This document is for licensed healthcare professionals only.
B I O S T R U C T U R A L M E D I C I N E Anti-catabolic/Healing
Nutricol® reinforces membrane and matrix structure (helps to halt damage that Indications
initiates inflammatory and spasmodic reactions) (26, 27, 31, 45, 46) Significant antioxidant and anti-catabolic benefits indicate Recovery® may be used Nutricol® increases membrane receptivity to hormones such as insulin, IGF and to reduce spasm and pain and improve rate and quality of post-trauma recovery.
thyroxine (required for anabolic repair/healing) (13, 14) age-related decline, breathing issues, digestive issues, pain (back, hip, knee, neck, Site of Action
shoulder, wrist, etc.), skin issues, trauma rehabilitation, wound healing Nutricol® embeds in the cell membrane and matrix. (43, 44, 48) The ability to decrease catabolism of cell structures associated with trauma and Mechanism of Action
degenerative disease is what gives Recovery® a potentially broad-spectrum The significant water and fat soluble antioxidant actions of Nutricol® produce the indication profile. Results observed by clinicians over the last 10 years warrant following anti-catabolic and inflammation-modulating effects: further research for the management of chronic skin, respiratory, gastrointestinal and “autoimmune” issues.
1. Stabilize collagen aldimine reducible cross-links to reinforce the strength and elasticity of connective tissues such as cartilage, synovium, ligaments, tendons, Pathophysiology
fascia, bone, blood vessel walls and the dermis of the skin.
Trauma, Catabolism and “Dis-ease”
2. Neutralize ROS and catabolic enzymes decreasing their negative impact on cellular When oxygen is utilized by the body, destructive “exhaust” called reactive oxygen and extra-cellular structure and function; this improves membrane receptivity to species (ROS) result. ROS include hydroxyl radicals, superoxides, hypochlorite growth factors such as insulin, somatomedins and thyroxin required for anabolic and hydrogen peroxide, etc. Minimal amounts of ROS, play necessary roles in repair and cell maintenance (4, 10 , 13, 28-30, 35, 49) metabolism; whereas, when ROS production increases and the cell’s ability to 3. Decrease excess production of catabolic substances such as collagenase, elastase, neutralize ROS decreases, tissues are damaged (aging and “dis-ease”). (1-4) hyaluronidase, TNF, NOS and xanthine oxidase*; these substances are released Increased production of ROS is linked to damage, spasm, inflammation, pain and from immune, microbial and damaged cells and cause damage to connective and loss of physiological function throughout the body. (5-7) epithelial tissue, resulting in joint pain, inflammation, capillary fragility and other soft-tissue damage (4, 25, 31-35) ROS react with cells initiating chain reactions that result in tissue damage causing inflammation, spasm, pain and disease. (1, 3) 4. Prevent the release of inflammation promoters such as histamine, serine proteases, prostaglandins and leukotrienes by non-competitively inhibiting the Antioxidants, such as Coenzyme Q10, alpha lipoic acid and NADH (nicotinamide release of the pro-inflammatory enzymes cyclo-oxygenase, lipoxygenase and adenine dinucleotide) and anti-catabolic enzymes, such as glutathione peroxidase, superoxide dismutase and catalase minimize the damage due to ROS. Younger healthy cells produce larger quantities of protective substances. (3, 5) 5. Improve protective epithelial mucosal surface integrity (digestive, respiratory & genitourinary tract) (37-40) Aging and disease result in diminished cell production of protective compounds leading to increased damage to cell membranes; inevitably, damage to membranes *Xanthine oxidase - enzyme that produces ROS. (4, 50) diminishes cellular ability to repair damaged tissue. (1, 7) Membrane and extra-cellular matrix damage leads to decreased ideal first-intention Ingredients Recovery Extra-Strength
Cell damage leads to:
glucosamine hydrochloride (vegan-source) Decreased long chain glycosaminoglycans (GAG’s) with an increase in shorter chain GAG’s, leads to tissue dehydration and loss of membrane function 2. Loss of Membrane Receptivity to Growth Factors Cell membrane desensitization to growth factors (somatomedins, insulin, etc.) necessary for cell repair, maintenance, protection and communication (13-15, 41) In a base of organic berries and fructo-oligosaccharides (water-soluble fiber).
*serving = 1 teaspoon powder or 5 vegetarian caps Deposition of heavily glycosylated, compact & inflexible collagen V & VI (12, 16-22) Dosage and Administration
Increased granulomatous second intention healing involving stromal elements (i.e. Suggested use (capsule form):
development of scar tissue) resulting in loss of cell/tissue function (9, 42) 5 capsules twice daily or as directed by a health practitioner.
