Ecklonia Cava Extract – Super Antioxidant & Beyond

 Ecklonia Cava Extract – Super Antioxidant & Beyond

Ecklonia Cava Extract: Polyphenol / Phlorotannin Derived from Brown Algae

 Disclaimer: For educational purposes only This information has not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease

Ecklonia Cava Extract (ECE) is a standardized natural complex of unique marine molecules that originate from a specific species of brown algae (Ecklonia cava). ECE represents a unique category of polyphenols often called phlorotannins. Their unique polyphenolic structure endows them with biological activities that are not found in land-based plants.

ECE naturally occurs as high-molecular weight tannin (Mw> 2,000 Dalton) and low-molecular weight tannin (Mw=400-1000 Dalton). ECE can be classified into four types depending on the ratio of high molecular weight and low molecular weight tannins. Various physiological activities of ECE have been evaluated in vitro, in vivo and clinically as individual compounds (ECE1-ECE14) and complex forms (ECE, Type I-IV).

Millions on Research

Dr. Haengwoo Lee and his team of M.D.’s and Ph.D.’s have spent over thirty million dollars on research, from in vitro to animal and human studies. Much of the work was done in Korea, and some at the University of Washington. ECE has been found to be an impressive therapeutic agent in a wide array of clinical applications.

SUPER ANTIOXIDANT

The power of an antioxidant is determined by its structure, which is made up of rings. These rings capture stray electrons from free radicals. Most flavonoids generally have three interconnected rings. ECE has up to eight interconnected rings, making its free-radical scavenging ability 10-100 times more powerful than other polyphenols. It is substantially more powerful than green tea catechins, which only have four rings.

Multiple Antioxidant Profiles of ECE

ECE’s antioxidant activities against various reactive oxygen species have been confirmed to be highly potent in physiologically relevant concentrations. The effective dose of ECE for free radical scavenging is in the 10-20 µg/mL range which belongs to most potent families of natural antioxidants. ECE itself and its individual compounds have demonstrated potent reducing power and radical scavenging activities against DPPH radical, oxidized LDL and peroxynitrite.*

Much Longer Half-Life

ECE is a unique polyphenol in that it has a very long half-life in the body. This is because ECE is a marine-based polyphenol which is 40% fat-soluble. Virtually all other polyphenols are derived from land-based plants and are water-soluble. The half-life of ECE is up to 12 hours, compared to 30 minutes for water-soluble, land-based polyphenols. ECE has the ability to cross the blood-brain barrier.

The Research of Martin Pall, Ph.D.

Peroxynitrite is the most notorious of the free radicals incriminated by Martin Pall, Ph.D.’s groundbreaking research on multiple chemical sensitivity, fibromyalgia, chronic fatigue syndrome, post traumatic stress disorder, Gulf War syndrome, and fourteen other conditions. Peroxynitrite plays a main role in Dr. Pall’s mechanism, along with NF-kappaB and other inflammatory mediators. ECE also reduces tissue specific NF-kappaB.

*Peroxynitrate is a central reactive oxidant, which appears to play a major role in many disease processes.

FIBROMYALGIA

ECE: Phase I Clinical Trial Results (Preliminary)

In an 8-week, double-blinded, placebo-controlled study of established fibromyalgia patients, ECE was used as an adjunct therapy to the patients’ current standard of physician care. The results established the general safety of ECE. ECE cut the time it took the participants to fall asleep by 47 minutes; it increased total nighttime sleep by 1.6 hours; it improved soundness of sleep by 80%; it boosted their energy levels by 71%; it gave them 2 1/4 more good days per week; it helped reduce their pain by 31%; and their general condition improved by 39%. Interestingly, these improvements were achieved at all doses. Patients given the placebo had no improvement during the study.

ECE & FIBROMYALGIA

BRAIN FUNCTION: MEMORY, RELAXATION, ALERTNESS

Acetylcholine & Memory

Memory is dependent on the neurotransmitter acetylcholine (ACh). In an animal study, ECE increased rodent ACh by 140% in brain regions responsible for learning and memory in seven days. Memory enhancement increased by 100-200% at an oral dose as low as 0.2-1mg/kg.

With regard to mechanism, it is thought that the mild acetylcholinesterase inhibitory activity of two phlorotannin compounds found in ECE, dieckol (DE) and phlorofurofucoeckol (PFF), may be involved in the up-regulation of acetylcholine.

Increased Blood Flow

ECE crosses the blood-brain barrier and significantly improves blood flow, which is likely another way ECE improves memory. More specifically, Dr. Lee’s group found that ECE can increase the velocity of blood flow in the carotid artery from an average of 36.68 cm/sec. to 40.09 cm/sec., while the placebo showed no improvement.

Relaxation & Alpha-Waves

An EEG study on brain waves of healthy middle age volunteers found that ECE compounds increase alpha-waves. Alpha-waves are an indicator of relaxation.

