Why choose natural antioxidants

Dietary Antioxidants and Human Health

Plants produce a very impressive array of antioxidant compounds, including carotenoids, flavonoids, cinnamic acids, benzoic acids, folic acid, ascorbic acid, tocopherols, and tocotrienols, and plant-based foods are our major source of dietary antioxidants. Antioxidant compounds are concentrated in the oxidation-prone sites of the plant, such as the oxygen-producing chloroplast and the PUFA-rich seeds and oils. Plants make antioxidants to protect their own structures from oxidant stress, and plants increase antioxidant synthesis at times of additional need and when environmental conditions are particularly harsh. Humans also can upregulate the synthesis of endogenous antioxidants, but this facility is very limited. For example, production of the antioxidant enzyme SOD is increased with regular exercise, presumably as an adaptation to the increased ROS load resulting from higher oxygen use. However, an increase in other endogenous antioxidants, such as bilirubin and uric acid, is...

Free Radicals and Antioxidants

The electrons in an atom are located in orbitals, with each orbital containing a maximum of two electrons. When an orbital has an unpaired electron, the molecule containing the unpaired electron is called a free radical. Free radicals are highly reactive in the body, oxidizing (removing an electron from) other atoms, or sometimes reducing (donating their electron to) other atoms. The major free radicals are referred to as reactive oxygen species, if they contain oxygen with an unpaired electron, or reactive nitrogen species, if they contain nitrogen with an unpaired electron. The unpaired electron is symbolized with a dot superscript. Thus, reactive oxygen species include the superoxide radical (O2), the hydroxyl radical (HO'), and others. Reactive nitrogen species include the nitric oxide radical (NO') and others. These free radicals are produced by many cells in the body and serve some important physiological functions. The superoxide radical and nitric oxide radical produced in...

Antioxidant Properties of Botanical Polysaccharides

Despite the significant role of mammalian antioxidant and repair mechanisms, oxidative damage is an inescapable outcome of aerobic life. When the production of ROS exceeds the ability of living organisms to prevent their accumulation, the result is oxidative stress. In this regard, oxidative stress has been implicated in many different diseases, including the ageing process in general (reviewed in 209-211 ). Excessive amounts of ROS, such as superoxide anion (O2*-), hydroxyl radical (OH*) Because of the role of ROS in the aetiology of inflammatory disease and tissue injury, considerable efforts have been directed towards the discovery of effective antioxidant compounds that can reduce inflammation and impede oxidant injury to tissues 214, 215 . There are a large number of antioxidant compounds e.g., vitamin E, probucol, butylated hydroxytoluene (BHT) and anti-inflammatory drugs , and these agents have been shown to be useful in the treatment of diseases involving the production or...

Free radicals and immune cell function

The most abundant circulating white blood cell, the neutrophil, utilizes reactive oxygen species to kill invading organisms. When stimulated, neutrophils have the capacity to take up molecular oxygen and generate oxygen-containing free radicals and other reactive molecules. This is often called the oxidative burst. Free radicals and singlet oxygen, along with other reactive molecules, can kill pathogens. Neutrophils can also generate highly toxic halogenated molecules (e.g. hypochlorous acid) when the myeloperoxidase halide enzyme system is activated during the oxidative burst. The halogenated species can also lyse the phagocytosed pathogen. Recently, another reactive oxygen species, peroxynitrite, has been identified as an important component in immune cell killing of pathogens.

Clinical examples of free radical antioxidant and immune function interactions

Approximately 30 of US adult women and 25 of adult men smoke. Cigarette smoke contains millions of free radicals per inhalation. Other harmful products in cigarette smoke can stimulate the formation of highly reactive molecules that further increase the free radical burden smokers have significantly higher breath pentane levels than nonsmokers. The micronutrient most affected by cigarette smoking appears to be the anti-oxidant, vitamin C. Smokers require about four times as much vitamin C per day to reach the same blood levels as nonsmokers. In addition to vitamin C, serum levels of vitamin E, folic acid and 3-carotene, as well as lung vitamin E concentrations, are significantly lower in smokers compared to nonsmokers. part be due to the overproduction of immunosuppressive free radicals by neutrophils and macrophages in their lungs. The lung of the healthy non-smoker contains very few neutrophils. In smokers, there is a constant activation of neutrophils and a consequent...