Suggested use adults (powder form - preferred for best absorption):
Loss of cell and tissue function results in further inability to repair damage, leading Typical 150lb man or woman: Introduce gradually over a two week period to a to increased tendency to bruising, excessive inflammation, spasm, joint stiffness, concentrated dose of two to three teaspoons spread throughout the day. Mix with digestive abnormalities and respiratory distress. (7, 9, 15, 20, 21, 23, 24) water or diluted juice. After 30 - 60 days it may be possible to reduce intake to 1/2 * Insulin shuttles amino acids, glucose, fatty acids, glucosamine and other precursors the concentrated dose as stated above.
into the cell so that the cell may synthesize required structures for tissue repair.
Suggested use children 12 and under (powder form):
Introduce gradually over a two week period to a concentrated dose of ½ teaspoon
Mechanism of Action
per 20 lbs body weight. Mix with food, water or diluted juice. After 30 - 60 days it Recovery® is designed to halt damage & pain at the “root”. may be possible to reduce intake to ¼ teaspoon per 20lbs body weight.
Nutricol®, a potent proprietary bioflavonoid complex containing EGCG, proanthocyanidins, theaflavin and resveratrol from grapes and tea, is the primary active ingredient in Recovery®.
Recovery is trademarked as Biostructural Medicine Recovery. Safety Data
By implementing Recovery® (a Biostructural® Medicine), health care professionals Recovery® has significant benefits with very low risk. All Recovery® ingredients are naturally-occuring and non-toxic.
can safely modulate inflammatory conditions, prevent tissue damage and improve the quality and rate of healing. Nutricol® constituents have been clinically observed to possess health-promoting properties in the liver, lung, breast, pancreas, bladder, prostate, skin and most of the Recovery® is believed to decrease trauma (from disease, surgery and injury) by gastrointestinal system (Fujiki. (1999) J. Cancer Res Clin Oncol.125:589-97).
increasing membrane receptivity to growth factors and stabilizing cell structures.
Effects on Liver Function
We believe Recovery® should be used to halt damage and pain and promote Due to anti-catabolic and anti-oxidative actions, Recovery® may aid in the proper elimination and metabolism of drugs and other toxins by supporting 4 Phase II liver pathways (glutathione conjugation, taurine conjugation, methylation, and Safely Combining with Drugs
Due to its antioxidant, inflammation-modulating and anti-catabolic action, combining Recovery® with drugs can lead to reduced drug toxicity and side effects: Drug and Food Interactions
Anti-inflammatory (NSAIDs/cox-2 inhibitors)
Mixing Nutricol® with dairy inhibits absorption. Most conventional NSAIDs interfere with cyclo-oxygenase and prostaglandins. Cell damage still continues because: Side effects and precautions
1. Oxidation of membranes remains unblocked Recovery® contains hypoallergenic ingredients; however, the introduction of any 2. With standard NSAIDs, the production of PG1 and PG3, normally involved in new food or drug may result in an allergy. Recovery® benefits alone or combined with NSAIDS include: Toxicology Data
1. Inhibiting the inflammatory cascade or “domino effect” by increasing a cell’s Nutricol®
ability to neutralize lysosomal enzymes and ROS released from neighboring EGCG (epigallocatechin gallate)
The LD50 in male rats is greater than 5g/kg and 3g/kg in female rats. The rats 2. Increasing delivery of certain hormones, neurochemicals and nutrients into the were Sprauge-Dawley rats (Yamane et al. (1995) Cancer 7:1662-7). Found to be non-toxic for cell and enhancing waste transport out of the cell - improving cell communication.
Rodents and Humans (Fujiki et al. 1998).
Studies demonstrate that the addition of Recovery® ingredients with Sulindac Procyanidolic oligomers, resveratrol
(NSAID) results in a reduction in GI side-effects that accompany Sulindac usage The LD50* found to be greater than 5g/kg body weight in a single oral intubation (Ohishi et al. Cancer Lett 2002, 177(1):49-56) to fasted male and female albino rats. (Bagchi et al. (2000) Toxicology 148:87-197) Corticosteroids
Glucosamine (2-amino-2-deoxy-alpha-D-glucose)
Corticosteroids mimic cortisol, which reduces inflammation; however, corticosteroids No mortalities in mice or rats at very high levels. LD50 is greater than 5g/kg of body inhibit immune response and ability to repair, predisposing individuals to risk of weight orally. (Pharmatherapeutica 1982; 3(3):157-68) Theoretically, long-term use infection and accelerated rate of tissue breakdown. of very high-doses of glucosamine may result in hyperglycemia. Excessive levels of nitric oxide synthase (NOS), an enzyme that produces nitric *Recovery® has demonstrated blood sugar regulating effects. Nutricol® increases oxide, are involved in the initiation and progression of cancer and inflammation. membrane insulin sensitivity. Recovery® is safe to administer to stable Type II Studies have shown higher levels of nitric oxide in various inflammatory bowel diseases, and that corticosteroids have no effect on reducing NOS. (N Leonard, et. al. J. MSM (methyl sulfonyl methane)
MSM has very low toxicity, with an LD50 in rats that exceeds 20g/kg body weight Recovery® may compliment corticosteroids as it can normalize levels of NOS (Yu-Li per day. In dogs, no toxicity was reported in a 30-day test receiving 3g/kg body Lin Molecular Parm: 1997 (52):465-472).
weight per day, administered both orally and intravenously. There was a drop in Acetaminophen
hematocrit in the later stages of the high dose intravenous study that returned to Recovery® ingredients reduce acetaminophen-induced kidney and liver toxicity normal post-treatment. (Metcalf, J.W. (1986) MSM status report, Eq. Vet. Data 7:332-334).
