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Inflammatory Remarks

skeleton inflammation points

During this holiday season, many will overindulge and have too much of a good thing. Perhaps its that second helping of sweet potato pie or third glass of eggnog. Maybe its days with the children home from school or the extra time the mother-in-law can stay to help clean up after the holiday party. Whatever it is, many will just want that extra holiday cheer to be over; they will count the days until they get can back to normal.

Inflammation is a lot like holiday excesses. Sure, Its a Wonderful Life is great, but not after watching Jingle All the Way and Shrek the Halls. Inflammation helps us stay healthy, but too much causes problems.

When it works, inflammation can be a bodys best friend. It is the bodys cellular and vascular response to injury and is essential for survival. Trauma to the body creates dead cells, and inflammation is there to help clear away the dead cells and pave the way for new ones. When damage occurs to the body via an impact or unknown pathogen, such as a bacteria or virus, histamine and cytokines are called to the wound. Cytokines are small signal-protein cells that are involved in the amplification and reduction of inflammatory reactions. Among these signals are tumor necrosis factoralpha (TNF-alpha) and interleukin 1 (IL-1), two highly potent pro-inflammatory molecules. Interleukins are a group of cytokines that are synthesized by lymphocytes, as well as through monocytes, macrophages and endothelial cells. Blood vessels also respond by developing leaks that allow other immune cells to invade the wounded area. Leukocytes take the lead to orchestrate the debris removal, proliferation, connective tissue synthesis and tissue removal. Macrophanges, neutrophils and lymphocytes attack any bacteria and damage cells with chemicals like nitric oxide (NO). As the pathogens are eliminated, healing begins with platelets, which form clots and close the wound. Then, the damage is repaired and cells wait for the next trauma. During the healing process, redness, swelling, stiffness and pain can occur; however, once inflammation finishes its job, the pain subsides and things go back to normal.

That is what it is like in a perfect world. However, sometimes the inflammation just cant say no to a second helping. Inflammation can be triggered in response to a false signal, as in autoimmune diseases where the immune cells view certain components of the bodys own tissue as foreign invaders and tries to eliminate them. Sometimes, chronic infections can keep the immune system on high alert causing prolonged inflammation. In chronic inflammation, the synovial membrane (synovium), the soft tissue that lines the non-cartilaginous surfaces of the joints and secretes synovial fluid, can become irritated and may thicken by infiltration of macrophages and connective tissue producing fibroblasts.

Because inflammation is designed to keep all parts of the body healthy, it can become a problem in all parts of the body. Inflammation of the heart (myocarditis) can cause shortness of breath or leg swelling; asthma is inflammation of the tubes that transport air to the lungs; colitis is inflammation of the large intestine and causes cramping and diarrhea. The list goes on. If left untreated, inflammation can cause heart attacks, stroke, cancer, premature aging and other health conditions.

And, a lot of the time, those who suffer from chronic inflammation dont even know it. Because inflammation can affect organs that dont have pain-sensitive nerves or the inflammation causes pain that is below an individuals threshold of pain, it is often referred to as silent inflammation. This type is responsible for serious conditions, such as cardiovascular disease (CVD) and Alzheimers disease. Coronary heart disease, major depression, aging and cancer are characterized by an increased level of IL-1. Similarly, arthritis, Crohn's disease, ulcerative colitis and lupus erythematosis are autoimmune diseases characterized by a high level of IL-1 and the proinflammatory leukotriene LTB(4).1

Silent inflammation can also be a problem for manufacturers of ingredients that address the condition. Consumers may not even know these ingredients can help them because they are unaware that they are facing a potentially life-threatening situation.

For consumers who are aware of their inflammation, they may turn to natural remedies because of their lack of side effects compared to the most-common over-the-counter (OTC) treatment, non-steroidal anti-inflammatory drugs (NSAIDs), which provide rapid relief of pain and stiffness. However, many try to avoid NSAIDs because along with bringing toxic effects to the liver, bone marrow and other organs, NSAIDs dont actually prevent joint damage or slow disease progression.