Antioxidant Defences Following Infection and Injury

Although the body strives to maintain them, observations in experimental animals and patients indicate that antioxidant defences become depleted during infection and after injury. For example, in mice infected with influenza virus, there were 27 , 42 and 45 decreases in the vitamin C, vitamin E and glutathione contents of blood, respectively (Hennett et al., 1992). In asymptomatic HIV infection, substantial decreases in glutathione concentrations in blood and lung epithelial-lining fluid have been noted (Staal et al., 1992). In patients undergoing elective abdominal operations, the glutathione content of blood and skeletal muscle fell by over 10 and 42 , respectively, within 24 h of the operation (Luo et al., 1996). While values in blood slowly returned to pre-operative values, concentrations in muscle were still depressed 48 h post-operatively. Furthermore, reduced tissue glutathione concentration has been noted in hepatitis C, ulcerative colitis and cirrhosis. In patients with...

Effects of Antioxidant Deficiency on Immune Function

One of the most obvious factors that could reduce antioxidant status is a dietary deficiency. Jacob et al. (1991) examined the effects of marginal vitamin C deficiency on immune and other parameters in healthy males. Serum, white blood cell and sperm vitamin C levels were significantly reduced when the daily diet contained 5, 10 or 20 mg of vitamin C for 2 months. DTH responses to seven antigens were also significantly depressed during the period of low vitamin C intake. In fact, when subjects initially consumed 250 mg day-1 of vitamin C, they responded to 3.3 out of seven antigens, which were reduced to less than one antigen after only 1 month at 5 mg day-1 of vitamin C. Even when intakes were increased back to 250 mg day-1 for 1 month, the average number of DTH responses did not increase above one out of seven antigens. The robustness of the responses (i.e. the diameter of the induration) was 35 mm at baseline, dropped to 11 mm when vitamin C intakes were 5, 10 or 20 mg for 2 months...

Free Radicals

Free radicals are incomplete molecules, unstable because they have an unpaired, free electron. The presence of the unpaired electron makes a free radical a strong oxidant and highly reactive. Free radicals can damage cell membranes, fatty acids, cholesterol, proteins, and DNA and play a role in the pathogenesis of many chronic degenerative diseases.1 Oxidation of cell proteins and membranes can produce tissue damage in rheumatoid arthritis, inflammatory bowel diseases, and Parkinson's disease.2 Oxidation of LDL cholesterol increases risk of atherosclerosis.3 Oxidative damage to DNA may contribute to development of cancer.1,4


Dietary antioxidants are compounds that (in theory) reduce oxidative damage to the body by free radicals. Free radicals are highly reactive chemicals that have the potential to attack critical molecules within the body, changing their chemical structures and affecting their function. Oxidative stress is defined as an imbalance between the levels of various reactive oxygen species (molecules or compounds that react easily and can cause cell damage, such as superoxide, hydrogen peroxide, hydroxyl radicals) and the ability of the body's natural protective mechanisms to control and cope with these reactive compounds before they cause damage to cells or cellular processes. Oxida-tive stress-induced damage and the consequent alterations to metabolism and biologic function are hypothesized to cause many chronic diseases and contribute to the natural aging process. The most well-known antioxidants are vitamins C, E, selenium, carotenoids (i.e., beta-carotene, lutein, and lycopene), and...

Radicals and disease ferryI gone wrong

As stated in the introduction, the ferryl ion is potentially as reactive as the hydroxyl radical 18 , Furthermore the mechanism of enzymes using ferryl intermediates usually involves the generation of free radicals, either on the protein or on the substrate. Although these proteins are careful to contain the reactive species, inevitably there are instances where reactions occur that are undesirable. Furthermore several proteins are able to form ferryl species accidentally. These can result in cell and membrane damage as these proteins are not designed to safely utilise such strongly oxidising intermediates. Furthermore there is the possibility that reactive ferryl iron is produced from the same low-molecular-weight iron species that can generate superoxide and hydroxyl radicals. Although both haemoglobin 155,231 and myoglobin produce ferryl iron and free radicals upon addition of H2O2, the latter reaction has been studied more extensively. In contrast to most peroxidases, at least two...