Alertness

Yet another study found that ECE compounds prevented sleepiness in bus drivers and in high school students during daytime activities. This is likely due to increased blood flow and oxygen delivery.

Neuroprotective Effects

ECE demonstrated powerful neuroprotective effects owing to several features of its components. ECE compounds are both powerful antioxidants and anti-inflammatory agents capable of scavenging free radicals and suppressing excessive inflammatory reactions. Fucoidan in ECE has recently been found to protect neuronal cells from ischemia-induced inflammatory reactions which often occur in the aged and highly stressed brain. ECE compounds also neutralize the neurotoxic free-radical peroxynitrite.

Enhancement of Acetylcholine Levels in Mice

After 7 days oral administration of two ECE compounds (DE 10mg/kg and PFF 2mg/kg), mice under ethanol-induced cognitive impairment showed substantial enhancement of acetylcholine in three brain regions related to memory formation, as compared with non-treated mice. Especially, 140% enhancement was observed in the frontal cortex that is crucial in long-term memory and associative thinking.

Resistance of Stress-Induced Learning Deficit in Mice

In a 5-day study, ECE treated mice showed significant resistance to electric shock treatment-induced learning deficiency, as compared to non-treated mice whose learning process was significantly retarded during the test period.

Memory Enhancement in Mice

The beneficial effects of ECE compounds on memory enhancement were further demonstrated by measuring the latency time avoiding the previously experienced electric shock treatment in mice as passive-avoidance memory testing. After 7 days oral administration of two ECE compounds DE and PFF (as low as 1 and 0.2mg/kg), mice under ethanol-induced cognitive impairment showed 130-140% improvement, especially in the PFF group.

Beta-Amyloid Deposition Inhibition in Rats

Researchers at the National Institute of Health’s aging research labs in Baltimore studied ECE in rats, and found it to inhibit beta-amyloid deposition in the brain. Beta-amyloid is the same substance that accumulates in Alzheimer’s disease. The rats also learned maze challenges faster, which demonstrated improvement in short-term memory.

ARTHRITIS, INFLAMMATION, NEURALGIA

Dr. Lee and colleagues found ECE to naturally suppress inflammatory responses and neutralize inflammatory damage caused by reactive oxygen species. The optimal combination of ECE’s natural anti-inflammatory and tissue-protective properties appears to enable dramatic improvement in both arthritis and neuralgia. In a human trial, ECE significantly reduced pain in a group of knee arthritis patients compared with placebo.

Comparable to Celebrex®

ECE’s ability to treat arthritis was found to be comparable to Celebrex®, the prescription drug that reduces inflammatory cox enzymes.

The influence of ECE in lipopolysaccharide (LPS)-induced generation of prostaglandin E2 (PGE2) using RAW  246.7 cells was studied. While PGE2 was barely detectable in non-stimulated cells, more than one hundred times the amount of PGE2 was detected in the stimulated cells. ECE, celecoxib (Celebrex®) and aspirin all showed significant inhibition of PGE2 generation in the concentration range tested. ECE showed inhibition of 61%, 85%, 92% and 99% at concentrations of 10, 30, 60 and 100 µg/mL, showing similar activity to celecoxib which showed 65%, 79%, 85% and 96%.

Cartilage Protecting Activities

As demonstrated above, ECE compared almost identically to celecoxib in the ability to reduce PGE2 by slowing down the lipoxygenase (LOX) system. ECE compounds have more than double the ability of resveratrol to inhibit LOX. These results were demonstrated in a study on rabbit cartilage cells. Those cells treated with ECE had up to an 80% reduction in degeneration.

Rabbit Model

In an animal study, rabbit articular cartilage explant culture was treated with recombinant human interleukin 1 (rhIL-1) to induce proteoglycan degradation. The amount of glycosaminoglycan released into the medium was measured as an index of proteoglycan degradation. When the rabbit cartilage explants were treated with rhIL-1 for 60 hours, the amount of released glycosaminoglycan into the culture medium increased significantly compared to the vehicle group (1.44 ± 0.06µg/mg vs. 0.30 ± 0.01µg/mg). Diclofenac, which is known as a selective COX-2 inhibitor was used as a positive control at a dose of 10µM (3.2µg/mL). ECE significantly interfered with the rhIL-1-mediated degradation of proteoglycan in all concentrations tested (p <0.001). It showed 53%, 79%, 81% and 70% of inhibition at 1, 3, 10 and 30 µg/mL concentration.

Neuropathy: 4-Week Clinical Trial

Researchers recently studied ECE on 40 patients with neuropathy. ECE reduced nerve pain by 40% in four weeks. Overall, 80% of the patients responded favorably.

Speculation about Neuropathy Mechanism

The strong lipid and cholesterol reducing potential of ECE supports reduced vascular inflammation. Increasingly, the scientific literature supports the notion that many forms of nerve pain or neuropathy are caused by nerve pressure, as exerted by swollen, inflamed blood vessels adjacent to the nerves.

