Natural approaches to modulation of inflammatory pathways.
Inflammation is a complex defense and repair mechanism that can be triggered by numerous stimuli, including injury, infection, chronic disease, abnormal proteins, allergens, and chemical toxins. In response to these provocations, cells upregulate the production and activity of a host of proinflammatory mediators that characteristically lead to redness, swelling, and pain in the involved tissues. At the same time, immune cells are recruited to sites of inflammation, where they help destroy and clear offending stimuli. The acute inflammatory response is normally self-limiting and an integral part of the healing process. Left unchecked, however, inflammation damages tissues and impedes the body's repair mechanisms, leading to chronic, debilitating diseases such as arthritis, bursitis, asthma, psoriasis, prostatitis, and inflammatory bowel disease. Moreover, inflammation is increasingly being implicated in the pathogenesis of numerous degenerative disorders, including atherosclerotic cardiovascular disease, hypertension, diabetes mellitus, metabolic syndrome, neurodegeneration, and carcinogenesis. (1-5)
Inflammation is primarily managed pharmacologically, but concerns over the safety and expense of anti-inflammatory drugs have led to increased interest in natural products as adjuncts or alternatives to conventional therapies. In vitro and in vivo studies show that many natural agents can modulate the activity of key inflammatory mediators such as nuclear factor-kappa B (NE-KB), tumor necrosis factor (TNF), and the enzymes cyclooxygenase (COX) and lipoxygenase (LOX). More importantly, human trials have documented the efficacy of natural products in reducing symptoms and improving clinical outcomes in a variety of acute and chronic inflammatory conditions.
Major Inflammatory Mediators and Pathways
Inflammation is complex and mediated by the activation, production, secretion, and activities of a host of cellular biochemicals. While it is beyond the scope of this article to discuss all the mediators involved and their intricate interactions, several of the more prominent inflammatory regulators, cytokines, and enzymes shall be reviewed.
Nuclear Factor-Kappa B (NF-[kappa]B)
NF-[kappa]B plays a pivotal role in the initiation and perpetuation of the inflammatory response. N F-[kappa]B proteins are a family of transcription factors for genes that encode proinflammatory cytokines, chemokines, and adhesion molecules. In nonstimulated cells, NE-[kappa]B exists in an inactive state in the cytoplasm bound to related inhibitor proteins termed I[kappa]B. Upon exposure to stimuli such as reactive oxygen species, viral or bacterial components, drugs, toxins, or cytokines, specific kinases of the mitogen-activated protein kinase (MAPK) family phosphorylate l[kappa]KB, leading to its degradation. Once released from I[kappa]KB, NF-[kappa]B translocates to the cell nucleus, where it induces transcription of numerous inflammatory mediators including interleukin-1 (IL-1), IL-2, IL-6, IL-8, tumor necrosis factor (TNF), and the enzymes cyclooxygenase (COX) and lipoxygenase (LOX). (6-8) Increased NE-[kappa]B activity has been associated with a variety of disorders, including Alzheimer's disease, asthma, atherogenesis, diabetes (types 1 and 2), diabetic complications including angiopathy, nephropathy, neuropathy, and retinopathy, osteoporosis, rheumatoid arthritis, sepsis, and certain types of cancer. (7, 9-19)
Tumor Necrosis Factor (TNF)