Fruits and vegetables their constituents and modes of action

There are several biologically plausible reasons why the consumption of fruits and vegetables might slow, or prevent, the onset of chronic diseases. They are a rich source of a variety of vitamins, minerals, dietary fibre and many other classes of bioactive compounds collectively called phytochemicals. Experimental dietary studies in animals, cell models and humans demonstrate the capacity of some of these constituents of fruits and vegetables to modify antioxidant pathways, detoxification enzymes, the immune system, cholesterol and steroid hormone concentrations, and blood pressure, and their capacity to act as antioxidant, antiviral and antibacterial agents. There has been extensive focus on antioxidant effects, as oxidative damage to biomolecules has been hypothesised to be responsible for CVD, cancer initiation, cataract formation, inflammatory disease and several neurological disorders. Our antioxidant defence system prevents the formation of damaging free radicals, removes...

Dietary Treatments Optimal Nutrition

Maintaining healthy joints starts with adequate nutrition. Athletes should get adequate levels of protein to maintain and repair muscles, tendons, ligaments, and joints. Fruits and vegetables provide antioxidants that can help reduce inflammation and improve recovery from and adaptation to exercise. Essential fats, especially omega-3 fatty acids, are beneficial for promoting prostaglandins that control inflammation and pain pathways. Some essential fatty acids, such as omega-6 fatty acids, are easy to obtain from dietary sources because they are readily available in plant oils. A 1 1 or 2 1 ratio of omega-6 to omega-3 fats in the daily diet has been suggested. The amount of omega-3 fatty acids can be achieved by eating fish two to three times per week and using flax oil regularly.

Oxidation and Disease an Overview

Many years ago, it was proposed that a common event could explain many of the findings we associate with diseases of various sorts, such as diabetes, heart attacks, strokes, arthritis, lupus, Alzheimer's disease, and other degenerative diseases of aging. That common event appears to be the destructive oxidation of tissues by free radicals, a process I have already described. Some have tried to separate disease from normal aging, while others have insisted that aging is a disease and that it is not normal for tissues to deteriorate with aging. This latter group of thinkers has grown in the last several decades to form a whole discipline dedicated to anti-aging medicine. Whether aging is a disease or a natural event, we know that both share a common factor damage to cells and tissues by a constant barrage of free radicals, and other reactive molecules, over a lifetime. Aging begins even before birth in fact, free radicals are formed from the very moment of conception. They produce some...

Nutrients That Can Help

People with rheumatoid arthritis tend to have low antioxidant levels, and two studies so far have found that natural vitamin E supplements significantly reduce symptoms of the disease. The dosage used in these studies was relatively high, 1,800 IU daily. Vitamin E also lowers levels of interleukin-6 and C-reactive protein, both of which promote inflammation. Selenium, another antioxidant, also might help, but the research has not been consistent. The mineral boosts production of glutathione peroxidase, one of the body's main antioxidants.

Nelda Fish Oil to Relieve Pain

She figured there had to be an alternative, so she visited Hugh D. Riordan, M.D., president of the Center for the Improvement of Human Functioning International in Wichita, Kansas. Laboratory tests showed Nelda sensitive to some of her favorite foods, specifically dairy products and white potatoes, which she immediately stopped eating. She also began taking a number of anti-inflammatory supplements, including fish oils and antioxidant vitamins.

Athletic and Other Injuries What Are Athletic Injuries

Injuries generate large numbers of free radicals released by activated white blood cells. Studies have found that broken bones and damaged cartilage increase free-radical levels, even without the presence of white blood cells. In addition, ischemic-reperfusion injuries also boost free-radical levels and tissue damage. Ischemia refers to a reduction of blood flow, often the first phase of an injury, which is followed by an influx of red blood cells both phases generate large quantities of free radicals.