(Res Commun Mol Pathol Pharmacol 2000; 107(1-2):137-66), (Ray S.D., Arch Biochem Biophys 1999 Sep 1; 369(1):42-58).
TMG (trimethylglycine)
Many cases have demonstrated Recovery® may be superior to acetaminophen for Safety studies show TMG to be very safe, with an acute LD50 in rats of over 11,000 chronic pain relief. Recovery® decreases the need for acetaminophen mg/kg body weight. (Life Science Research 1990).
2 studies report anti-bacterial action was enhanced when Recovery® ingredients
were combined with ampicillin/sulbactam, benzylpenicillin, oxacillin, methacillin, Taking natural products should be a decision based on personal research and cephalexin (Journal of Antimicrobial Chemotherapy, 2001, (48), 361-364), (Antimicrobial Agents and understanding of the role food-derived components play in health and wellbeing.
Chemotherapy, 2001, 45, (6), 1737-1742).
The information contained within this document is for informational purposes Since 1998, there have been observations with several patients on warfarin and only and is not intended as a substitute for advice from a physician or other Recovery®. There were no changes in prothrombin time reported, nor any signs of health care professional, and should not be used for diagnosis or treatment of increased bleeding. Recovery® may have anti-platelet activity related to normalizing any health problem or for prescription of any medication or other treatment. A excessive platelet adhesiveness. (Kang WS., Thromb Res 1999 Nov 1; 96(3):229-37) health care professional should be consulted before starting any diet, exercise or supplementation program, before taking any medication, or if you have or suspect Amiodarone, Doxorubicin, Idarubicin, 4-HC
you might have a health problem. Do not discontinue any other medical treatments The ingredients in Recovery® reduce organ and serum toxicity induced by these drugs (Bagchi D., Drugs Exp Clin Res 2001; 27(1): 3-15), (Res Commun Mol Pathol Pharmacol 2000; 107(1-2): Recovery is trademarked as Biostructural Medicine Recovery. 15. Bradley JL, et al, Acta Neuropathol (Berl) 2000 May; 99(5):539-46 The extracellular Clinical References
matrix of peripheral nerve in diabetic polyneuropathy.
1. Stohs SJ., J Basic Clin Physiol Pharmacol 1995; 6(3-4):205-28 The role of free radicals 16. Barnes M J. Collagens in atherosclerosis. Collagen and related research 1985; 5: 65-97.
in toxicity and disease. Oxidative stress associated with production of reactive oxygen Type V and VI collagens are increased in atherosclerotic plaques.
species is believed to be involved not only in the toxicity of xenobiotics but also in 17. Hibbs M S, Hoidal J R, Kang A H. Expression of a metalloproteinase that degrades native the pathophysiology of aging, and various age-related diseases, including cataracts, type V collagen and denatured collagens by cultured alveolar macrophages. Journal of atherosclerosis, neoplastic diseases, diabetes, diabetic retinopathy, chronic inflammatory Clinical Investigation 1987; 80: 1644-50 Glycosylation increases with age and leads to diseases of the gastrointestinal tract, aging of skin, diseases associated with cartilage, Alzheimer’s disease, and other neurological disorders. 18. Mohan P S, Carter W G, Spiro R G. Occurrence of type VI collagen in extracellular matrix 2. Jaeschke H, et al, Toxicol Sci 2002 Feb; 65(2):166-176 Because of its unique metabolism of renal glomerulus and its increase in diabetes. Diabetes 1990; 39: 31-7. Type VI collagen and relationship to the gastrointestinal tract, the liver is an important target of the toxicity is seen most prominently in pathological situations. of drugs, xenobiotics, and oxidative stress.