TNF (formerly TNF-[alpha]) is an early-responding cytokine that helps initiate defensive actions against infection and other forms of tissue insult. A variety of stimuli induce production of TNF, including bacteria, viruses, immune complexes, cytokines, complement factors, tumor cells, and tissue trauma.(20) These stimuli lead to enzymatic cleavage of TNF from a transmembrane complex and its release into the extracellular environment, where it encounters and binds to receptors on TNF-responsive cells. Regulation of TNF production is complex and involves a web of positive and negative feedback mechanisms, some of which are initiated by TNF itself. For example, TNF induces the production of chemical mediators such as IL-1, IL-2, and NF-[kappa]B, which can in turn heighten production of TNF.(6,20) Low to moderate TNF activity is thought to provide a necessary boost to host defenses, but at higher levels TNF causes excessive inflammation that can lead to tissue damage and dysfunction.(20) One group of proinflammatory chemicals stimulated by TNF are adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM1).(21) Adhesion molecules are central players in recruiting leukocytes to areas of inflammation and thus increasing the inflammatory response. TNF also induces production of a group of proteolytic enzymes called matrix metalloproteinases (MMPs).(22) MMPs are associated with some homeostatic activities such as tissue repair and bone remodeling, but have been implicated in a number of pathological processes, including tumor growth, vascular intimal thickening, chronic inflammation, and progression of arthritis. (23-25)
Cyclooxygenase (COX) and Lipoxygenase (LOX)
One of the more well-known and heavily researched pathways involved with inflammation is the arachidonic acid (AA) cascade. Cells exposed to inflammatory stimuli release AA from their membranes into the cytosol. AA is a substrate for cellular COX and LOX enzymes, which initiate its conversion into prostaglandins, thromboxanes, prostacyclins, leukotrienes, and other chemical compounds collectively known as eicosanoids.(26),(27) Two COX isoforms that share an approximate 60% homology have been identified. COX-1 is expressed ubiquitously and plays an important role in homeostatic activities such as regulation of platelet function and production of cytoprotective prostaglandins that maintain the integrity of the stomach lining. COX-2 is induced during acute inflammation and catalyzes the production of proinflammatory prostaglandins such as prostaglandin [E.sub.2] (PG[E.sub.2]). LOX enzymes can be constitutively expressed, like COX-1, but are more commonly induced by inflammatory stimuli and catalyze a series of reactions leading to the biosynthesis of leukotrienes.(27-29) One LOX enzyme in particular, 5-LOX, has been implicated in the production of the highly inflammatory cysteinyl leukotrienes and leukotriene (LT[B.sub.4]).(29) Both COX-2 and 5-LOX enzymes can be upregulated by NF-KB and TNF.(7, 8, 30, 31)
Natural Agents to Modulate Inflammation
Conventional treatment for acute and chronic inflammatory conditions typically involves use of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and selective inhibitors of the COX-2 enzyme. Unfortunately, these agents have been linked with serious gastrointestinal, renal, and cardiovascular side effects.(32) Newer medications such as disease-modifying antirheumatic drugs and biologics aimed at reducing inflammatory cytokine activity have achieved some success, but are not universally effective and have their own adverse effects. These limitations have led to interest in safer, more natural approaches to treating inflammatory conditions. Fortunately, a number of functional foods, nutrients, and herbs have been identified as natural anti-inflammatory agents. In many instances, the safety and efficacy of these agents is supported by their long history of use. Scientific investigations are also finding that these natural substances can exert potent modulatory effects on key inflammatory mediators such as NF-[kappa]B, TNF, COX-2, and 5-LOX. Most importantly, results from human trials are providing evidence that natural products can function as safe and effective adjuncts or alternatives to pharmacotherapy in the clinical management of disorders characterized by inflammation.