Chapter Ten things to do for better health

Eliminate saturated fats, trans fats and cholesterol. Fats are very calorie dense. (9 calories per gram compared to 7 calories per gram for alcohol and 4 calories per gram for protein and carbohydrates.) Saturated fats and cholesterol clog your arteries and lead to heart attacks and strokes. Trans fats present a problem with free radicals, which damage body cells. Replace the bad fats with the good fats. The good fats are polyunsaturated and monounsaturated fats. 9. Some herbs and spices have been shown to be great aids for better health. Garlic, cloves and cinnamon are especially beneficial. Raw garlic is used by some to treat the symptoms of acne and there is some evidence that it can assist in managing high cholesterol levels. Garlic is high in anti oxidants to counter the effects of free radicals. Cloves and cinnamon both help lower blood glucose levels for diabetics and help lower the bad cholesterols. There are also other natural herbs that used wisely can improve your health.

Series Editor Introduction

Cardiovascular and cerebrovascular diseases are the focus of the third section. Long-chain omega-3 fatty acids (LC PUFA) have been associated with reduced risk of CVD in survey studies for the past 50 years, and the potential mechanisms for reduction in risk continue to be elucidated, but include antiinflammatory, antiarrhythmic and antiproliferative actions at the cellular level and beneficial alterations in lipid profiles, especially triglycerides. This chapter contains a detailed description of the effects of LC PUFA on lipids, lipoproteins, triglycerides, apolipoprotein levels, turnover, and metabolism. New data on the role of LC PUFA in diabetics are also included. LC PUFA are examples of good fats. The next chapter describes the adverse effects to the cardiovascular system caused by trans fats, examples of bad fats. The majority of trans fats are found in foods that contained hydrogenated oils or contained fats that went through other production processes that resulted in their...

Lyme Disease and Rickettsia

In the nervous system, the organism can cause a condition called neuroborreliosis, which appears to involve the glutamate neurotransmitter system. In fact, viral infection acts through the same mechanism. It has been shown that the bacteria or virus activates microglia in the nervous system, which move around within the brain and spinal cord seeking out the spirochetes. When it encounters them, the microglia are activated and begin to pour out large amounts of free radicals and immune chemicals (cytokines). Together, these two block the uptake mechanism for the glutamate neurotransmitter.535 This brings us to a special concern of mine killing organisms too rapidly without sufficient protection. When microorganisms invade tissues, the immune system sends in billions of white blood cells (mostly lymphocytes, phagocytes, and NK cells) to kill the organism. As part of this process, the white blood cells generate a storm of free radicals and release powerful cytokine immune chemicals that...

Connective tissue disease

Systemic sclerosis (SSc) or scleroderma. There are two forms of SSc, a diffuse cutaneous form, associated with auto-antibodies to topoisomerase-1, and a limited cutaneous form, the CREST syndrome (calcinosis, RP, esophageal dysmotility, sclerodactyly, and telangiectasia), associated with anti-centromere antibodies. Most (90 to 95 ) patients with SSc exhibit RP, which is frequently the presenting feature of the disease. RP is usually worse in limited SSc. On examination, sclerodactyly, evidence of ischemic tissue necrosis with digital pitting, digital ulcerations, and even gangrene may be present. Nailfold capillary microscopic abnormalities include enlargement of the capillary loops and the presence of intervening avascular areas. The latter predict transition to diffuse SSc. Endothelial cell damage or dysfunction is a prominent and early characteristic in the disease course, but the underlying mechanisms are unknown. Oxygen free radicals generated during reperfusion injury from...

