Inflammation Pathophysiology

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Trauma, Catabolism and Disease

The ability to decrease catabolism of cell structures associated with trauma and degenerative disease is what gives Biomedica Lab's Recovery a potentially broad-spectrum indication profile. Results observed by clinicians over the last 10 years warrant further research for the treatment of chronic skin, respiratory, gastrointestinal and autoimmune conditions.

When oxygen is utilized by the body, damaging "exhaust" called reactive oxygen species (ROS) are released. ROS include hydroxyl radicals, superoxides, hypochlorite and hydrogen peroxide, to name a few. Minimal amounts of ROS play necessary roles in metabolism; whereas, when ROS production increases and the cell's ability to neutralize ROS decreases, the overall effect on tissues is destructive (aging and disease). (1-4)

Increased cell production of ROS is linked to most degenerative conditions including heart disease, arthritis, cancer, periodontal disease, liver disease, cataracts, macular degeneration, diabetes, gastrointestinal diseases, autoimmunity and asthma. (1-4)

ROS react with cells initiating chain reactions that result in tissue damage causing inflammation, spasm, pain and disease. (1, 3)

Antioxidants, such as Coenzyme Q10, alpha lipoic acid and NADH (nicotinamide 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)

Aging and disease result in diminished cell production of protective compounds leading to increased damage to cell membranes; inevitably, damage to membranes diminishes cellular ability to repair damaged tissue.(1, 7)

Membrane and extra-cellular matrix damage leads to decreased ideal first-intention healing involving parenchyma. (8-10)

Cell damage leads to:

1. Dehydration and Loss of Cell Function
   Decreased production of long chain glycosaminoglycans (GAG's) with an increase in shorter chain Gag's, resulting in dehydration of tissue and loss of membrane function. (9, 11, 12)
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)
3. Sclerosing of Tissue
   Deposition of heavily glycosylated, compact and inflexible collagen types V and VI. (12, 16-22)
4. Compromised Ability to Heal
   Increased granulomatous second intention healing involving stromal elements (i.e. development of scar tissue) resulting in loss of cell/tissue function. (9, 42)

Consequences

Loss of cell and tissue function results in further inability to repair damage, leading to increased tendency to bruising, excessive inflammation, spasm, joint stiffness, digestive abnormalities and respiratory distress. (7, 9, 15, 20, 21, 23, 24)

* Insulin normally acts as a shuttle to drive amino acids, glucose, fatty acids, glucosamine and other precursors into the cell so that the cell may synthesize required structures for tissue repair.

Recovery with Nutricol - Mechanism of Action

Recovery is a functional food engineered to treat and prevent degeneration and inflammation at the "root". (43, 44)

Nutricol is a potent proprietary bioflavonoid complex containing EGCG, proanthocyanidins, theafavin and resveratrol from grapes and tea, is the primary active ingredient in Recovery.

Nutricol reinforces membrane and matrix structures (halts damage that initiates inflammatory and spasmodic reactions) (26, 27, 31, 45, 46)

Nutricol increases membrane receptivity to hormones such as insulin, IGF and thyroxine (required for anabolic repair/healing) (13, 14)

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What Can We Do For You?

We make available Recovery, a functional food engineered to treat and prevent degeneration and inflammation at the root. It is made with Nutricol, a potent proprietary bioflavonoid complex containing EGCG, proanthocyanidins, theaflavin and resveratrol from grapes and tea. Nutricol is the primary active ingredient in Recovery.

Nutricol reinforces membrane and matrix structures (halts damage that initiates inflammatory and spasmodic reactions). Nutricol also increases membrane receptivity to hormones such as insulin, IGF and thyroxine (required for anabolic repair/healing)

The significant water and fat soluble antioxidant actions of Nutricol produce significant anti-catabolic and anti-inflammatory effects in your body:

1. Stabilize collagen aldimine reducible cross-links to reinforce the strength and elasticity of connective tissues such as cartilage, synovium, ligaments, tendons, fascia, bone, blood vessel walls and the dermis of the skin. (26, 27)
2. Neutralize ROS and catabolic enzymes decreasing their negative impact on cellular and extra-cellular structure and function; this improves membrane receptivity to growth factors such as insulin, somatomedins and thyroxin required for anabolic repair and cell maintenance. (4, 10 , 13, 28-30, 35, 49)
3. Decrease excess production of catabolic sustances such as collagenase, elastase, hyaluronidase, TNF, NOS and xanthine oxidase (enzyme that produces ROS); these substances are released from immune, microbial and damaged cells and cause damage to connective and epithelial tissue, resulting in joint pain, inflammation, capillary fragility and other soft-tissue damage. (4, 25, 31-35)
4. Prevent the release of inflammation promoters such as histamine, serine proteases, prostaglandins and leukotrienes by non-competitively inhibiting the release of the proinflammatory enzymes cyclo-oxygenase, lipoxygenase and phosphodiesterase. (33, 36)
5. Improve protective epithelial mucosal surface integrity (digestive, respiratory & genitourinary tract). (4, 50)