ALLERGIES / ASTHMA

Overall, ECE appears to significantly relieve allergic reactions without drowsiness, dizziness and other side effects of anti-histamine drugs.

Allergic Inflammation: Mouse Model

Dr. Lee and his team found that ECE significantly reduced allergic inflammation in mice. Specifically, ECE reduced the migration of eosinophils to the lungs by 75%. Inflammatory white blood cells (CD4+4 T Cells, resultant cytokines Il-4, 5, 13) were reduced by 50%. Mucus plugs in the airways were reduced by 75%. Airway epithelial hyperplasia reduced by 75%. Collagen-causing fibrosis in lung interstitium (fibrosis, airway remodeling) and smooth muscle cell thickness was reduced by 20% and 32%. These latter findings suggest that ECE compounds can prevent or reverse the progression of chronic lung disease such as asthma and Chronic Obstructive Pulmonary Disease (COPD).

5-Lipoxygenase (5-LOX)

5-Lipoxygenase (5-LOX) catalyzes the first step in the oxygenation of arachidonic acid, thus leading to the production of biologically active compounds such as leukotrienes and 5-hydroxyeicosatetraenoic acid. The peptidoleukotrienes (leukotriene C4, leukotriene D4 and leukotriene E4) are powerful spasmogens, which have been implicated in inflammatory and allergic responses. Therefore, inhibition of 5-LOX is a medicinal target for the treatment of inflammatory diseases. One of the ECE compounds (8,8-BE) significantly inhibits 5-LOX compared with other well-known natural medicinal compounds such as resveratrol and EGCG.

University of Washington Asthma Mouse Model

The efficacy of ECE for asthma was demonstrated in an allergen-induced murine asthma mouse model by Dr. Emil Chi, Chairman, Department of Histopathology, University of Washington.

The researchers tested an ECE product (KLS) in a mouse model of allergen-induced chronic lung inflammation and fibrosis. BALB/c mice, after intraperitoneal antigen sensitization on day 0 and day 14, were given weekly intranasal inhalations of antigen from day 14-60. The antigen-treated and challenged mice developed an extensive eosinophil and mononuclear cell inflammatory response, mucus cell hyperplasia and mucus occlusion of the airway.

KLS was found to be effective in reducing allergic reaction in inflammation. By feeding at a concentration of 5.4 mg/ml in the drinking water for 12 days, KLS reduced the airway mucus plugging, and sub-epithelial fibrosis in the antigen-sensitized / challenged mice. The reduced BAL fluid eosinophil indicated that KLS is effective in improving the asthmatic lung structures. No pathological alterations in the liver, kidney, spleen, or small intestine were found.

CARDIOVASCULAR BENEFITS

Coronary Artery Disease

ECE has been shown to improve coronary artery disease (CAD). Researchers found that ECE is even more potent at inhibiting the oxidation of LDL cholesterol than green tea catechins, and appears to scrub the plaque off the endothelial lining. ECE also reduces vascular inflammation by preventing oxidation, which also directly effects inflammatory mediators such as inflammatory prostaglandins, etc.

Coronary Artery Disease: 6-Week Clinical Trial

A clinical trial using ECE was conducted confirming its capacity to regenerate vascular endothelium and recover plasticity of blood vessels after 6 weeks of treatment by measuring flow-mediated dilation (FMD) & nitroglycerin-mediated dilation (NMD) of normal and CAD patients with narrowed coronary arteries by 50+%. FMD indicates nitric oxide (NO) releasing ability of endothelial cells to expand blood vessels by detecting shear stress caused by incoming blood flow (low FMD value can indicate endothelium damage).

After 6 weeks of treatment with ECE, clinical data showed that FMD, the endothelium-dependent dilation, was greatly enhanced in the CAD group, indicating its remarkable activity of inducing recovery of endothelial cells. NMD, the endothelium-independent dilation, which represents the vascular plasticity, also showed remarkable improvement in the CAD group, again supporting ECE’s ability to support restoration of vascular integrity by reversing atherosclerosis.

Cholesterol: 6-Week ClinicalTrial

Researchers gave 39 adults (average age 55.6) low dose (100 mg) ECE compounds for six weeks. Their average cholesterol dropped from 228 to 224. LDL dropped from 141 to 135. HDL rose from 46.5 to 50.7 (highly significant). Triglycerides fell from 215 to 195, and the atherogenic index dropped 12.5%.

Some of the parameters from the above study show very mild changes, which in themselves, may not be statistically significant. However, all parameters went in a health-positive direction, so taken together, the changes in LDL, HDL, triglycerides, blood pressure, and antioxidant protection are very significant. Also, endothelial cells were protected against oxidative damage, and were able to produce significantly more NO, which dilates blood vessels. Dramatic increases in blood flow were also found at this low dose.