Fish oil is a concentrated source of omega-3 polyunsaturated fatty acids (omega-3 PUFA) and can thus impede inflammation by competing with the omega-6 fatty acid AA for metabolism by COX and LOX enzymes. Upon exposure to inflammatory stimuli, AA is released from cell membrane phospholipids and converted by COX and LOX enzymes to inflammatory land 4-series eicosanoids such as PG[E.sub.2] and LT[B.sub.4]. Emerging evidence suggests that AA may also be able to directly activate or induce inflammatory mediators such as NF-[kappa]B, TNF, IL-1, and IL-6.(33) Consumption of fish oils leads to replacement of AA in cell membranes by omega-3 PUFA such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). When released from membranes into the cytosol, EPA and DHA are converted by COX and LOX enzymes into far less inflammatory 3- and 5-series eicosanoids. Studies show that EPA and DHA also inhibit cytokineinduced gene expression of COX and LOX.(33) A number of studies find that feeding fish oils to animals or humans results in significant declines in inflammatory mediators. While this effect does not appear to be universal and can be affected by variables such as dose and gene polymorphisms, one study reported reductions of up to 86% in levels of TNF and IL-6 in the blood cells of healthy volunteers following consumption of 1 gm/day of omega3-rich fish oil. Interestingly, this study also found that co-consumption of antioxidants augments the inhibitory effect of fish oil on inflammatory cytokine production.(34)
Probiotics are living microorganisms that support the development and maintenance of a healthy, balanced intestinal microflora. As the gut microbiota is intimately involved with normal immune function through its interaction with gut-associated lymphoid tissue (GALT), probiotics can exert significant modulatory effects on the inflammatory responses of immune cells. Probiotic organisms such as Lactobacillus and Bifidobacterium, for example, have been shown to attenuate inflammation by balancing the activity of effector T lymphocytes (Th1, Th2, and Th17) with regulatory T lymphocyte ([T.sub.reg]) populations and reducing the activity of inflammatory mediators such as NE-[kappa]B and TNE.(35-39) Probiotics also strengthen the integrity of the gut mucosal barrier and thus limit the translocation of inflammatory and allergy-provoking agents from the intestinal tract into the bloodstream. Clinical trials support the use of probiotics in the management of inflammatory conditions. Supplementing healthy infants with lactobacilli has been shown to balance production of Th1/ Th2 cytokines while significantly reducing the incidence of eczema.(35) Administration of Lactobacillus and Bifidobacterium organisms to persons with ulcerative colitis has also been found to significantly lower the risk of relapse and markedly reduce expression of NE-[kappa]B and TNF in intestinal mucosal samples.(36)
Proteolytic enzymes have long been used as a natural remedy to reduce inflammation and promote tissue healing. The key to achieving systemic effects with supplemental enzymes is to take them between meals to prevent their degradation by the body's own endogenously produced enzymes. Though the notion was once controversial, studies have clearly shown that enzymes can pass intact through the intestinal mucosa into the bloodstream.(40),(41) Once absorbed, proteolytic enzymes appear to downregulate the activities of several chemical mediators of inflammation and pain transmission including PG[E.sub.2], bradykinin, and substance P.(42),(43) In clinical studies, combinations of various proteolytic enzymes such as bromelain, papain, trypsin, and chymotrypsin have been used to help reduce swelling and edema associated with arthritides, injuries, and other inflammatory conditions.(44-48) A lesser-known protease, Serratia peptidase (also called serrapeptase and serralysin), has also shown considerable promise in modulating inflammation. In one trial, 10 mg of Serratia peptidase given twice daily for 6 weeks resulted in significant improvement of both electrophysiological measurements and subjective symptoms of pain, numbness, and paresthesia in persons with carpal tunnel syndrome.(49)Another trial found that 10 mg of Serratia peptidase given 3 times daily for 7 to 8 days significantly reduced pain, dysphagia, and nasal obstruction compared with placebo in a group of patients suffering from acute or chronic inflammatory otorhinolaryngological conditions.(50)
Turmeric (Curcuma Longa)