When consumers turn to natural ingredients, they may not even be looking for a health claim related to inflammation. Because the effects of the condition are so wide spread, consumers are likely to look for condition-specific supplements geared toward certain health concerns. For example, a man with arthritis will look for joint health products and a woman with colitis will head to the digestion section of her natural products store, even though they are both suffering from inflammation.

But, once those consumers turn to natural products, they will find many options. Inflammation-fighting ingredients can be found in functional foods, ready-to-drink (RTD) beverages, cereals, extracts, dairy products, bars and candies; but, capsules and tablets still seem to be the most popular delivery option.

Ingredients that Ease Inflammation

The big fish of natural ingredients that help reduce chronic inflammation is omega-3 essential fatty acids (EFAs), found in fatty fishsalmon, herring, mackerel, anchovies and sardinesand some plants flax, kiwi, chia and nuts. EFAs play a key role in the inflammation process. Fatty acids are the precursors to the molecules that attack perceived pathogens. Eicosanoids, derived from omega-3 long-chain poly-unsaturated fatty acids (LCPUFAs), modulate the intensity and duration of inflammatory reactions. On the other hand, omega-6 EFAs contain compounds that promote inflammation. When working in equilibrium, these EFAs balance each other and inflammation is kept in check. However, most Western diets are overrun with omega-6 and dont contain enough omega-3, which causes increased inflammation. Thus, supplementing with omega-3s may help balance this equation and reduce inflammation.

Indeed, in one French study, omega-3 PUFAs significantly reduced the production of IL-6 stimulated with TNF-alpha, whereas the omega-6 PUFAs (arachidonic acid), even used at the highest concentration, was ineffective.2

Another study exposed human leukemia monocytic THP-1 cells to bacterial endotoxin for six hours, which significantly activated tissue factor activity and the production of NO, TNF-alpha and IL-1.3 Pretreatment with omega-3s resulted in suppression of not only tissue factor activation, but also the NO, TNF-alpha and IL-1. Docosahexaenoic acid (DHA), a specific omega-3, decreased cytokine-induced expression of endothelial leukocyte adhesion molecules, secretion of inflammatory mediators and leukocyte adhesion to cultured endothelial cells in a Harvard study.4 DHA, but not eicosapentaenoic acid (EPA), decreased in a dose- and time-dependent fashion the expression of vascular cell adhesion molecule 1 (VCAM-1) induced by IL-1, TNF and IL-4, (bacterial lipopolysaccharide). DHA also limited cytokine-stimulated endothelial cell expression and the secretion of IL-6 and IL-8.

Omega-3s have been shown to address many conditions whose root cause is inflammation. A 2009 systemic review by the American Dietetic Association found many clinical and epidemiologic studies have shown positive roles for omega-3 fatty acids in infant development; cancer; CVD; and mental illnesses, including depression, attention-deficit hyperactivity disorder (ADHD) and dementia.5 These fatty acids are known to have pleiotropic effects, including effects against inflammation, platelet aggregation, hypertension and hyperlipidemia, according to the review.

Inflammation in the heart and blood vessels can lead to CVD, which omega-3s have been shown to reduce, maybe due to its anti-inflammatory properties. Supplementation of the human diet with low DHA dosages improved lymphocyte activability.6 Eight subjects consumed increasing daily doses of DHA (200, 400, 800, 1600 mg) for two weeks each dose. DHA intake dose-dependently increased the proportion of DHA in mononuclear cell phospholipids, the augmentation being significant after 400 mg of DHA/d. Oxidized low-density lipoprotein (LDL) cholesterol apoptotic effect was significantly reduced after 400 mg of DHA/d and the protective effect was maintained throughout the experiment, although to a lesser extent at higher doses. Supplementation also increases monocyte resistance to oxidized LDL-induced apoptosis, which may be beneficial in the prevention of atherosclerosis. Omega-3s also improved the cardiovascular risk profile of subjects with metabolic syndrome, having effects on weight, systolic blood pressure, lipid profile, and markers of inflammation and autoimmunity in a 2009 study from Iran.7 Subjects with metabolic syndrome (mean age of 52.9 +/- 11.9 years) were randomly allocated to one of two groups: 42 subjects were given 1 g of fish oil as a single capsule, containing 180 mg of EPA and 120 mg of DHA acid daily for six months. Control subjects (n=42) did not receive any supplementation over the same period. Treatment with omega-3 supplements was associated with a significant fall in body weight (P<0.05), systolic blood pressure (P<0.05), serum LDL cholesterol (P<0.05), and total cholesterol (P<0.05), triglycerides (P<0.05), high-sensitivity C-reactive protein (hs-CRP) (P<0.01) and Hsp27 antibody titres (P<0.05).