Hypertension: 4-Week Animal Study

The remarkable effect of ECE on vasodilation was clearly demonstrated in renovascular clipping induced hypertensive rats. Renovascular clipping surgery is known to increase ACE activity via the renin-angiotensin-aldosterone system, which increased systolic blood pressure (SBP) from 140 to over 200 mm Hg after 4 weeks. Upon oral administration of phlorotannin (99.4%, 50 mg/kg) or enalapril (commercial hypotensive drug, 10 mg/kg) SBP dropped to as low as 160 and 140 mm Hg. Upon cessation of treatment, SBP increased again in both cases. Although ECE showed a similar pattern to the drugs, it also showed a slower rebounding of blood pressure during the no treatment period, which indicates its potential as a vascular protector with prolonged oral administration.

ACE Inhibition

Angiotensin-converting enzyme (ACE), is responsible for conversion of angiotensin I to angiotensin II and degradation of bradykinin, and is a key component in the renin-angiotensin-aldosterone system. Angiotensin II regulates cellular proliferation, inflammation, and endothelial function, and is therefore important in the pathogenesis of atherosclerosis and its complications. Aging or various vascular risk factors tend to increase ACE levels resulting in excessive vasoconstriction and hypertension. Current hypotensive drugs block the action of ACE or its by-product angiotensin II.

ECE tannins have been found to be potent natural ACE inhibitors, demonstrating more than 15 times the power to inhibit ACE as the most powerful land-based polyphenols, including the natural hypotensive substance catechin found in green tea. One of the compounds found in ECE, THP-BE is comparable to the physiological vasodilative hormone bradykinin.

Antiplasmin Inhibition

Plasmin (a fibrinolytic enzyme that breaks down blood clots) is rapidly blocked by a protein called antiplasmin. ECE compounds are natural potent inhibitors of anti-plasmin, capable of efficient promotion of plasmin that performs fibrinolysis. ECE compounds have shown remarkable activity which is 40-200 times greater than synthetic compounds Flufenamate and Chloramine T. One study on ECE compounds found a small but significant rise in prothrombin time and a fall in fibrinogen levels.

ERECTILE FUNCTION – ECE V. VIAGRA®

Nitric Oxide

ECE can regenerate the vascular endothelium, the cells critical to the inner lining of the blood vessels. They generate the chemical nitric oxide (NO), which keeps the arterial walls relaxed and dilated. After a six-week study of ECE, flow mediated dilation and NO mediated dilation increased by 60% and 50%. In another study, coronary artery disease patients were given ECE for six weeks. Blood flow controlled by NO increased 50-60%. These results confirm that ECE can rejuvenate damaged endothelial cells to produce NO. This effect was further confirmed in a study on erectile dysfunction (see below). Interestingly, Viagra® works by increasing NO in the penile artery.

ECE v.Viagra®: 8-Week Clinical Trial

Scientists studied 31 men with erectile dysfunction (ED) for over six months. They compared eight weeks of ECE use to Viagra®. They looked at orgasmic function (OF), intercourse satisfaction (IS), overall satisfaction (OS), and erectile function (EF). Over those eight weeks, ECE scored 87%, 74%, 62%, and 66%. Viagra® scored 27%, 44%, 39%, and 66%. No side effects were reported with ECE:

Population with 25+% Improvement in IIEF (International Index of Erectile Function) score was as high as 81%. Total IIEF score significantly increased from 29.1 ± 13.1 to 47.0 ± 14.5 with 62% of improvement. When the IIEF scores were grouped into five separate domains, mean IIEF scores at the 8th week were significantly greater than those at week 0 for all domains (all p<0.01). The degree of improvement was significant in the following order: OF (87%), IS (74%), EF (66%), and OS (62%). Scores on key questions (asking frequency of penetration and asking frequency of maintaining an erection after penetration), which directly indicate the ability to achieve and maintain an erection sufficient for sexual activity, were improved up to 74% and 77%, respectively (p<0.01).

It is very important to note that despite the marginal improvement in sexual desire (20%) that is of psychological nature, great improvements were reported in the domains directly related with erection that is of physical nature and dependent on normal vascular function of the penile artery.

Also noteworthy, was a significant increase in the orgasmic function score (87%), intercourse satisfaction (74%) and overall satisfaction (62%) as well as erectile function (66%) in comparison with the results for sildenafil reported by Marks, et al. (Marks, et al., 1999) (27%, 44%, 39% and 66%, respectively), which indicates that ECE significantly contributed to the normalization of the general vascular conditions around the sexual organ.

These results strongly indicate that the long-term administration of ECE significantly contributes to the neutralization of oxidative risk factors, thereby improving peripheral blood circulation around muscles and nerves involved in sexual function as well as the penile artery. No side effects were reported.

Vasodilation & Erectile Function

It has been reported that vasculogenic ED patients have elevated levels of angiotensin II for the duration of the erection process. The demonstrated action of ECE on ACE and resulting vasodilation is thought to play an important role in inducing successful erectile function.

Long-Term Improvement Via Vascular Protection

As discussed, ECE phlorotanins have potent antioxidant and anti-inflammatory effects. Together with ECE’s ACE inhibitory activity, which is also beneficial to vascular homeostasis, these activities, upon long-term oral administration, may all contribute to supporting a healthy vascular system, including the penile artery.