19. Narayanan A S, Page R C. Synthesis of type V collagen by fibroblasts derived from 3. Sen CK., Sports Med 2001; 31(13):891-908 Studies during the past 2 decades suggest normal, inflamed and hyperplastic human connective tissues. Collagen and Related Research that during strenuous exercise, generation of reactive oxygen species (ROS) is elevated 1985; 5: 297-304 An increased content of type V collagen is apparent in inflammatory and to a level that overwhelms tissue antioxidant defense systems. The result is oxidative proliferative disease, and hypertrophic scars.
stress. Although excessive oxidants may cause damage to tissues, lower levels of oxidants in biological cells may act as messenger molecules enabling the function of numerous 20. Hillmann G, et al, Clin Oral Investig 2001 Dec; 5(4):227-35 Immunohistological and morphometric analysis of inflammatory cells in rapidly progressive periodontitis and adult periodontitis. At baseline, the inflamed gingival tissue consists mainly of collagen types V 4. Lin JK, Chen PC, Ho CT, Lin-Shiau SY., J Agric Food Chem 2000 Jul;48(7):2736-43. Inhibition and VI in areas with infiltrates of inflammatory cells.
of xanthine oxidase and suppression of intracellular reactive oxygen species in HL-60 cells by theaflavin-3,3’-digallate, (-)-epigallocatechin-3-gallate, and propyl gallate. The 21. Primorac D, et al, Croat Med J 2001 Aug; 42(4):393-415 Osteogenesis imperfecta (OI), antioxidative activity of polyphenols and PG is due not only to their ability to scavenge or brittle bone disease, is a heritable disorder characterized by increased bone fragility. In superoxides but also to their ability to block XO and related oxidative signal transducers.
most cases, there is a reduction in the production of normal type I collagen or the synthesis of abnormal collagen as a result of mutations in the type I collagen genes.
5. Droge W. free radicals in the physiological control of cell function. Physiol Rev 2002 Jan; 82(1):47-95 Division of Immunochem., Deutsches Krebsforschungszentrum, Heidelberg.
22. Kitamura M, et al, Clin Cardiol 2001 Apr; 24(4):325-9 Collagen remodeling and cardiac dysfunction in patients with hypertrophic cardiomyopathy: the significance of type III and 6. Vaziri ND, et al, Hypertension 2002 Jan; 39(1):135-41 Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in renal insufficiency. Reactive oxygen species (ROS) avidly reacts with nitric oxide (NO) producing cytotoxic reactive nitrogen 23. CORA TABAK, et al, Am. J. Respir. Crit. Care Med., Volume 164, Number 1, July 2001, 61- species capable of nitrating proteins and damaging other molecules.
64 Chronic Obstructive Pulmonary Disease and Intake of Catechins, Flavonols, and Flavones The MORGEN Study 7. Gillery P, Monboisse JC, Maquart FX, Borel JP, Med Hypotheses 1989 May; 29(1):47-50. Does oxygen free radical increased formation explain long term complications of diabetes 24. Karran EH, et al, Ann Rheum Dis 1995 Aug; 54(8):662-9 An in vivo model of cartilage mellitus? Oxygen free radicals (OFR) can form by reaction of glycated proteins with degradation that permits the measurement of proteoglycan and collagen in both non- molecular oxygen. The most significant complications of diabetes, for example polyneuritis, calcified articular cartilage and calcified cartilage compartments.
retinopathy, microangiopathy, perforating ulcers, impaired healing, may depend on the 25. Paquay JB, et al, J Agric Food Chem 2000 Nov; 48(11):5768-72 It is found that excessive production of OFR by glycated proteins.
catechins are able to protect against nitric oxide (NO (*)) toxicity in several ways.
8. Lalazar A, et al, Gene 1997 Aug 22; 195(2):235-43 Activation of mesenchymal cells is 26. Rao CN, Rao VH, Steinmann B., Scand J Rheumatol 1983; 12(1):39-42. Bioflavonoid- a central event in the wound healing response of most tissues. mediated stabilization of collagen in adjuvant-induced arthritis. In rats with adjuvant- 9. Hildebrand KA, Frank CB, Can J Surg 1998 Dec; 41(6):425-9 Scar formation and induced arthritis, the effect of (+)-catechin (CA)) on the cross linking of collagen was ligament healing. Injuries to ligaments induce a healing response that is characterized studied. All results may collectively indicate that catechins promote the cross linking of by the formation of a scar. The scar tissue is weaker, larger and creeps more than normal ligament and is associated with an increased amount of minor collagens (types III, V and 27. Rao CN, Rao VH, Steinmann B., Ital J Biochem 1981 Jul-Aug; 30(4):259-70. Influence of VI), decreased collagen cross-links and an increased amount of glycosaminoglycans.
bioflavonoids on the metabolism and cross linking of collagen. The results of the present 10. Monboisse JC, Borel JP, EXS 1992; 62:323-7. Oxidative damage to collagen. Extracellular study indicate that the synthesis of collagen is unaffected, the cross linking of collagen is matrix molecules, such as collagens, are good targets for oxygen free radicals. Collagen is promoted and the degradation of soluble collagen is decreased in the bioflavonoids treated the only protein susceptible to fragmentation by superoxide anion as demonstrated by the liberation of small 4-hydroxyproline-containing-peptides.