Those who suffer from asthma may also benefit from omega-3 supplementation, especially EPA. Subjects given 120 micro of EPA and EPA-rich media significantly (P<0.05) suppressed TNF-alpha and IL-1beta mRNA expression and the production leukotriene (LT)B(4), prostaglandin (PG)D(2), TNF-alpha and IL-1beta in cells obtained from asthmatic patients to a much greater extent than 120 micro of pure DHA and DHA-rich media respectively.8

Out of sea and into the world of plant components, luteolin is a flavonoid found in high concentrations in celery and green pepper. It contains the proinflammatory mediator in Lipopolysaccharide (LPS)-stimulated macrophages, fibroblasts and intestinal epithelial cells. It has also been shown to help inflammation in the brain. In a 2008 study, mice were provided drinking water supplemented with luteolin for 21 days and then they were injected with LPS.9 Luteolin consumption reduced LPS-induced IL-6 in plasma four hours after injection, as well as decreased the induction of IL-6 mRNA by LPS in the hippocampus, but not in the cortex or cerebellum. Thus, researchers stated luteolin may be useful for mitigating neuroinflammation. In a study from the Netherlands, luteolin, apigenin and chrysin inhibited both pro-inflammatory cytokine production and metabolic activity of LPS-stimulated peripheral blood mononuclear cells (PBMC), whereas quercetin and naringenin had no effects on cytokines, metabolic activity or on the number of cells in the studied cell populations.10

Nobiletin, a polymethoxyflavonoid found in citrus fruits, has been studied as an effective anti-inflammatory phytochemical. In rats, it was shown to inhibit the eosinophilic airway inflammation by lowering the levels of the cytokine Eotaxin.11 Asthmatic rats who received 1.5 and 5.0 mg/kg Nobiletin (given intraperitoneally) experienced a significant reduction in eosinophils (important effector cells in asthmatic airway inflammation), remarkably lowered the level of Eotaxin in blood and broncho-alveolar lavage fluid (BALF). A Japanese study determined the anti-inflammatory actions of nobiletin are similar to those of anti-inflammatory steroids such as dexamethasone, but also has the unique action of augmenting the production of the endogenous MMP inhibitor, TIMP-1.12 In that study, nobiletin suppressed the IL-1-induced production of prostaglandin (PG) E(2) in human synovial cells in a dose-dependent manner (<64 microM). Nobiletin also interfered with the gene expression of proinflammatory cytokines including IL-1alpha, IL-1beta, TNF-alpha and IL-6 in mouse macrophages. In addition, nobiletin downregulated the IL-1-induced gene expression and production of proMMP-1/procollagenase-1 and proMMP-3/prostromelysin-1. An additional study found nobiletin, compared to luteolin, had a wider distribution and ambulation in tissues at four to 24 hours after ingestion by rats, suggesting it is more bioavailable.13

Active constituents in grape seed extract, oligomeric proanthocyanidins (OPCs), are also flavonoid-rich compounds. A Boston University study found grape seed extract had anti-inflammatory properties and a beneficial effect on platelet release of reactive oxygen intermediates.14 Incubation of platelets with grape seed extract led to a decrease in platelet aggregation from 68.8+/-19.8 percent to 45+/-3.6 percent (P<0.05). Platelet incubation with grape seed extract led to a marked decrease in superoxide release from 73+/-6.2 to 2+/-3.4 (<0.05), as well as a significant increase in radical-scavenging activity. In addition, incubation with grape seed extract led to an immediate attenuation of release of the inflammatory mediator, soluble CD40 ligand. Thus, the researchers concluded, the extracts from purple grape seeds inhibit platelet function and platelet-dependent inflammatory responses at pharmacologically relevant concentrations. Further, OPCs from grape seed extract inhibited hind paw edema in rats and croton ear swelling in mice in a dose-dependent manner.15 OPCs at 10 mg/kg reduced malondialdehyde (MDA) content in inflamed paws, inhibited beta-NAG and NOS activity, and lowered the content of NO, IL-1beta, TNF-alpha, and PGE2 in exudate from edema paws of rats induced by carrageenan. Dexamethasone 2 mg/kg was not as effective as OPCs in the study.

