Inhibition of prostaglandin and leukotriene generation by the plant alkaloids tetrandrine and berbamine. Int J Immunopharmacol. 1990; 12:321-26.
12. Sailer E, et al. Acetyl-11-keto-[beta]-boswellic acid (AKBA): structure requirements for binding and 5-lipoxygenase inhibiting activity. Br J Pharmacol. 1996;117:615-18.
13. Uz T, et al. Aging-associated up-regulation of neuronal 5-lipoxygenase expression: putative role in neuronal vulnerability. FASEB J. 1998;12:439-49.
14. Steele V, et al. Lipoxygenase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prev. 1999;8:467-83.
15. Rasmark O. Editorial: 5-lipoxygenase-derived leukotrienes. Mediators also of atherosclerotic inflammation. Arterioscler Throm Vasc Biol. 2003; 23:1140-42.
16. Manev H, et al. Putative role of neuronal 5-lipoxygenase in an aging brain. FASEB J. 2000;14:1464-69.
17. Gupta I, et al. Effects of Boswellia serrata gum resin in patients with ulcerative colitis. Eur J Med. 1997;2:37-43.
18. Gupta I, et al. Effects of Boswellia serrata gum resin in patients with bronchial asthma: results of a double-blind, placebo-controlled, 6-week clinical study. Eur J Med Res. 1998;3:511-14.
19. Kriegelstein C, et al. Acetyl-11-keto-beta-boswellic acid, a constituent of a herbal medicine from Boswellia serrata, attenuates experimental ileitis. Int J Colorectal Dis. 2001;16:88-95.
20. Kimmatkar N, et al. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee—A randomized double blind placebo controlled trial. Phytomed. 2003;10:3-7.
21. Kotanidou A, et al. Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice. Am J Respir Crit Care Med. 2002;165:818-23.
22. Ueda H, et al. Luteolin as an anti-inflammatory and anti-allergy constituent of Perilla frutescens. Biol Pharm Bull. 2002;25:1197-1202.
23. Ueda H, et al. A hydroxyl group of flavonoids affects oral anti-inflammatory activity and inhibition of systemic tumor necrosis factor-[alpha] production. Biosci Biotechnol Biochem. 2004;68:119-25.
24. Kimata M, et al. Effects of luteolin and other flavonoids on IgE-mediated allergic reactions. Planta Med. 2000;66:25-29.
25. Kim J, et al. Inhibitory effect of luteolin on TNF-alpha-induced IL-8 production in human colon epithelial cells. Int Immunopharmacol. 2005; 5:209-17.
26. Kimata M, et al. Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin Exp Allergy. 2000;30:501-08.
27. Shimoi K, et al. Metabolic fate of luteolin and its functional activity at focal site. Biofactors. 2000;12:181-86.
28. Shimoi K, et al. Intestinal absorption of luteolin and luteolin-7-O-beta-glucoside in rats and humans. FEBS Lett. 1998;438:220-24.
29. Klingelhoefer S, et al. Antirheumatic effect of IDS23, a stinging nettle leaf extract, on in vitro expression of T helper cytokines. J Rheumatol. 1999; 26:2517-22.
30. Broer J, Behnke B. Immunosuppressant effect of IDS30, a stinging nettle leaf extract, on myeloid dendritic cells in vitro. J Rheumatol. 2002;29:659-66.
31. Konrad A, et al. Ameliorative effect of IDS30, a stinging nettle leaf extract, on chronic colitis. Int J Colorectal Dis. 2005;20:9-17.
32. Teucher T, et al. [Cytokine secretion in whole blood of healthy subjects following oral administration of Urtica dioica L. plant extract.] Arzneimitt. 1996;46:906-10.
33. Riehemann K, et al. Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappa B. FEBS Lett. 1999;442:89-94.
34. Newmark T, Schulick P. Beyond Aspirin. Hohm Press, Prescott AZ 2000, Ch. 9.
35. Kelm M, et al. Antioxidant and cyclooxygenase inhibitory phenolic compounds from Ocimum sanctum Linn. Phytomed. 2000;7:7-13.
36. Ringbom T, et al. Ursolicacid from Plantago major, a selective inhibitor of cyclooxygenase-2 catalyzed prostaglandin biosynthesis. J Nat Prod. 1998; 61:1212-15.
37. Godshani S, et al. Ocimum sanctum: an experimental study evaluating its anti-inflammatory, analgesic and antipyretic activity in animals. J Ethnopharmacol. 1987;21:153-63.
38. Archana R, Namasivayam A. Effect of Ocimum sanctum on noise induced changes in neutrophil functions. J Ethnopharmacol. 2000;73:81-85.
39. Sembulingam K, et al. Effects of Ocimum sanctum Linn on noise induced changes in plasma corticosterone level. Indian J Physiol Pharmacol. 1997;41:139-43.
40. Dona M, et al. Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis. J Immunol. 2003;170:4335-41.
41. Ahmed S, et al. Green tea polyphenol epigallocatechin-3-gallate inhibits the IL-1 beta-induced activity and expression of cyclooxygenase-2 and nitric oxide synthase-2 in human chondrocytes. Free Rad Biol Med. 2002;33:1097-1105.
42. Kundu J, et al. Inhibition of phorbol ester-induced COX-2 expression by epigallocatechin gallate in mouse skin and cultured human mammary epithelial cells. J Nutr. 2003;133:3805S-10S.
43. Wheeler D, et al. Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1[beta]-dependent proinflammatory signal transduction in cultured respiratory epithelial cells. J Nutr. 2004;134:1039-44.
44. Aktas O, et al. Green tea epigallocatechin-3-gallate mediates T cellular NF-kB inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol. 2004;173:5794-5800.
45. Hussain T, et al. Green tea constituent epigallocatechin-3-gallate inhibits COX-2 without affecting COX-1 expression in human prostate carcinoma cells. Int J Cancer. 2005;113:660-69.
46. Varilet G, et al. Green tea polyphenol extract attenuates inflammation in interleukin-2-deficient mice, a model of autoimmunity. J Nutr. 2001;131:2034-39.
47. Beyond Aspirin op cit, Ch 14.
48. Srivastava K, Mustafa T. Ginger (Zingiber officinale) and rheumatic disorders. Med Hypoth. 1989;29:25-28.
49. Jolad S, et al. Fresh organically grown ginger (Zingiber officinale): composition and effects on LPS-induced PGE2 production. Phytochem. 2004;65:1937-54.
50. Park K, et al. Inhibitor effects of [6]-gingerol, a major pungent principle of ginger, on phorbol ester-induced inflammation, epidermal ornithine decarboxylase activity and skin tumor promotion in ICR mice. Cancer Lett. 1998;129:139-44.

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