Drug Therapy Conventional and Alternative Therapies

Function as an antioxidant, and to improve portal blood flow. However, a recent Cochran review evaluated PTU therapy for ALD, including alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and or cirrhosis, and no beneficial effect was noted. We do not recommend use of PTU in ALD. Silymarin is probably the most widely used form of complementary and alternative medicine (CAM) in the treatment of liver disease in the United States. It has antioxidant activities, it protects against lipid peroxidation, and it has anti-inflammatory and antifibrotic effects. Large controlled trials of silymarin have been performed in Europe, with varying results using doses between 140 to 150 mg orally 3 times daily. In all studies performed thus far, the drug appears quite safe. Other Antioxidants Dilinoleoylphosphatidylcholine Dilinoleoylphosphatidyl-choline (a form of lecithin soybean extract) has antioxidant, antifibrotic, and anticytokine activity in experimental rat models of ALD. However, a...

Systemic Immune Mediated Diseases

MMP-9 in tears (produced by infiltrating granulocytes), and MMP-2 overexpression by cultured keratocytes from perforated corneas have been reported 18 . Activated MMP-2 and MMP-9 target type IV basement membrane collagen and may initiate perforation by breaching the corneal basement membranes (epithelial cell and Descemet's) 19 . Apparently O and NO may be generated by activated macrophages and neutrophils, as a result of immunological responses to pro-inflammatory cytokines, and these free radicals may activate MMPs, inactivate tissue inhibitors of metalloproteinases, and breach epithelial cell barriers if these cells were already the target of an inflammatory cell attack in systemic disease 18 . Given the evidence that corneal epithelial cell surface proteins may be targeted by circulating antibodies in RA patients 20 , the authors suggest that once the corneal basement membranes have been disrupted by activated MMP-9 MMP-2, the corneal stroma may be freely invaded by macrophages...

Use in Prevention and Therapy

Selenium has anticancer properties, possibly through its effects on the immune system or its antioxidant actions (Fig. 3.16). Regions of the USA with the highest intakes of selenium tend to have lower rates of cancer,8,9 and higher blood levels of selenium are associated with lower risk of cancer.8,9 Supplementation in older men can reduce risk of lung, colon, and prostate cancer by nearly 50 .9 Fig. 3.16 Role of selenium in primary prevention of cancer. In an intervention trial including nearly30000 adults, 7500 received an antioxidant supplement con taining 50 ig selenium (along with 30 mg vitamin E and 15 mg beta-carotene) for 5 years. The supplemented group had a significant 13 reduction in cancer mortality, compared with those not receiving the supplement. (Adapted from Blot WJ, etal. J Nat Cancer Inst. 1993 85 148)

Inflammation and Oxidative Damage

Many diseases that have an inflammatory basis such as cancer, sepsis, and chronic inflammatory diseases such as rheumatoid arthritis (RA) have symptoms mediated by pro-inflammatory mediators named cytokines. These mediators, which include interleu-kins (IL) 1-8, tumor necrosis factors (TNF), and interferons, are essential for protection from invading bodies. They act by producing a situation in which immune cells are attracted to the inflammatory site and are activated. An inflammatory stimulus, such as tissue damage incurred by trauma or invasion of tissue by bacteria or viruses, induces production of IL-1, IL-6, and TNF from a range of immune cells, including phagocytic leucocytes and T and B lymphocytes. Once induced, IL-6, IL-1, and TNF further induce each other's production, leading to a cascade of cytokines, which are capable of producing metabolic and immune effects. Inflammatory stimuli also bring about the activation of neu-trophils to release free radicals, which enhance the...

Other Physiological Effects

The extremely low rate of CHD in countries with high consumption of olive oil, for instance, suggests the benefits of substituting this fat for other fats. This kind of analysis has been expanded further by noting that MUFA intake is inversely associated with total mortality as well as with CHD. Some effects may well be because of the amount of anti-oxidant vitamins olive oil contains. Vegetable oils are the most important source of a-tocopherol in most diets, and olive oil contains about 12mgper100g. Evidence indicates that a-toco-pherol functions as a free-radical scavenger to protect cellular membranes from oxidative destruction. Oxidative stress has been linked to an increased risk of many chronic diseases, including atherosclerosis, cancer, and inflammatory disorders. Other injuries such as cataract and reperfusion injury are also associated with an increase in oxidative stress and a decrease in antioxidant activity. See also Antioxidants Diet and Antioxidant Defense. Arthritis....