28. Matteucci E, Cell Biol Int 2001; 25(8):771-6 Studies show erythrocyte sodium/hydrogen 11. Roughley P J, Mort J S. Aging and the aggregating proteoglycans of human articular exchange inhibition by (-) epicatechin could be one of the major mechanisms underlying cartilage. Clinical Science 1986; 71: 337-44. With increasing age, there is an overall the antiproliferative effects of catechins. decrease in long-chain glycosaminoglycan production and an increase in shorter chain 29. Aucamp J, et al, Anticancer Res 1997 Nov-Dec; 17(6D):4381-5 Inhibition of xanthine oxidase by catechins. The liver enzyme, xanthine oxidase (XO) produces uric acid and 12. Nerlich AG, et al, Virchows Arch 1998 Jan; 432(1):67-76 Immunolocalization of major reactive oxygen species (ROS) during the catabolism of purines. Excess of the former can interstitial collagen types in human lumbar intervertebral discs of various ages. Collagens lead to gout and of the latter to increased oxidative stress.
III and VI were significantly increased in areas of minor to advanced degeneration in all 30. Rao CN, Rao VH, Verbruggen L, Orloff S., Scand J Rheumatol 1980;9(4):280-4. Effect anatomical settings, while collagen V showed only minor changes in its staining pattern. In of bioflavonoids on lysosomal acid hydrolases and lysosomal stability in adjuvant- general, histological signs of tissue degeneration coincided with significant quantitative, but induced arthritis. Results demonstrate the fragility of lysosomes in arthritic tissues. also with certain qualitative, changes in the composition of the collagenous disc matrix.
Administration of CA or HR to the arthritic animals was found to have a prophylactic action 13. Rizvi SI, J Physiol Pharmacol 2001 Sep; 52(3):483-8 Intracellular reduced glutathione by stabilizing liver lysosomes and reducing the free lysosomal enzyme activities in serum, content in normal and type 2 diabetic erythrocytes: effect of insulin and (-) epicatechin. A liver, kidney and spleen. CA was more effective than HR higher content of dietary flavonoids may thus protect diabetic patients against long-term 31. Yu-Li Lin, MOLECULAR PHARMACOLOGY 52:465-472 (1997). Epigallocatechin-3-gallate Blocks the Induction of Nitric Oxide Synthase by Down-Regulating Lipopolysaccharide- 14. Rizvi SI, Clin Exp Pharmacol Physiol 2001 Sep; 28(9):776-8 Insulin-like effect of (-) Induced Activity of Transcription Factor Nuclear Factor- B. Nitric oxide (NO) plays an epicatechin on erythrocyte membrane acetylcholinesterase activity in type 2 diabetes 32. L Liu, Abnormalgenesis, Vol 12, 1203-1208, 1991. Catechin could inhibit the metabolism and DNA damage induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific toxin. Results demonstrate that (+)-catechin inhibits the formation of DNA- 47. Rao CN, Rao VH, Ital J Biochem 1980 Mar-Apr; 29(2):89-101. Effect of bioflavonoids on damaging intermediates by selectively impairing the enzymatic activation of NNK. the urinary excretion of hydroxyproline, hydroxylysyl glycosides and hexosamine in adjuvant arthritis. The effects of (+)--Catechin (AC) and 0--(beta hydroxyethyl) rutosides (HR) on the 33. Chan MM, et al, Biochem Pharmacol 1997 Dec 15; 54(12):1281-6 Inhibition of inducible urinary collagen metabolites were studied up to 49 days in rats with adjuvant-induced nitric oxide synthase gene expression & enzyme activity by epigallocatechin gallate. Chronic arthritis. The elevated levels of urinary total, non-dialysable and dialysable hydroxyproline, inflammation is implicated as an underlying factor in the pathogenesis of many disorders. hydroxylysyl glycosides and total hexosamine in the arthritic animals were found to be 34. Sazuka M, et al, Biosci Biotechnology Biochem 1997 Sep; 61(9):1504-6 Inhibition of slightly decreased in the acute phase and significantly decreased in the chronic phase of collagenases from abnormally produced mouse lung cells by catechins. Results suggest that the disease due to the administration of bioflavonoids. Of the two bioflavonoids tests, CA (-)-epigallocatechin gallate inhibit abnormal cell invasion by inhibiting type IV collagenases was found to afford more protective action than HR.
48. Nakayama T, et al, Biofactors 2000; 13(1-4):147-51 Interaction of catechins with 35. Monboisse JC, Braquet P, Randoux A, Borel JP, Biochem Pharmacol 1983 Jan 1; lipid bilayers has been investigated with liposome systems. Epicatechin gallate had the 32(1):53-8. Non-enzymatic degradation of acid-soluble calf skin collagen by superoxide highest affinity for lipid bilayers, followed by epigallocatechin gallate, epicatechin, and ion: protective effect of flavonoids. This work confirms that collagen may be degraded epigallocatechin. Epicatechin gallate and epigallocatechin gallate in the surface of lipid during the process of inflammation and that some flavonoids are endowed with bilayer perturbed the membrane structure.