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Clinical References

1. Stohs SJ., J Basic Clin Physiol Pharmacol 1995; 6(3-4):205-28 The role of free radicals in toxicity and disease. Oxidative stress associated with production of reactive oxygen species is believed to be involved not only in the toxicity of xenobiotics but also in the pathophysiology of aging, and various age-related diseases, including cataracts, atherosclerosis, neoplastic diseases, diabetes, diabetic retinopathy, chronic inflammatory diseases of the gastrointestinal tract, aging of skin, diseases associated with cartilage, Alzheimer’s disease, and other neurological disorders.

2. Jaeschke H, et al, Toxicol Sci 2002 Feb; 65(2):166-176 Because of its unique metabolism and relationship to the gastrointestinal tract, the liver is an important target of the toxicity of drugs, xenobiotics, and oxidative stress.

3. Sen CK., Sports Med 2001; 31(13):891-908 Studies during the past 2 decades suggest that during strenuous exercise, generation of reactive oxygen species (ROS) is elevated to a level that overwhelms tissue antioxidant defense systems. The result is oxidative 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 physiological processes.

4. Lin JK, Chen PC, Ho CT, Lin-Shiau SY., J Agric Food Chem 2000 Jul;48(7):2736-43. Inhibition of xanthine oxidase and suppression of intracellular reactive oxygen species in HL-60 cells by theafl avin-3,3’-digallate, (-)-epigallocatechin-3-gallate, and propyl gallate. The antioxidative activity of polyphenols and PG is due not only to their ability to scavenge superoxides but also to their ability to block XO and related oxidative signal transducers.

5. Droge W. free radicals in the physiological control of cell function. Physiol Rev 2002 Jan; 82(1):47-95 Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.

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 insuffi ciency. Reactive oxygen species (ROS) avidly reacts with nitric oxide (NO) producing cytotoxic reactive nitrogen species capable of nitrating proteins and damaging other molecules.

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 mellitus? Oxygen free radicals (OFR) can form by reaction of glycated proteins with molecular oxygen. The most significant complications of diabetes, for example polyneuritis, retinopathy, microangiopathy, perforating ulcers, impaired healing, may depend on the excessive production of OFR by glycated proteins.

8. Lalazar A, et al, Gene 1997 Aug 22; 195(2):235-43 Activation of mesenchymal cells is a central event in the wound healing response of most tissues.

9. Hildebrand KA, Frank CB, Can J Surg 1998 Dec; 41(6):425-9 Scar formation and ligament healing. Injuries to ligaments induce a healing response that is characterized 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 VI), decreased collagen cross-links and an increased amount of glycosaminoglycans.

10. Monboisse JC, Borel JP, EXS 1992; 62:323-7. Oxidative damage to collagen. Extracellular matrix molecules, such as collagens, are good targets for oxygen free radicals. Collagen is the only protein susceptible to fragmentation by superoxide anion as demonstrated by the liberation of small 4-hydroxyproline-containing-peptides.

11. Roughley P J, Mort J S. Aging and the aggregating proteoglycans of human articular cartilage. Clinical Science 1986; 71: 337-44. With increasing age, there is an overall decrease in long-chain glycosaminoglycan production and an increase in shorter chain glycosaminoglycan production.

12. Nerlich AG, et al, Virchows Arch 1998 Jan; 432(1):67-76 Immunolocalization of major interstitial collagen types in human lumbar intervertebral discs of various ages. Collagens III and VI were significantly increased in areas of minor to advanced degeneration in all anatomical settings, while collagen V showed only minor changes in its staining pattern. In general, histological signs of tissue degeneration coincided with signifi cant quantitative, but also with certain qualitative, changes in the composition of the collagenous disc matrix.

13. Rizvi SI, J Physiol Pharmacol 2001 Sep; 52(3):483-8 Intracellular reduced glutathione content in normal and type 2 diabetic erythrocytes: effect of insulin and (-) epicatechin. A higher content of dietary fl avonoids may thus protect diabetic patients against long-term complications.