Turmeric has a long history of use in Asia as both a spice and a traditional remedy for liver ailments and inflammatory conditions. The rhizomes of turmeric contain an orange-yellow polyphenolic compound called curcumin that exerts widespread modulatory activity on NE-[kappa]B, TNF, COX-2, IL-1, IL-6, and a number of other inflammatory mediators.(51) Preliminary data from human studies indicate that curcumin can favorably influence the course of serious inflammatory conditions. A double-blind, placebo-controlled trial was conducted to assess the effects of 2 gm/day of curcumin as an adjunct to sulfasalazine or mesalamine therapy in a group of subjects with quiescent ulcerative colitis. After 6 months, the rate of symptom recurrence in the curcumin group was significantly lower than in the placebo group (4.65% vs. 20.51%). Clinical and endoscopic indices of disease activity were also significantly reduced by curcumin in this study.(52) Despite turmeric's therapeutic potential, its efficacy is somewhat limited by poor bioavailability of its curcuminoid constituents. Recent advancements in biotechnology have led to the development of phospholipid delivery systems that dramatically improve the absorption of curcumin.(53) Clinical trials have found curcumin-phospholipid complexes to be highly effective in reducing symptoms associated with inflammatory conditions such as uveitis and osteoarthritis of the knee.(54-56)
Green Tea (Camellia Sinensis)
Tea is one of the most widely consumed beverages in the world and exerts a host of beneficial effects on human health. Nonfermented green tea leaves contain high levels of health-promoting catechin polyphenols such as epigallocatechin gal late (EGCG), epigallocatechin (EGC), and epicatechin gallate (ECG). Green tea and its polyphenol constituents have been found to provide benefits in an array of health conditions, including cancer, cardiovascular disease,diabetes,obesity,osteoporosis, cognitive dysfunction, and inflammatory disorders.(57) Many of green tea's salutary effects on health are thought to derive from its anti-inflammatory properties. In vitro, the polyphenol EGCG has been shown to significantly downregulate production of inflammatory mediators IL-8, macrophage inflammatory protein-3[alpha] (MIP-3[alpha]), and PG[E.sub.2].(58) EGCG has also been found to inhibit NE-[kappa]B activity in multiple human cell types, including T-lymphocytes, gastric carcinoma cells, bronchial epithelial cells, umbilical vein endothelial cells, chondrocytes, and epidermal keratinocytes.(59-64) Data from human clinical trials support the use of green tea to help combat a number of inflammation-related diseases. In a series of blinded, controlled, multicenter studies, administration of a catechin-rich green tea beverage was shown to significantly reduce blood pressure in overweight, hypertensive individuals and exert an insulinotropic effect in persons with type 2 diabetes.(65),(66) As inflammation has been linked with the pathogenesis of hypertension and loss of insulin-secreting capacity, these beneficial effects may be attributable to green tea's anti-inflammatory activity. In a separate double-blind, placebo-controlled trial, daily administration of a green tea preparation enriched with catechin polyphenols and L-theanine (an amino acid component of green tea) resulted in significant reductions in levels of serum amyloid-a and systolic and diastolic blood pressures in a group of healthy individuals.(67) Serum amyloid-a is an acute phase protein and marker for inflammation which, like C-reactive protein (CRP), is considered a strong predictor of cardiovascular disease.
Ginger (Zingiber Officinale)
Ginger is a culinary spice and medicinal herb cultivated in India, China, Africa, the West Indies, and Jamaica. Constituents of ginger, especially gingerols and shogaols, have been found to exert anti-inflammatory and analgesic actions through modulation of eicosanoid and cytokine pathways. In vitro, ginger components effectively suppress the synthesis of both inflammatory prostaglandins and leukotrienes. Gingerols reduce COX-2 production and activity by inhibiting genetic expression of COX-2 mRNA, while 6-shogaol and gingerdione antagonize 5-LOX activity.(68-71) Ginger extracts further block production of a range of inflammatory cytokines including TNF, IL-1[beta], macrophage inflammatory protein-1[alpha] (MIP-1[alpha]), monocyte chemoattractant protein-1 (MCP-1), and interferon-inducible protein 10 (IP-10).(72) Studies in humans confirm the efficacy of ginger in ameliorating symptoms associated with inflammatory conditions. A blinded, controlled trial involving 120 osteoarthritis patients compared a 30 mg daily dose of ginger extract with 1200 mg/day of ibuprofen and found that both treatments reduced joint pain and swelling and improved joint motion to a similar degree.(73) Another trial compared the effects of 1000 mg/day of unextracted ginger powder with 1000 mg/day mefenamic acid or 1200 mg/day ibuprofen in a group of female medical students with primary dysmenorrhea. Verbal and written responses to standardized tests measuring pain severity and degree of pain relief revealed ginger to be as effective as either mefenamic acid or ibuprofen in relieving menstrual pain.(74)
Boswellia (Boswellia Serrata)