49. Waltner-Law ME, et al, J Biol Chem 2002 Sep 20;277(38):34933-40 Epigallocatechin 36. Nakagawa K, et al, J Agric Food Chem 1999 Oct; 47(10):3967-73 Catechin supplementation gallate represses hepatic glucose production. Results demonstrate that changes in the increases antioxidant capacity and prevents phospholipid hydroperoxidation in plasma of redox state may have beneficial effects for the treatment of diabetes and suggest a potential role for EGCG as an antidiabetic agent.
37. Spencer JP, et al, Antioxid Redox Signal 2001 Dec; 3(6):1023-39 Bioavailability of flavan- 50. Shi X, et al, Mol Cell Biochem 2000 Mar; 206(1-2):125-32 EGCG efficiently 3-ols and procyanidins: gastrointestinal tract influences and their relevance to bioactive scavenges *OH radicals with reaction rate of 4.62 x 10(11) M (-1) sec (-1), which forms in vivo. Studies suggest that the major bioactive forms of flavonol monomers and is an order of magnitude higher than several well recognized antioxidants, such as procyanidins in vivo are likely to be metabolites and/or conjugates of epicatechin. One ascorbate, glutathione and cysteine. It also scavenges O2*- radicals as demonstrated such metabolite, 3’-O-methylepicatechin, has been shown to exert protective effects by using xanthine and xanthine oxidase system as a source of O2*- radicals. Through its against oxidative stress-induced cell death. antioxidant properties, EGCG exhibited a protective effect against DNA damage induced by Cr (VI).
38. Hara Y., J Cell Biochem Suppl 1997; 27:52-8 Influence of tea catechins on the digestive tract. The bactericidal property of catechins plays several roles in the digestive tract. In the small intestine, catechins inhibit alpha-amylase activity, and a certain amount is absorbed into the portal vein. Although catechins are bactericidal, they do not affect lactic acid bacteria. 39. Murakami S, et al, J Pharm Pharmacol 1992 Nov; 44(11):926-8 Five catechins, (+)-catechin, (-)-epicatechin, (-)-epicatechin gallate, (-)-epigallocatechin and (-)-epigallocatechin gallate, inhibited gastric H+, K (+)-ATPase activity. These findings suggest that the anti-secretory and anti-ulcerogenic effects of catechins previously reported, are due to their inhibitory activity on gastric H+, K(+)-ATPase.
40. Hassan A, et al, Methods Find Exp Clin Pharmacol 1998 Dec; 20(10):849-54 Role of antioxidants in gastric mucosal damage induced by indomethacin in rats. These results suggest that like plasma, the gastric mucosa has an antioxidant capacity and only when this capacity is exhausted are the lesive effects of the oxygen free radicals manifested.
41. Somasundaram R, et al, J Biol Chem 2000 Dec 8; 275(49):38170-5 Collagens serve as an extracellular store of bioactive interleukin 2. The binding of certain growth factors and cytokines to components of the extracellular matrix can regulate their local availability and modulate their biological activities.
42. Bensadoun ES, et al, Eur Respir J 1997 Dec; 10(12):2731-7 Proteoglycans in granulomatous lung diseases. In this study, we examined the localization of proteoglycans and collagen in the granulomatous lung conditions, sarcoidosis, extrinsic allergic alveolitis (EAA) and tuberculosis (TB).
43. Kajiya K, Biosci Biotechnology Biochem 2001 Dec; 65(12):2638-43 Steric effects on interaction of catechins with lipid bilayers. Trans-type catechins with the galloyl moiety were located on the surface of the lipid bilayer, as well as cis-type catechins with the galloyl moiety, and perturbed the membrane structure. 44. Tsuchiya H., Chem Biol Interact 2001 Mar 14; 134(1):41-54 Stereospecificity in membrane effects of catechins. At lower concentrations (5-100 microM), (-)-epigallocatechin gallate and (-)-epicatechin gallate reduced membrane fluidity more significantly than (-)-epicatechin, suggesting that the intensive membrane effect contributes to the potent medicinal utility of (-)-epigallocatechin gallate. 45. Nagasawa T, et al, Biosci Biotechnol Biochem 2000 May; 64(5):1004-10 The results of this study show that the antioxidative property of EGCG was effective for suppressing oxidative modification of the skeletal muscle protein induced by electrical stimulation. This finding demonstrates that EGCG has a beneficial effect in vivo on the free radical-mediated oxidative damage to muscle proteins.