Pyconogenol, a plant extract from the bark of the maritime pine tree, decreased systemic inflammatory markers in osteoarthritis (OA) joints in patients with elevated CRP and plasma-free radicals.16 In the German study, 29 subjects received Pycnogenol and 26 patients received a placebo. All subjects showed CRP levels higher than 3 mg/l at baseline. Three months of treatment showed Pycnogenol significantly decreased plasma free radicals to 70.1 percent of baseline values. Plasma CRP levels decreased from baseline 3.9 mg/l to 1.1 mg/l in the Pycnogenol group whereas the control group had initial values of 3.9 mg/l which decreased to 3.6 mg/l. Fibrinogen levels also were found to be lowered to 62.8 percent of initial values (P<0.05) in response to Pycnogenol. No significant changes for plasma free radicals, CRP and fibrinogen were found in the placebo-treated group. In a London study, Pycnogenol supplementation inhibited cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) gene expression and reduced leukotriene biosynthesis in human polymorphonuclear leukocytes (PMNL) in response to an inflammatory stimulus ex vivo.17 Healthy volunteers aged 35 to 50 years were supplemented with 150 mg/d Pycnogenol for five days. PMNL were primed with LPS and stimulated with the receptor-mediated agonist formyl-methionyl-leucyl-phenylalanine (fMLP) to activate the arachidonic acid pathway and the biosynthesis of leukotrienes, thromboxane and prostaglandins. Pycnogenol supplementation inhibited 5-LOX and COX-2 gene expression and phospholipase A2 (PLA2) activity. This effect was associated with a compensatory up-regulation of COX-1 gene expression.

The extract of the botanical boswellia, a.k.a frankincense, demonstrated anti-inflammatory properties in patients with knee OA.18 In the study, it was compared to the COX-2 inhibitor Valdecoxib. In patients who received boswellia extract, pain, stiffness difficulty in performing daily activities showed significant improvement with two months of therapy and the effects lasted one month after the therapy. Patients who received Valdexocib also reported statistically significant improvements in all parameters, but the effects only lasted as long at the therapy. The anti-inflammatory properties of boswellia extract may be form P-selectin-mediated recruitment of inflammatory cells.19 In this study, boswellia treatment significantly blunted colitis activity in mice as assessed both grossly and by histology. Similarly, the recruitment of adherent leukocytes and platelets into inflamed colonic venules was profoundly reduced. In addition, boswellia largely prevented the P-selectin upregulation normally associated with colitis. All of the protective responses observed with boswellia were comparable to that in mice treated with a corticosteroid.

Another plant, the rose, may also help reduce chronic inflammation, and one study suggested it might be used as a replacement or supplement for conventional drug therapies in some inflammatory diseases such as arthritis.20 Researchers in Denmark found rose hip extract at concentrations higher than 500 mug/m1 inhibited the chemotaxis and chemiluminescence of peripheral blood polymorphonuclear leucocytes in vitro. Daily intake of rose hip powder at doses of 45 g or lower by healthy subjects resulted in reduced chemotaxis of peripheral blood PMNs and reduced the level of serum creatinine and acute phase protein CRP. Those same Danish researchers earlier found rose-hip extract reduced chemotaxis of peripheral blood neutrophils and monocytes of healthy subjects as well as those with OA in vitro.21 Daily intake of rose-hip powder for four weeks by healthy volunteers and patients suffering from OA resulted in reduced serum CRP levels and reduced chemotaxis of peripheral blood neutrophils.