Boswellia, also known as Indian frankincense, has long been recognized as an herb with anti-inflammatory properties. The gum resin of boswellia contains boswellic acids (BA), a group of pentacyclic triterpenoids that noncompetitively inhibit 5-LOX activity."(75) The most potent BA inhibitor of 5-LOX is 3-O-acetyl-11-keto-beta-boswellic acid (AKBA). AKBA also downregulates TNF-induced gene expression and blocks the activation and nuclear translocation of NF-[kappa]B.(75),(76) In rats and mice, boswellia extract significantly inhibits both carrageenan- and dextraninduced hind paw edema and effectively reduces infiltration of polymorphonuclear leukocytes and pleural exudate volume in animal models of pleurisy.(77),(78) Two separate double-blind, placebo-controlled studies have found that administration of boswellia extract significantly reduces pain and stiffness and improves joint function in persons with clinically diagnosed osteoarthritis of the knee.(79),(80) Clinical trials of boswellia extract involving patients with inflammatory bowel disease and asthma have also reported symptomatic benefit.(81-83)
Uncaria Tomentosa Aqueous Extract
Hot-water extracts of the roots and bark of U. tomentosa, commonly known as cat's claw, have been used for centuries by traditional healers in the Amazon River Basin for various ailments, including immunologic, inflammatory, and gastrointestinal disorders.(84) Carboxyl alkyl esters, especially quinic acid esters, appear to be responsible for many of U. tomentosa's health benefits and are readily obtained by hot water extraction rather than solvents.(85) Studies indicate that U. tomentosa exerts antioxidant effects and attenuates inflammatory processes in the body by modulating the activity of NF-[kappa]B and inhibiting TNF production.(86),(87) These biochemical restraints on inflammation translate into measurable anti-inflammatory activity in vivo. In indomethacin-induced enteritis rat models of inflammatory bowel disease, oral administration of aqueous U. tomentosa extract significantly diminishes the inflammatory response and prevents the pronounced disruption of intestinal mucosal architecture observed in rats treated with indomethacin alone.(87) In humans, aqueous U. tomentosa extracts have been found to be effective in treating in arthritis when used alone or in conjunction with standard pharmaceuticals.(85),(88) In view of its clinical benefits and proven ability to reduce TNF, U. tomentosa is an underappreciated and underutilized natural remedy for inflammatory conditions.
Inflammation is a natural, protective response to tissue insult or injury, but its persistence can lead to harmful and debilitating chronic inflammatory disorders. While it is clearly wise to identify and remove the cause of inflammation wherever possible, it is also essential to try to limit chronic inflammatory processes to prevent host tissue damage. In recent years, many natural products have come to the fore as potential adjuncts or alternatives to pharmaceuticals in the treatment of inflammation. Fish oil; probiotics; proteolytic enzymes; and herbs such as turmeric, green tea, ginger, boswellia, and U. tomentosa represent some of the most promising natural anti-inflammatory agents. Preclinical studies indicate that these substances, and/or their chemical constituents, regulate inflammatory responses through a number of mechanisms, including modulation of NF-[kappa]B, TNF, COX, LOX, and other key mediators of inflammation. Importantly, results from human clinical trials are providing increasing evidence of the safety and efficacy of these natural remedies in the management of some of today's most prevalent inflammatory conditions.
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by David Wolfson, ND; Stephen Olmstead, MD; Dennis Meiss, PhD; and Janet Ralston, BS
David Wolfson, ND, is a Technical Research Associate at ProThera[R], Inc. Dr. Wolfson received his naturopathic training at the National College of Naturopathic Medicine in Portland, Oregon, managed a private practice in Central California for several years, and has had more than a decade of experience in the nutraceutical industry, specializing in nutrition and botanical medicine.
Stephen Olmstead, MD, is chief science officer at ProThera Inc., where he directs clinical trials of ProThera and Klaire Labs nutraceutical products. His current research focus is the use of enzymes and chelating agents to disrupt pathogenic GI biofilm. Dr. Olmstead graduated from the University of New Mexico with distinction in biology and chemistry. He attended the University of New Mexico School of Medicine, and trained at Harvard Medical School, Massachusetts General Hospital. He is board certified in both internal medicine and cardiovascular diseases.
Dennis E. Meiss, PhD, is a founder of ProThera, Inc. and acts as president and CEO. He is the primary formulator of ProThera and Klaire Labs products and directs the company's management team. Dr. Meiss received his PhD in neurobiology from the University of Connecticut.
Janet Ralston, BS, is a founder of ProThera, Inc. She serves as vice-president of the company where she directs marketing efforts and client service programs. She is a graduate of the University of California, Davis Nutrition and Dietetics program