46. Erba D., et al, Journal of Nutrition. 1999; 129:2130-2134 Observed protective effects can be attributed to epigallocatechin gallate and we cannot exclude contributions by other catechins. These data support a protective effect against oxidative damage. Conclusion: Our results indicate that EGCG inhibits the IL-1beta-induced production of
Bioflavonoids & Osteoarthritis
NO in human chondrocytes by interfering with the activation of NF-kappaB through a novel mechanism. Our data further suggest that EGCG may be a therapeutically Singh R, Ahmed S, Malemud CJ, Goldberg VM, Haqqi TM, J Orthop Res 2003 Jan;21(1):102- effective inhibitor of IL-1beta-induced inflammatory effects that are dependent on NF- 9 Epigallocatechin-3-gallate selectively inhibits interleukin-1beta-induced activation
kappaB activation in human OA chondrocytes.
of mitogen activated protein kinase subgroup c-Jun N-terminal kinase in human
osteoarthritis chondrocytes.

Takita H, Kikuchi M, Sato Y, Kuboki Y, Connect Tissue Res 2002;43(2-3):520-3
Inhibition of BMP-induced ectopic bone formation by an antiangiogenic agent

Activation of mitogen activated protein kinases (MAPK) is a critical event in pro-inflammatory (epigallocatechin gallate)
cytokine-induced signalling cascade in synoviocytes and chondrocytes that lead to the production of several mediators of cartilage damage in an arthritic joint. Green tea (Camellia Epigallocatechin gallate (EGCG), which is one of the components of green tea, was sinensis) is a widely consumed beverage and we earlier showed that polyphenols present recently shown to inhibit endothelial cell growth in vitro and angiogenesis in vivo [5]. in green tea (GTP) inhibit the development of inflammation and cartilage damage in an We have previously shown that bone and cartilage formation by bone morphogenetic animal model of arthritis. In this study we evaluated the role of epigallocatechin-3-gallate protein (BMP) is highly dependent on the geometry of the carrier (vasculature- (EGCG), a green tea polyphenol which mimics its anti-inflammatory effects, in modulating inducing or -inhibiting geometry [2]. To verify the function of angiogenesis in the the IL-1beta-induced activation of MAPK’s in human chondrocytes. We discovered that EGCG BMP induction system, we examine in this article whether inhibition of angiogenesis inhibited the IL-1beta-induced phosphorylation of c-Jun N-terminal kinase (JNK) isoforms, enhances chondrogenesis and suppresses osteogenesis. Fibrous glass membrane used accumulation of phospho-c-Jun and DNA binding activity of AP-1 in osteoarthritis (OA) as a BMP carrier was mixed with 1.2 micrograms rhBMP-2 and 1-10 micrograms of EGCG chondrocytes. Also IL-1beta, but not EGCG, induced the expression of JNK p46 without and was implanted into rats subcutaneously. As the dose of EGCG increased, alkaline modulating the expression of JNK p54 in OA chondrocytes. In immunocomplex kinase phosphatase activity and calcium content were decreased, whereas the type II collagen assays, EGCG completely blocked the substrate phosphorylating activity of JNK but not of content was increased. Conclusion: The results clearly indicated that inhibition of
p38-MAPK. EGCG had no inhibitory effect on the activation of extracellular signal-regulated vascularization enhanced chondrogenesis and suppressed osteogenesis.
kinase p44/p42 (ERKp44/p42) or p38-MAPK in OA chondrocytes. EGCG or IL-1beta did not alter the total non-phosphorylated levels of either p38-MAPK or ERKp44/p42 in OA Chen PC, Wheeler DS, Malhotra V, Odoms K, Denenberg AG, Wong HR, Inflammation chondrocytes. Conclusion: These are novel findings and indicate that EGCG may be of
2002 Oct; 26 (5):233-41 A green tea-derived polyphenol, epigallocatechin-3-
potential benefit in inhibiting IL-1beta-induced catabolic effects in OA chondrocytes that are gallate, inhibits IkappaB kinase activation and IL-8 gene expression in respiratory
Ahmed S, Rahman A, Hasnain A, Lalonde M, Goldberg VM, Haqqi TM, Free Radic Biol Med Interleukin-8 (IL-8) is a principle neutrophil chemoattractant and activator in humans. 2002 Oct 15;33 (8):1097-105 Green tea polyphenol epigallocatechin-3-gallate inhibits
There is interest in developing novel pharmacological inhibitors of IL-8 gene expression the IL-1 beta-induced activity and expression of cyclooxygenase-2 and nitric oxide
as a means for modulating inflammation in disease states such as acute lung injury. synthase-2 in human chondrocytes.