Curcumin spices things up for inflammation. It is the principal curcuminoid of the Indian spice turmeric, which is a member of the ginger family (Zingiberaceae). Ayurveda and traditional Chinese medicine (TCM) have used turmeric to treat different inflammatory diseases for thousands of years. Modern science revealed curcumin mediates its effects by modulation of several important molecular targets, including transcription factors (e.g., NF-kappaB, AP-1, Egr-1, beta-catenin and PPAR-gamma), enzymes (e.g., COX2, 5-LOX, iNOS and hemeoxygenase-1), cell cycle proteins (e.g., cyclin D1 and p21), cytokines (e.g., TNF, IL-1, IL-6, and chemokines), receptors (e.g., EGFR and HER2) and cell surface adhesion molecules.22 In a systematic review from University of California, San Francisco, curcumin demonstrated anti-inflammatory activity in six human trials; and laboratory studies identified a number of different molecules involved in inflammation that are inhibited by curcumin, including phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes, thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, TNF and interleukin-12 (IL-12).23 Curcumin inhibited the 5-LOX activity in rat peritoneal neutrophils as well as the 12-lipoxygenase and the cyclooxygenase activities in human platelets in an in vitro experiment.24

Consumers with OA may benefit form eggshell membrane for its anti-inflammatory properties. Natural Eggshell Membrane (NEM®) from ESM Technologies, contains glycosaminoglycans and proteins and was shown to significantly reduced both joint pain and stiffness in patients with OA compared to placebo.25 The multicenter, double blind, placebo-controlled study included 67 patients randomly assigned to receive either oral NEM 500 mg (n=34) or placebo (n=33) daily for eight weeks. Supplementation with NEM produced a statistically significant (up to 26.6 percent) decrease in both pain and stiffness versus placebo at all time points for, but not for function and overall Western Ontario and McMasters Universities (WOMAC) scores. Rapid responses were seen for mean pain subscores (15.9 percent reduction, P=0.036) and mean stiffness subscores (12.8 percent reduction, P=0.024) occurring after 10 days of supplementation. And, two single-center, open-label human clinical studies found supplementation with NEM 500 mg taken once daily, significantly reduced pain at seven and 30 days.26 Eleven (single-arm trial) and 28 (double-arm trial) patients received oral NEM500 mg/d for four weeks. In the single-arm trial, supplementation with NEM produced a significant treatment response at seven days for flexibility (27.8 percent increase; P=0.038) and at 30 days for general pain (72.5 percent reduction; P=0.007), flexibility (43.7 percent increase; P=0.006) and range of motion associated pain (75.9 percent reduction; P=0.021). In the double-arm trial, supplementation with NEM produced a significant treatment response for pain at seven days for both treatment arms (18.4 percent reduction; P=0.021 in one group and 31.3 percent reduction; P=0.014 in the other group). The significant treatment response continued through 30 days for pain (30.2 percent reduction; P=0.0001).

As mentioned before, inflammation affects the heart as well as the joints, and chromium can help reduce inflammation associated with heart disease. Elevated blood levels of the IL-6, IL-8 and the cytokines monocyte chemoattractant protein-1(MCP-1) increase insulin resistance and the risk of CVD. In a Louisiana State University study, cells were cultured with control, high glucose (HG), and acetoacetate (AA) in the absence or presence (0.5-10 microM) of chromic chloride, chromium picolinate, or chromium niacinate at 37 degrees C for 24 hours.27 The data showed a significant stimulation of IL-6, IL-8, and MCP-1 secretion and an increase in oxidative stress in cells treated with HG or AA. The effect of HG on cytokine secretion was reduced by chromium niacinate, and to a lesser extent by chromic chloride and chromium picolinate. The effect of HG on oxidative stress was reduced by chromium niacinate. Similarly, chromium niacinate decreased the cytokine secretion in HG and AA-treated cells. In another study, chromium niacinate significantly decreased standard oxidant induced cytokine secretion, which suggests that reduction of cytokine secretion by chromium niacinate is in part mediated by its antioxidative effect. Chromium niacinate also lowered the blood levels of proinflammatory cytokines TNF-alpha (P=0.04), IL-6 (P=0.02), CRP (P=0.02); oxidative stress and lipids levels (P=0.01), glycosylated hemoglobin (P=0.02); triglycerides (P=0.04); and cholesterol (P=0.04) in diabetic rats.28