WEIGHT LOSS

DGAT Inhibition

Diacylglycerol acetyl transferase (DGAT) is the enzyme involved in the final step of triglyceride synthesis. Triglycerides are circulating fat bodies that ultimately wind up in the fat cells, and are almost always elevated in diabetes. They also have emerged as a major risk factor in vascular disease.

Dr. Lee found that ECE compounds inhibited DGAT more than 50%. In genetically caused obese laboratory rats, ECE reduced body fat and increased physical activity. In another study, ECE caused leanness and fat-resistance in animals given a high fat diet.

ECE Beverage: 2-Week Clinical Trial

In a human study, 141 young adults were given a beverage containing ECE at 200 mg daily. In two weeks their average weight dropped nearly 2.5 pounds, muscle mass increased by nearly 2.5 pounds, and body fat dropped by 4 pounds, or 7.48%. ECE stimulates the body to burn fat by increasing muscle mass.

OBESITY

Obesity & Cardiovascular Disease

As discussed, ECE contains an optimal combination of natural compounds capable of suppressing triglyceride synthesis, while promoting cholesterol removal and cardiovascular protection. ECE provides additional cardiovascular protection for obese patients prone to CVD and CHD through lowering LDL cholesterol and scavenging free radicals.

DGAT Inhibition & Obesity

DGAT inhibition has recently been recognized as a novel and safe target for the treatment of obesity. DGAT is involved in intestinal fat absorption, lipoprotein assembly, regulation of plasma TG concentration, fat storage in adipocytes, and energy metabolism in muscle. DGAT knockout mice have been shown to have obesity resistance with a high-fat diet, the mechanism of which was confirmed to be through energy expenditure.

DIABETES

Aldose Reductase Inhibition

When blood sugar levels become elevated, aldose reductase is the enzyme that converts excess glucose into the sugar alcohol sorbitol. Sorbitol can build up in critical cells and cause damage. Recent research found that animals deficient in aldose reductase were protected from the retinal complications of diabetes. ECE compounds have been found to be potent aldose reductase inhibitors, which may be of benefit for patients with metabolic syndrome, syndrome X, or diabetes.

Reduced Fat in Liver & Pancreas

A mouse study showed that ECE reversed fat deposition in liver and pancreas cells. Furthermore, this same study showed that ECE served to markedly inhibit NF-kappaB inflammation in the pancreas. A recent Harvard (Joslin School of Diabetes) mouse study directly implicates excessive fat deposition in the mouse pancreas as turning on the NF-kappaB inflammation pathway, resulting in full-blown type II diabetes and insulin insensitivity in the mice.

SAFETY

ECE is manufactured from edible algae through food-compatible processes. Tens of thousands of people throughout the world have experienced ECE in various forms of product without side effects. To date, Dr. Lee’s team has not found any toxicity at any level. Several toxicity tests have been performed, and no adverse effects have been found at the effective human dose level of 1-10 mg/kg.

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Fighting Free Radicals: The Role of Bark Extractives

 

Fighting Free Radicals: The Role of Bark Extractives

by Kelvin Duncan, Ph.D. (more info)
listed in antioxidants, originally published in issue 44 – September 1999

A stand of young Pinus radiata

The rapidly growing volume of evidence in the scientific literature about the nature and role of free radicals has lead to an increasing awareness of their importance in health and disease. Free radicals have been implicated in a great number of human conditions and the literature on the subject is vast (Ames et al., 1993, Bland, 1995, Diplock, 1994, Halliwell, 1996 and the references in Table 1).

Table 1. Recent references to health conditions in which flavonoids are thought to be beneficial.

Disease/Benefit Degenerative disease/ helps prevent or slow down General diseases/ prevents or ameliorates Cancer and cardiovascular/ protects Inflammatory bowel disease/ helps Heart attacks/ reduced risk Strokes/ reduced risk Clots/ prevent abnormal clots Endothelial cells/ protect and strengthens Plaque/ reduced rate of formationHair/ increases hair growth and follicle cell density Anti-inflammatory, esp. arthritis/ reduces Oedema/ reduces Tumours/ inhibits early tumours Tumours/ reduces incidence of spontaneous tumours in elderly mice Allergies/ anti-allergenic Carcinogens and mutagens/ chemoprotective Skin cancer/ reduces or prevents skin cancers induced by UV Prostate cancer/ anticarcinogenic against prostate cancer Insulitis/ protect pancreas and help lower or prevent insulitis . HIV, may help HIV

Reference Ames et al., 1993 . Cross et al., 1987 Gey, 1993 Grishanan, 1994 Hertog et al., 1993 Keli et al., 1996 Rice-Evans, 1996 Kaneko et al., 1999 Xu et al., 1998 Takashashi et al., 1999 You et al., 1999 Pelzer et al., 1998, Lairir-Chatterjee et al., 1999 Duncan, 1998 Cheong et al., 1998 Sohn et al., 1998 . Ahmad et al., 1998 . Zi et al., 1998 Soto, et al., 1998 Scrhramm & German, 1998 Kitamura, et al., 1998

However, not all free radical reactions in the body are harmful; some are entirely natural and are necessary for the correct functioning of many metabolic processes. (Cheesman and Slatter, 1993). These benign, natural free radicals do not concern us here since they are well controlled by the body’s metabolism. Rather it is the damaging free radicals, which are largely caused by non-natural events, that are the focus of this article.