Herein we determined the effects of epigallocatechin-3-gallate (EGCG), a green tea-derived polyphenol, on tumor necrosis factor-alpha (TNF-alpha)-mediated expression We have previously shown that green tea polyphenols inhibit the onset and severity of of the IL-8 gene in A549 cells. EGCG inhibited TNF-alpha-mediated IL-8 gene expression collagen II-induced arthritis in mice. In the present study, we report the pharmacological in a dose response manner, as measured by ELISA and Northern blot analysis. This effect effects of green tea polyphenol epigallocatechin-3-gallate (EGCG), on interleukin-1 beta appears to primarily involve inhibition of IL-8 transcription because EGCG inhibited TNF- (IL-1 beta)-induced expression and activity of cyclooxygenase-2 (COX-2) and inducible alpha-mediated activation of the IL-8 promoter in cells transiently transfected with nitric oxide synthase (iNOS) in human chondrocytes derived from osteoarthritis (OA) an IL-8 promoter-luciferase reporter plasmid. In addition, EGCG inhibited TNF-alpha- cartilage. Stimulation of human chondrocytes with IL-1 beta (5 ng/ml) for 24 h resulted mediated activation of IkappaB kinase and subsequent activation of the IkappaB in significantly enhanced production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) alpha/NF-kappaB pathway. Conclusion: We conclude that EGCG is a potent inhibitor of
when compared to untreated controls (p <.001). Pretreament of human chondrocytes with IL-8 gene expression in vitro. The proximal mechanism of this effect involves, in part, EGCG showed a dose-dependent inhibition in the production of NO and PGE(2) by 48% and inhibition of IkappaB kinase activation.
24%, respectively, and correlated with the inhibition of iNOS and COX-2 activities (p <.005). In addition, IL-1 beta-induced expression of iNOS and COX-2 was also markedly inhibited in Adcocks C, Collin P, Buttle DJ, J Nutr 2002 Mar; 132 (3):341-6 Catechins from green
human chondrocytes pretreated with EGCG (p <.001). Parallel to these findings, EGCG also tea (Camellia sinensis) inhibit bovine and human cartilage proteoglycan and type II
inhibited the IL-1 beta-induced LDH release in chondrocytes cultures. Conclusion: Overall,
collagen degradation in vitro.
the study suggests that EGCG affords protection against IL-1 beta-induced production of catabolic mediators NO and PGE (2) in human chondrocytes by regulating the expression Polyphenolic compounds from green tea have been shown to reduce inflammation in a and catalytic activity of their respective enzymes. Furthermore, our results also indicate murine model of inflammatory arthritis, but no studies have been undertaken to investigate that ECGC may be of potential therapeutic value for inhibiting cartilage resorption in whether these compounds are protective to joint tissues. We therefore investigated the effects of catechins found in green tea on cartilage extracellular matrix components using in vitro model systems. Bovine nasal and metacarpophalangeal cartilage as well as human Singh R, Ahmed S, Islam N, Goldberg VM, Haqqi TM, Arthritis Rheum 2002 Aug; 46 (8):2079- nondiseased, osteoarthritic and rheumatoid cartilage were cultured with and without 86 Epigallocatechin gallate inhibits interleukin-1beta-induced expression of nitric
reagents known to accelerate cartilage matrix breakdown. Individual catechins were added oxide synthase and production of nitric oxide in human chondrocytes: suppression
to the cultures and the amount of released proteoglycan and type II collagen was measured of nuclear factor kappaB activation by degradation of the inhibitor of nuclear factor
by metachromatic assay and inhibition ELISA, respectively. Possible nonspecific or toxic effects of the catechins were assessed by lactate output and proteoglycan synthesis. Catechins, particularly those containing a gallate ester, were effective at micromolar Human chondrocytes were derived from OA cartilage and were treated with EGCG (100 concentrations at inhibiting proteoglycan and type II collagen breakdown. No toxic effects microM) and IL-1beta (2 ng/ml) for different periods, and inducible nitric oxide synthase of the catechins were evident. Conclusion: We conclude that some green tea catechins
(iNOS) messenger RNA and protein expression was determined by real-time quantitative are chondroprotective and that consumption of green tea may be prophylactic for arthritis reverse transcriptase-polymerase chain reaction and Western blotting, respectively. and may benefit the arthritis patient by reducing inflammation and slowing cartilage Production of NO was determined as nitrite in culture supernatant. Activation and breakdown. Further studies will be required to determine whether these compounds access translocation of nuclear factor kappaB (NF-kappaB), levels of inhibitor of nuclear factor the joint space in sufficient concentration and in a form capable of providing efficacy in kappaB (IkappaB), and NF-kappaB DNA binding activity were determined by Western blotting and a highly sensitive and specific enzyme-linked immunosorbent assay. Activity of IkappaB kinase was determined using in vitro kinase assay. Human chondrocytes cotreated with EGCG produced significantly less NO compared with chondrocytes stimulated with IL-1beta alone (P < 0.005). The inhibition of NO production correlated with the suppression of induction and expression of NF-kappaB-dependent gene iNOS. EGCG inhibited the activation and translocation of NF-kappaB to the nucleus by suppressing the degradation of its inhibitory protein IkappaBalpha in the cytoplasm.


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