From minerals to vitamins, vitamin C has shown anti-inflammatory effects in various studies. One cross-sectional study examined 3,258 men aged 60 to79 with no diagnosis of myocardial infarction, stroke or diabetes.29 In the men, fruit intake and dietary vitamin C intake were significantly and inversely associated with mean concentrations of CRP and tissue plasminogen activator (t-PA) antigen, a marker of endothelial dysfunction, even after adjustment for confounders. Plasma vitamin C showed inverse associations with both fibrinogen concentrations and blood viscosity. In a University of California study, vitamin C has similar effects on CRP levels compared to statin drugs.30 Healthy nonsmokers (n=396) were randomized to three groups, 1,000 mg/d of vitamin C, 800 IU/d vitamin E or placebo, for two months. Among participants with CRP indicative of elevated cardiovascular risk (more than 1.0 mg/L), vitamin C reduced the median CRP by 25.3 percent versus placebo (P=0.02) (median reduction in the vitamin C group was 0.25 mg/L or 16.7 percent).Researchers reported these effects are similar to those of statins. Vitamin E effect did not produce significant effects. In another study focused on vitamin C and E, the combination of both nutrients lowered inflammation and improved insulin action through a rise in non-oxidative glucose metabolism in elderly subjects.31 Administration of vitamin E (1000 mg/d) and vitamin C (1,000 UI/d) for four weeks reduced insulin, glucose, lipid, TNF-alpha and [8-]isoprostane levels in 13 older men with impaired fasting glucose in the controlled-trial.

While inflammation may not know how to say no to overindulgence, natural products may be able to help keep it from getting that second helping.

References on the next page...

References for  "The Inflammation Equation"

1.       Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002 Dec;21(6):495-505.

2.       Khalfoun B, et al. Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human endothelial cell production of interleukin-6. Adv Exp Med Biol. 1997;400B:589-97.

3.       Chu AJ, et al. Blockade by polyunsaturated n-3 fatty acids of endotoxin-induced monocytic tissue factor activation is mediated by the depressed receptor expression in THP-1 cells. J Surg Res. 1999 Dec;87(2):217-24.

4.       De Caterina R, et al. The omega-3 fatty acid docosahexaenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells. Arterioscler Thromb. 1994 Nov;14(11):1829-36.

5.       Riediger ND, et al. A systemic review of the roles of n-3 fatty acids in health and disease. J Am Diet Assoc. 2009 Apr;109(4):668-79.

6.       Mebarek S, et al. Effects of increasing docosahexaenoic acid intake in human healthy volunteers on lymphocyte activation and monocyte apoptosis. Br J Nutr. 2009 Mar;101(6):852-8. Epub 2008 Aug 19.

7.       Ebrahimi M., et al. Omega-3 fatty acid supplements improve the cardiovascular risk profile of subjects with metabolic syndrome, including markers of inflammation and auto-immunity. Acta Cardiol. 2009 Jun;64(3):321-7.

8.       Mickleborough TD, et al. Eicosapentaenoic acid is more effective than docosahexaenoic acid in inhibiting proinflammatory mediator production and transcription from LPS-induced human asthmatic alveolar macrophage cells. Clin Nutr. 2009 Feb;28(1):71-7. Epub 2008 Dec 2.

9.       Jang S, Kelley KW, Johnson RW. Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci U S A. 2008 May 27;105(21):7534-9.

10.   Hougee S,et al. Decreased pro-inflammatory cytokine production by LPS-stimulated PBMC upon in vitro incubation with the flavonoids apigenin, luteolin or chrysin, due to selective elimination of monocytes/macrophages. Biochem Pharmacol. 2005 Jan 15;69(2):241-8.

11.   Wu YQ, et al. Antagonistic effects of nobiletin, a polymethoxyflavonoid, on eosinophilic airway inflammation of asthmatic rats and relevant mechanisms. Epub 2005 Dec 9.

12.   Lin N, et al. Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages. Biochem Pharmacol. 2003 Jun 15;65(12):2065-71.