How do free radicals form?

Free radicals can form naturally since some of the body’s molecules have weak bonds that spontaneously break and cause the molecule to become a free radical. Also, for unknown reasons a small proportion of normal oxidative reactions result in the formation of free radicals. Other causes of damaging free radicals are ionising radiation, such as light, or ultra violet, or other forms of radiation. Mariner’s skin, that scourge of skin which makes people look far older than they really are, is a result of excessive exposure to light and to UV radiation: the skin changes in thickness, it becomes dehydrated, its collagen becomes thickened and hardened, and wrinkles and dryness result. Radioactivity, whether from natural or man made sources, also causes free radicals to form. Finally, a great number of chemicals, especially human-
produced synthetic compounds can cause free radical formation.

Antioxidants

The damaging effects of free radicals can be countered by antioxidants. These work by either stopping free radical damage by donating an electron without becoming a damaging free radical themselves, or by preventing oxidation commencing.

There are three main types of antioxidants that are important in human metabolism. These are: antioxidant enzymes produced by the body; essential nutritional dietary compounds such as vitamin C, and small plant-derived substances which intercept free radicals and prevent them from causing damage. The full range of antioxidants found in the body include vitamins C and E, carotenes, glutathionine, uric acid, taurine, and plant flavonoids and flavonoid derivatives, and some other compounds. This article considers only the flavonoids, which are small compounds synthesised by plants, but not animals, so must be taken in our diet. They are water soluble compounds based on a unit involving carbon ring structures containing phenols (-OH) groups. There are more than four thousand known, not all of which have antioxidant activity, and a great number remain to be discovered (Colgan 1994). They scavenge free radicals without becoming themselves becoming damaging free radicals or causing other chemical species to become free radicals.

In living plants, flavonoids are produced as pigments, defences against fungi and bacteria, anti-parasitics, and as antioxidants protecting against cellular oxidative stress.

Tree bark in history

Tree bark is a particularly rich source of a wide variety of kinds of medicinal compounds, and this has been known to many cultures for many centuries. Two thousand years ago Hippocrates, the Greek physician known as the father of medicine, recommended chewing on white willow bark to relieve pain and fever. In England, this was a common practice in the Renaissance. The active ingredient was isolated in 1828 and was given its current name, salicylic acid in 1938. It was stabilised in 1897 as acetylsalicylic acid. Even though the new product enjoyed great market success, its mode of action was not known until John Vane, a British Pharmacologist, found that they inhibited the body’s production of prostaglandins that promote inflammation and thereby cause pain. Vane received a Nobel Prize for this work. Salicylic acid, a natural product, has been found to have widespread and beneficial effects on many human conditions, including heart attacks and strokes (Graeda and Ferguson 1993).

Decoctions or infusions of barks and leaves were commonly used as poultices and therapies throughout Europe and Asia. The great navigator, Captain James Cook, was well aware of the value of bark and leaves as antiscorbutics (antiscurvy agents). After an enormously long and difficult voyage to New Zealand he would set out to collect materials for “spruce beer”, an optimistic name designed, no doubt, to make the bitter concoction more palatable to his reluctant crew. Spruce, or white, or Norwegian beer was well known then, as it continues to be today, and even if not loved, it was at least accepted for its effects! But Cook’s spruce beer was neither spruce, nor was it beer. What it was is revealed in a letter he wrote to the errant Furneaux, the captain of the accompanying ship on the second of Cook’s voyages. Unlike Cook, Furneaux had a serious scurvy problem amongst his crew because he had not previously followed Cook’s detailed instructions. So, in his letter Cook gave instructions to “brew” beer of the inspissated (thickened) juice of wort, essence of spruce and tea plants. By spruce he meant anything that vaguely resembled spruce, since there was then no spruce in New Zealand, and by tea plants he meant manuka-like plants. Manuka is a ubiquitous and cheerfully scruffy charmer of a scrub or small tree in New Zealand. Like many plants, Manuka contains powerful anti-microbial compounds and other useful biologically active ingredients. Recent work has shown that those evergreen southern equivalents to conifers, the Podocarps, to which Cook’s “spruce” belongs, have an abundance of flavonoids . As much as they hated his brews, Cook’s crews did consume them and their health was remarkably good (Hough 1994). Cook delivered a paper to the Royal Society describing his work in conquering scurvy and other health problems on long sea voyages. He did not claim to have discovered the health benefits of vegetables and plant extracts, as others had experimented with such diets and treatments earlier, but his fame was such that he was greatly instrumental in popularising them to the enormous benefit of seafarers’ health.