Effect of HA1077 on Cerebral Infarction

HA1077 had been shown to inhibit migration of white blood cells to the ischemic brain in rats (Satoh et al. 1999a,b). In addition, in in vitro system, HA1077 inhibits production of free radicals by NADPH oxidase in WBC through the inhibition of PKC (Arai et al. 1993). Decrease of free radical production by inhibition of PKC seems to be an important part of the effectiveness of HA1077. As HA1077 inhibits the phosphorylation of calponin in the intact artery, the effects of HA1077 on both cerebral vasospasm and infarction can be attributed to both vasodilatation and anti-inflammation. In a recent clinical study, a double-blind trial of HA1077 in patients with acute cerebral infarction due to thrombosis showed that HA1077 significantly decreased motor weakness and improved ADL (unpublished data). Effectiveness of HA1077 has experimentally been suggested in many other diseases where Rho kinase is believed to be involved, including angina pectoris (Katsumata et al. 1997), bronchial asthma...

Collagen Dissolving in Chronic Inflammation

What happens if an inflammation continues for a long time because the invaders' attack is too powerful and the body engages too many of its police cells The result is that the eating cells secrete high quantities of their defense substances over a long period of time. This defense weapon consists not only of collagen-digesting enzymes but also of a load of free radicals. As we saw in the example of the lung infection, the police cells use collagen-destroying enzymes to move through thick connective tissue to get to the area of infection. If the immune system's battle on the site of the inflammation takes too long, then huge amounts of collagen-dissolving enzymes are secreted, creating a problem the inflammation will erode the surrounding connective tissue and turn into a chronic (long-term) process.

Summary and Conclusion A Summary

The reasons for the loss of HA from the skin were attributed to depolymerization induced by both endogenous and exogenous free radicals. This hypothesis is supported by findings that indicate that free radical scavengers inhibit UV-light-mediated cleavage of HA in vitro. It was found that the UV-light irradiation of skin in vivo resulted in increased GAG biosynthesis in hairless mice and albino rats but providing vitamin E in the rat's diet reversed the latter results. Because vitamin E is a natural free radical scavenger, the data support a free radical involvement. In the absence of UV-light irradiation, depolymerization may be caused by endogenous free radicals, which are natural products of metabolism, or by enzymatic degradation. Results on this area are conflicting some workers reported HA depolymerization in rat skin, while others found no significant age-related changes in HA size. HA is an essential heteropolysaccharide of mammalian connective tissue. It is a free radical...

The Cascade of Inflammatory Signaling

Oxidative stress in the diabetic, due to depleted levels of nitric oxide, can increase the pathways that lead to inflammatory signaling by upregulation of peroxyl nitrite free radicals. These processes accelerate pathological changes in endothelial tissues. Another vector associated with inflammatory signaling is obstructive sleep apnea syndrome. Sleep apnea produces more inflammatory signaling, which leads to more accumulation of visceral fat - cycles of the downward metabolic spiral. Surgical removal of visceral fat can reverse sleep apnea in a substantial number of patients,

Candidate Genes in Cutaneous Lupus Erythematosus

Association in other autoimmune disorders is reported for various loci encoding cytokines, cytokine receptors, antioxidant enzymes, and adhesion molecules in rheumatoid arthritis, dermatomyositis, and SLE. It is therefore possible that the polymorphisms at these loci may be candidates for the related autoimmune CLE. Several genetic regions outside the MHC seem to confer susceptibility to cutaneous forms of LE or demonstrate association or linkage with the anti-Ro SSA response, including loci encoding cytokines, cytokine receptors, molecules involved in antigen recognition, and antioxidant enzymes, all of which are plausible candidates and are summarized in Table 15.1. 3. Antioxidant enzyme The antioxidant enzymes encoded by the glutathione S-transferase (GST) genes are widely expressed in mammalian tissues. Ollier et al. (Ollier et al. 1996) examined the role of the GSTM1 null polymorphisms in the production of anti-Ro SSA and anti-La SSB in SLE using PCR to identify GSTM1 chromosome...