13.   Murakami A, et al. Characteristic rat tissue accumulation of nobiletin, a chemopreventive polymethoxyflavonoid, in comparison with luteolin. Biofactors. 2002;16(3-4):73-82.

14.   Vitseva O, et al. Grape seed and skin extracts inhibit platelet function and release of reactive oxygen intermediates. J Cardiovasc Pharmacol. 2005 Oct;46(4):445-51.

15.   Li WG, et al. Anti-inflammatory effect and mechanism of proanthocyanidins from grape seeds. Acta Pharmacol Sin. 2001 Dec;22(12):1117-20.

16.   Belcaro G, et al. Variations in C-reactive protein, plasma free radicals and fibrinogen values in patients with osteoarthritis treated with Pycnogenol. Redox Rep. 2008;13(6):271-6.

17.   Canali R,et al. The anti-inflammatory pharmacology of Pycnogenol in humans involves COX-2 and 5-LOX mRNA expression in leukocytes. Int Immunopharmacol. 2009 Sep;9(10):1145-9. Epub 2009 Jun 7.

18.   S. Sontakke, et al. Open, randomized, controlled clinical trial of Boswellia serrata extract as compared to valdexocib in osteoarthritis of the knee. Indian J Pharmacol. 2007 Feb; 35(1)27-39

19.   Anthoni C, et al. Mechanisms underlying the anti-inflammatory actions of boswellic acid derivatives in experimental colitis. Am J Physiol Gastrointest Liver Physiol. 2006 Jun;290(6):G1131-7.

20.   Kharazmi A, Winther K. Rose hip inhibits chemotaxis and chemiluminescence of human peripheral blood neutrophils in vitro and reduces certain inflammatory parameters in vivo. Inflammopharmacology. 1999;7(4):377-86.

21.   Winther K, Rein E, Kharazmi A. The anti-inflammatory properties of rose-hip. Inflammopharmacology. 1999;7(1):63-8.

22.   Shishodia S, Sethi G, Aggarwal BB. Curcumin: getting back to the roots. Ann N Y Acad Sci. 2005 Nov;1056:206-17.

23.   Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Altern Complement Med. 2003 Feb;9(1):161-8.

24.   Ammon HP,et al. Mechanism of antiinflammatory actions of curcumine and boswellic acids. J Ethnopharmacol. 1993 Mar;38(2-3):113-9.

25.   Ruff KJ, et al. Eggshell membrane in the treatment of pain and stiffness from osteoarthritis of the knee: a randomized, multicenter, double-blind, placebo-controlled clinical study. Clin Rheumatol. 2009 Aug;28(8):907-14. Epub 2009 Apr 2.

26.   Ruff KJ,et al. Eggshell membrane: A possible new natural therapeutic for joint and connective tissue disorders. Results from two open-label human clinical studies. Clin Interv Aging. 2009;4(1):235-40. Epub 2009 Jun 9.

27.   Jain SK, Rains JL, Croad JL. High glucose and ketosis (acetoacetate) increases, and chromium niacinate decreases, IL-6, IL-8, and MCP-1 secretion and oxidative stress in U937 monocytes. Antioxid Redox Signal. 2007 Oct;9(10):1581-90.

28.   Jain SK, Rains JL, Croad JL. Effect of chromium niacinate and chromium picolinate supplementation on lipid peroxidation, TNF-alpha, IL-6, CRP, glycated hemoglobin, triglycerides, and cholesterol levels in blood of streptozotocin-treated diabetic rats.  Free Radic Biol Med. 2007 Oct 15;43(8):1124-31.

29.   Wannamethee, S. et al. Association of Vitamin C status, Fruit, and Vegetable Intakes, and Markers of Inflammation and Hemostasis. Am. J. Clin. Nutr. 2006, 83, 567 574.

30.   Block G,et al. Vitamin C treatment reduces elevated C-reactive protein. Free Radic Biol Med. 2009 Jan 1;46(1):70-7. Epub 2008 Oct 10.

31.   Rizzo MR, et al. Evidence for anti-inflammatory effects of combined administration of vitamin E and C in older persons with impaired fasting glucose: impact on insulin action.  J Am Coll Nutr. 2008 Aug;27(4):505-11.



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