Asian cultures used bark extensively to treat and heal. Indian Ayurvedic medicine has a 5000 year history. Punarvasu in about 800 BC, wrote the Susrita Samhita which describes 1500 plants and 300 medicines of therapeutic value. Barks are important components of Ayurvedic practice. The bark of the arjuna tree has been used for at least 3000 years for the treatment of heart failure and for reducing the swelling due to fluid accumulation in ankles and legs when the heart is not pumping properly. This traditional use has been confirmed by western science and it is used by many healers today including Western-trained healers.

The dried bark of the varuna tree has provided relief from kidney and bladder stones. It is now being used in Western medicine to prevent stone formation and related urinary tract infections (Chevellier 1996).

The Chinese, too, have used bark products in their traditional medicine for very many centuries. A herbal and medicinal source book, written over 2500 years ago, the Shen Nung Pen Tsao Ching of China lists over 360 medicinal drugs made from plants. Barks are used extensively. Every Chinese herbalist uses a wide variety of barks, each with its own characteristics and specific uses. Cinnamon, the dried bark of Cinnamomum cassia, is used to control fever and diarrhoea, to aid menstrual problems, and to soothe indigestion. Recently, scientific medicine has confirmed its potency as an antiseptic agent and has shown its potency in reducing the insulin dependency in diabetics. Magnolia barks are prescribed in Chinese herbal medicine as a skeletal muscle relaxant, analgesic and anti-hypertensive. Phelledendron spp., are commonly prescribed to treat diarrhoea and inflammation (Griggs, 1993).

Extensive research in China and Japan is elucidating the active ingredients in these remedies, but only a small fraction of the myriad complex compounds in bark have been identified.

Polynesian and American indigenous people also made use of bark (Whistler, 1991; MacDonald, 1993, Garrett and Garrett, 1996; Wyatt, 1994).

Industrial preparation of flavonoids

Today, various barks are used extensively for health purposes. Following the great success of Taxol, there has been a massive search by ethnobotanists and biochemists for useful bark extractives and a number of useful substances have been discovered. Bark flavonoids are amongst the most useful. They can be extracted industrially using solvent extraction or hot water extraction. This process isolates and concentrates the flavonoids by partitioning them between two different phases of mutually insoluble solvents – like oil and water. More of the desired compounds dissolve in one phase and the unwanted material in the other so it is then easy to separate the two phases mechanically. Further purification can be undertaken by “salting out” – precipitation of the desired material by adding increasing amounts of common salts, such as magnesium sulphate. The salt remains in solution but throws the less soluble flavonoids out of solution as a precipitate so they can be collected. The trouble is that these two processes, solvent partitioning and salting out, do not yield completely pure products. Some of the undesirable compounds get through, necessitating repeated cycles of solvent extraction and salting down in order to obtain yields of sufficient purity. But three main problems still remain with this approach: solvent residues may contaminate the product, undesirable by-products may contaminate the product, and micro-organisms may survive the processing to be present in the product. Furthermore, the process is expensive.

In contrast, the process used to produce a recent new product – enzogenol – is based on water extraction in the absence of oxygen (to prevent the possibility of oxidation of the flavonoids) of clean and selected bark from the Monterey Pine – a coastal species from the Pacific Northwest of North America which is grown extensively in New Zealand. The desired mixture of flavonoids can be selected from the decoction or liquor by a purely physical process. This excludes all the undesirable by- products and micro-organisms to yield a very pure product of controlled composition. The by-products are used as a soil enhancer, so no wastes are produced from the process. Even the water can be recycled (Gilmour in Duncan, 1998).

Bark as a source of antioxidants

Why should bark contain so many antioxidants? The reason is that oxidative stress is a great problem faced by the stem of trees. Stems are intended to last many decades or centuries, so that they have to have powerful and long-lasting protection against attack, decay and disease. Bark is the structure that performs this protection, and since oxygen diffuses from the outside of the stem through the bark, antioxidants are present in the bark and the tissues immediately underneath it so as to provide protection in the event of free radical formation.

Table 2. Kinds of flavonoids and their origin The six classes of flavonoids: flavonones, found in citrus flavones, found in herbs flavonols, found in all fruits and vegetables isoflavonoids, found in legumes anthocyanidins and flavans, found in fruits.None are synthesised by animals, and our sources are entirely from the plants we eat. We should eat a wide variety of types and not rely on only a few.