14. Rizvi SI, Clin Exp Pharmacol Physiol 2001 Sep; 28(9):776-8 Insulin-like effect of (-) epicatechin on erythrocyte membrane acetylcholinesterase activity in type 2 diabetes mellitus.

15. Bradley JL, et al, Acta Neuropathol (Berl) 2000 May; 99(5):539-46 The extracellular matrix of peripheral nerve in diabetic polyneuropathy.

16. Barnes M J. Collagens in atherosclerosis. Collagen and related research 1985; 5: 65-97. Type V and VI collagens are increased in atherosclerotic plaques.

17. Hibbs M S, Hoidal J R, Kang A H. Expression of a metalloproteinase that degrades native type V collagen and denatured collagens by cultured alveolar macrophages. Journal of Clinical Investigation 1987; 80: 1644-50 Glycosylation increases with age and leads to increased stable crosslinking.

18. Mohan P S, Carter W G, Spiro R G. Occurrence of type VI collagen in extracellular matrix of renal glomerulus and its increase in diabetes. Diabetes 1990; 39: 31-7. Type VI collagen is seen most prominently in pathological situations.

19. Narayanan A S, Page R C. Synthesis of type V collagen by fibroblasts derived from normal, inflamed and hyperplastic human connective tissues. Collagen and Related Research 1985; 5: 297-304 An increased content of type V collagen is apparent in infl ammatory and proliferative disease, hypertrophic scars and carcinomata.

20. Hillmann G, et al, Clin Oral Investig 2001 Dec; 5(4):227-35 Immunohistological and morphometric analysis of infl ammatory cells in rapidly progressive periodontitis and adult periodontitis. At baseline, the inflamed gingival tissue consists mainly of collagen types V and VI in areas with infi ltrates of inflammatory cells.

21. Primorac D, et al, Croat Med J 2001 Aug; 42(4):393-415 Osteogenesis imperfecta (OI), or brittle bone disease, is a heritable disorder characterized by increased bone fragility. In 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.

22. Kitamura M, et al, Clin Cardiol 2001 Apr; 24(4):325-9 Collagen remodeling and cardiac dysfunction in patients with hypertrophic cardiomyopathy: the signifi cance of type III and VI collagens.

23. CORA TABAK, et al, Am. J. Respir. Crit. Care Med., Volume 164, Number 1, July 2001, 61-64 Chronic Obstructive Pulmonary Disease and Intake of Catechins, Flavonols, and Flavones The MORGEN Study

24. Karran EH, et al, Ann Rheum Dis 1995 Aug; 54(8):662-9 An in vivo model of cartilage degradation that permits the measurement of proteoglycan and collagen in both non-calcified articular cartilage and calcifi ed cartilage compartments.

25. Paquay JB, et al, J Agric Food Chem 2000 Nov; 48(11):5768-72 It is found that catechins are able to protect against nitric oxide (NO (*)) toxicity in several ways.

26. Rao CN, Rao VH, Steinmann B., Scand J Rheumatol 1983; 12(1):39-42. Biofl avonoidmediated stabilization of collagen in adjuvant-induced arthritis. In rats with adjuvantinduced arthritis, the effect of (+)-catechin (CA)) on the cross linking of collagen was studied. All results may collectively indicate that catechins promote the cross linking of collagen in arthritic animals.

27. Rao CN, Rao VH, Steinmann B., Ital J Biochem 1981 Jul-Aug; 30(4):259-70. Influence of bioflavonoids on the metabolism and cross linking of collagen. The results of the present study indicate that the synthesis of collagen is unaffected, the cross linking of collagen is promoted and the degradation of soluble collagen is decreased in the bioflavonoids treated groups.

28. Matteucci E, Cell Biol Int 2001; 25(8):771-6 Studies show erythrocyte sodium/hydrogen exchange inhibition by (-) epicatechin could be one of the major mechanisms underlying the antiproliferative effects of catechins.

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 reactive oxygen species (ROS) during the catabolism of purines. Excess of the former can lead to gout and of the latter to increased oxidative stress, mutagenesis and possibly cancer.