Applications of Both Physicochemical Properties and Cell Biological Functions of Hyaluronan

Homandberg et al. (37) showed that HA, of 900 X 103 average molecular weight, suppressed both the alteration in proteoglycan synthesis induced by fibronectin fragments and subsequent cartilage degradation. In addition, HA suppressed the production of free radicals and reversed proteoglycan synthesis induced by interleukin-1 b (IL-1 b) in cultured bovine articular chondrocytes (23). Further, HA84 suppressed IL-1b production in cultured synovial cells from rheumatoid arthritis patients (38). Takahashi et al. (39) have found that the

Treatment strategies based on correcting neurotransmitter defects

For the past 20 years, an increased understanding of the pathology of AD has led to the development of numerous drugs for the treatment of the disorder. At the present time, there are at least 60 drugs estimated to be in development for the symptomatic treatment of AD, some of which may ultimately be expected to affect the development of the disease. The drugs in current use can be broadly divided into those that are designed to enhance cholinergic function and those that reduce the synthesis of free radicals, the anti-inflammatory agents, the oestrogens and a miscellaneous group of natural products which include the Ginkgo biloba alkaloids. In addition, some drugs are in development which are aimed at counteracting the possible causes of neuronal cell loss by counteracting the neurotoxic effects of Ab. These include the inhibitors of gamma secretase and vaccines against Ab. Some of these drugs will now be considered. Antioxidants Free radicals have been considered to play an...

Cytosine Methylation And Dna A Note On Cancer Prevention

As a concluding note, we discuss a promising approach to prevention (and perhaps eventually treatment) that is closely related to what has been covered so far. I already mentioned the possibility that antioxidants may help prevent abnormal methylation patterns. It seems likely that methyl donors have an important role to play in promoting normal methylation as well. (Information on a related topic, polyamine synthesis, is provided in Appendix C for those readers who want more information on other potential cancer prevention and treatment strategies.)

Toxicological vs Physiological Functions Of Ros

During the normal aerobic metabolism, ROS are generated at low levels as unwanted by-products as a consequence of the transfer of a single electron. ROS, which include oxygen free radicals and their nonradical derivatives, play an integral role in maintaining and modulating a wide spectrum of vital physiological functions. In recent years, it has become more apparent that ROS are important mediators of intracellular signaling and redox regulation responsible for cellular home-ostasis (4-6). In fact, some growth factors, cytokines, hormones, and neurotransmitters utilize ROS as secondary messengers in executing normal physiological processes (7). However, excessive production of ROS by exogenous redox chemicals, physical agents (e.g., ultraviolet and ionizing radiations), bacterial or viral infection, or under abnormal pathophysiologic conditions such as oxygen shortage (hypoxia) can be destructive. ROS not only induce direct damage to critical biomolecules, such as DNA, proteins,...

Pro Inflammatory Molecular Targets Eicanosoids Cytokines Second Messenger Pathways and Effector Molecules

Another important pro-inflammatory gene that is up-regulated during inflammation is the inducible form of nitric oxide synthetase (iNOS). The inhibitory effect of Hp extracts and harpagoside on iNOS expression has been reported. As discussed above, an Hp water extract decreased the level of iNOS mRNA in LPS-stimulated fibroblasts 35 . Kaszkin et al. 37 used isolated rat kidney mesengial cells activated by application of the pro-inflammatory cytokine, interleukin (IL)1b, as a model for kidney inflammation and investigated the effect of two special extracts of Hp on ILlb-induced iNOS expression. Both extracts were water extracts containing high levels of harpagoside (8.8 and 27 respectively) and inhibited ILlb-induced iNOS expression as evidenced by a dose-dependent reduction in the levels of iNOS mRNA (measured by Northern blot), iNOS protein (measured by western blot) and nitrite (product of iNOS) synthesis. This study also demonstrated that the inhibitory effects of Hp extracts were...