Human metabolism does produce some antioxidants naturally, but these are not sufficient to combat all the free radicals formed in our bodies. We rely on dietary sources to augment and complete our defences. The trouble is that the rate of formation of free radicals has probably increased over the last few centuries due to increas- ing sources of free radical forming agents as industrial processes extend further and further into our lives. Further- more, our diet has become more and more deficient in free radicals owing to changing dietary habits away from sources rich in antioxidants (raw leafy vegetables, onion, nuts, fruits) toward overly processed foods from which flavonoids, Vitamin E and many other nutrients have been removed. More people are living longer, so these two influences are affecting more and more people. It seems a great pity that modern food processors exploit our two Achilles heels of diet – our fondness for fat and sugar. Most of us are far too fond of these for our own good. This was not a problem when our only sources of food had limited amounts of fats and sugars, but today we can greatly modify our food and over-process it to an extent that it poses a risk to human well being. Nor do I believe that supplementation of these over-processed foods by adding back in synthetic forms of the extracted nutrients is at all wise. There is evidence that such practices are doubly inimical to human health – not only has the over processing removed essential nutrients, the addition of synthetic forms of these poses chronic risk through the loading of the body with antichiral synthetics (manufactured forms of nutritional or medical compounds which have the correct gross chemistry, but which have the wrong stereoisometry for appropriate biochemical action).

Determining the health value of flavonoids

There are six main ways by which the effects of dietary flavonoids on human health may be evaluated: direct measurement of oxidative stress levels, epidemiological studies, repeated measures tests, laboratory (in vitro or in glass) biochemical or cytological studies, randomised double blind trials, and animal testing.

We can measure the site and extent of oxidative stress in human subjects by urine analysis. The beneficial effects of antioxidants can be assessed by measuring the decrease in oxidative stress levels following administration of dietary supplements. This is being researched at the present time and results are still to be evaluated, but initial results appear extremely promising.

Epidemiological studies can be divided into two types: observational and experimental. Observational studies compare the incidence of disease and longevity in flavonoid-rich populations, such as in the Mediterranean countries, with flavonoid-poor countries, such as the United Kingdom and the United States. The results indicate that a flavonoid-rich diet does, indeed, lead to increased longevity and better health, but other factors, such as genetic factors, may be involved. It is essential to maintain a wide range of different flavonoids from a variety of sources if you rely on natural dietary sources alone.

Experimental epidemiological studies rely on repeated measures, which are a scientific kind of “before and after” studies. An example of such studies is the Spanish women smokers study completed last year. Little benefit was recorded in lowering the incidence or outcome of lung cancer from a diet rich in flavonoids, but this is what may be expected in such a rampant form of cancer as lung cancer. Other studies have indicated that flavonoid supplements have very great benefits in both preventing diseases and in mitigating their effects.

Laboratory studies have shown that plant-derived antioxidants have great antioxidant activity. Platelet aggregation, thrombosis formation and plaque deposition are all reduced, thus explaining the epidemiological observations of reduced incidence of strokes and heart disease. The effects of flavonoids on cancer formation and propagation are also becoming understood. Again, the evidence is accumulating that flavonoids can help prevent certain cancers forming, growing and undergoing metastasis.

However, randomised double blind clinical trials of chronic effects of flavonoids are not as common, mainly because of expense and experimental difficulties. If you are studying the rate and age of onset chronic degenerative diseases it is scarcely practical to undertake clinical trials of twenty or thirty year duration. For similar reasons, “longitudinal” (life long) animal trials are rare. They are very expensive and are liable to be affected or destroyed by factors beyond control. The longer the duration of the experiment, the more likely these destructive events are to occur. So chronic experimentation, whether it is by the double blind methodology or fully controlled animal trials, tends to be rare. There have been some, however. Trials on vinegar flies in the early 1970s showed greatly increased longevity, and recent trials on mice have shown greatly reduced incidence of spontaneous old-age cancers, healthier and thicker coats, better cognitive skills, and increased longevity (Duncan, 1998).

Short-term studies of flavonoids are more popular amongst researchers. Recent studies are given in the references to this article.

Other benefits of flavonoids

Besides combating free radicals, flavonoids have been shown to have other beneficial effects including: adhesion receptor expression, slowing down or preventing bacterial replication (one of their main functions in living plants), slowing down viral replication, inhibiting proteolytic enzyme action, oestrogenic effects and carbohydrate induced AGE, (advanced glycosylation end products, where glucose and its polymers bond on to protein and cause the proteinacous materials of the body to become mucoid or amyloid material that “gums up the works”. An example of this is ageing of skin where collagen thickens and becomes less flexible because of glycosylation, and less flexible because of the cross linking due again to glycosylation. This, coupled with the loss of subdermal fat due to free radical damage and glycosylation, causes the appearance of old skin).

Conclusion

Free radicals are implicated as a major cause of many disease states in the human body, particularly chronic inflammatory and degenerative diseases such as arthritis, heart disease and cancer. There is a great deal of evidence suggesting that positive health benefits can be achieved by the adoption of a healthier lifestyle, a healthier diet richer in flavonoids and taking dietary supplements if the normal diet is deficient in flavonoids. The incidence of oxidative cell damage and general degenerative diseases is lowered by dietary flavonoids. There is also excellent evidence that the onset of these conditions can be delayed or even prevented by diets rich in flavonoids.

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