30. Rao CN, Rao VH, Verbruggen L, Orloff S., Scand J Rheumatol 1980;9(4):280-4. Effect of biofl avonoids on lysosomal acid hydrolases and lysosomal stability in adjuvantinduced arthritis. Results demonstrate the fragility of lysosomes in arthritic tissues. Administration of CA or HR to the arthritic animals was found to have a prophylactic action by stabilizing liver lysosomes and reducing the free lysosomal enzyme activities in serum, liver, kidney and spleen. CA was more effective than HR

31. Yu-Li Lin, MOLECULAR PHARMACOLOGY 52:465-472 (1997). Epigallocatechin-3-gallate Blocks the Induction of Nitric Oxide Synthase by Down-Regulating Lipopolysaccharide-Induced Activity of Transcription Factor Nuclear Factor- B. Nitric oxide (NO) plays an important role in infl ammation and multiple stages of carcinogenesis.

32. L Liu, Carcinogenesis, 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- specifi c carcinogen. Results demonstrate that (+)-catechin inhibits the formation of DNA-damaging intermediates by selectively impairing the enzymatic activation of NNK. They suggest that (+)-catechin could be an effective preventive agent against NNK hepatocarcinogenicity.

33. Chan MM, et al, Biochem Pharmacol 1997 Dec 15; 54(12):1281-6 Inhibition of inducible nitric oxide synthase gene expression and enzyme activity by epigallocatechin gallate. Chronic inflammation has been implicated as the underlying factor in the pathogenesis of many disorders. In the past decade, inflammation-related endogenous production of reactive nitrogen species, similar to oxygen free radicals, has also been suggested as a risk factor for cancer, in addition to the well-studied exogenous nitroso compounds.

34. Sazuka M, et al, Biosci Biotechnology Biochem 1997 Sep; 61(9):1504-6 Inhibition of collagenases from mouse lung carcinoma cells by catechins. Results suggest that (-)-epigallocatechin gallate inhibit tumor cell invasion by inhibiting type IV collagenases of the LL2-Lu3 cells.

35. Monboisse JC, Braquet P, Randoux A, Borel JP, Biochem Pharmacol 1983 Jan 1; 32(1): 53-8. Non-enzymatic degradation of acid-soluble calf skin collagen by superoxide ion: protective effect of flavonoids. This work confirms that collagen may be degraded during the process of inflammation and that some flavonoids are endowed with protective properties.

36. Nakagawa K, et al, J Agric Food Chem 1999 Oct; 47(10):3967-73 Catechin supplementation increases antioxidant capacity and prevents phospholipid hydroperoxidation in plasma of humans.

37. Spencer JP, et al, Antioxid Redox Signal 2001 Dec; 3(6):1023-39 Bioavailability of flavan-3-ols and procyanidins: gastrointestinal tract influences and their relevance to bioactive forms in vivo. Studies suggest that the major bioactive forms of flavonol monomers and procyanidins in vivo are likely to be metabolites and/or conjugates of epicatechin. One such metabolite, 3’-O-methylepicatechin, has been shown to exert protective effects against oxidative stress-induced cell death.

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 Stereospecifi city 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.

47. Rao CN, Rao VH, Ital J Biochem 1980 Mar-Apr; 29(2):89-101. Effect of bioflavonoids on 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 urinary collagen metabolites were studied up to 49 days in rats with adjuvant-induced arthritis. The elevated levels of urinary total, non-dialysable and dialysable hydroxyproline, hydroxylysyl glycosides and total hexosamine in the arthritic animals were found to be slightly decreased in the acute phase and significantly decreased in the chronic phase of the disease due to the administration of biofl avonoids. Of the two bioflavonoids tests, CA 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 lipid bilayers has been investigated with liposome systems. Epicatechin gallate had the highest affinity for lipid bilayers, followed by epigallocatechin gallate, epicatechin, and epigallocatechin. Epicatechin gallate and epigallocatechin gallate in the surface of lipid bilayer perturbed the membrane structure.

49. Waltner-Law ME, et al, J Biol Chem 2002 Sep 20;277(38):34933-40 Epigallocatechin gallate represses hepatic glucose production. Results demonstrate that changes in the redox state may have beneficial effects for the treatment of diabetes and suggest a potential role for EGCG as an antidiabetic agent.

50. Shi X, et al, Mol Cell Biochem 2000 Mar; 206(1-2):125-32 EGCG efficiently scavenges *OH radicals with reaction rate of 4.62 x 10(11) M (-1) sec (-1), which is an order of magnitude higher than several well recognized antioxidants, such as ascorbate, glutathione and cysteine. It also scavenges O2*- radicals as demonstrated by using xanthine and xanthine oxidase system as a source of O2*- radicals. Through its antioxidant properties, EGCG exhibited a protective effect against DNA damage induced by Cr (VI).