French Maritime Pine Bark Extract

A complex of some 40 antioxidant flavonoids and organic acids working together synergistically, it is one of the polyphenol extracts known as oligomeric proanthocyanidins (OPCs), which also include grape seed extract. Effects One of the most potent antioxidants available (it is 50 times more powerful than vitamin E and 20 times more powerful than vitamin C), it can extend the effectiveness of vitamin C over a longer period of time and can effectively protect against the hydroxyl free radical, which can directly damage DNA. The extract can also cross the blood brain barrier and protect brain cells from harmful compounds in the body. It also aids the immune system, strengthens and repairs connective tissue, helps prevent heart disease, strengthens the capillaries, and has antiinflammatory properties that protect against such ailments as arthritis and allergic reactions. Studies have also shown that it can protect against stroke, stress-related ulcers, diabetic retinopathy, and some...

The Role of Curcumin in Modern Medicine

Abstract Curcumin (diferuloylmethane) is an orange-yellow component of turmeric (Curcuma longa), a spice often found in curry powder. Since the time of Ayurveda numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, and liver disorders. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and thus has a potential against various malignant cancers, diabetes, allergies, arthritis, Alzheimer's disease, and other chronic illnesses. These effects are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes. Thus, curcumin, by virtue of its effect on multiple cell signaling pathways, could prove to be a panacea for modern human diseases. Keywords Curcuma longa Curcumin Antioxidant Anticancer

General Information

Pentoxifylline (oxipentifylline) is a methylxanthine that antagonizes the vasoconstrictor effects of catecholamines and increases cyclic AMP concentrations, causing smooth muscle to relax. It has also been claimed to correct impaired microcirculation, by improving various factors that disturb blood rheology, and to reduce the generation of toxic free radicals from leukocytes during ischemic leg exercise in patients with intermittent claudication. Pentoxifylline has been used to suppress overproduction of tumor necrosis factor alfa in conditions such as falci-parum malaria and rheumatoid arthritis and in transplant recipients, with varied success.

Treatment and Outcome

Uric acid is the final breakdown product of purines in humans. Purines are essential for manufacturing DNA and RNA and are therefore present in all animal cells. Humans have higher uric acid levels than most other animals because the animals produce an enzyme called uricase that breaks uric acid down further. Humans actually have the gene for uricase but have inactivated it at some stage during evolution. uric acid is a powerful antioxi-dant. it is believed that the uricase gene was inactivated because of the advantages of having a powerful antioxidant. Given the current enthusiasm for taking antioxidants such as vitamin C and vitamin E as well as a host of others marketed as health supplements, it is interesting to look at how much trouble one of our natural inbuilt antioxi-dants has caused the human race.

Curcumin The Indian Solid Gold

Abstract Turmeric, derived from the plant Curcuma longa, is a gold-colored spice commonly used in the Indian subcontinent, not only for health care but also for the preservation of food and as a yellow dye for textiles. Curcumin, which gives the yellow color to turmeric, was first isolated almost two centuries ago, and its structure as diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 bc) numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, and liver disorders. Extensive research within the last half century has proven that most of these activities, once associated with turmeric, are due to cur-cumin. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes,...

Vitamin E and Other Diseases

Neurodegenerative disease including Alzheimer's and Parkinson's disease are associated with aging, inflammatory processes, free radical damage, and other metabolic processes that influence well-being of the older population (165). Antioxidant intake has been postulated to influence onset and progression of many such disease states. Martin et al. (165) exhaustively reviewed the literature through 2000 on the roles of vitamins E and C on neurodegenerative disease and cognitive performance. Their general conclusion was that vitamin E and vitamin C have some protective effects on age-related deficits in behavioral function when vitamin intake is steady and started early in life. They further stated, A rationale for possible clinical benefits of antioxidants for several degenerative conditions has arisen from the many years of basic science, including clinical and epidemiological studies. Substantial evidence implicates nutrition in the pathogenesis of...

Reactive oxygennitrogen species

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) of biological importance are listed in Table 4.4. ROS comprise oxygen-centred free radicals and non-radical derivatives of oxygen. These species can be generated within the body by a variety of processes and, if not adequately removed, can subject the body to oxidative stress. Severe oxidative stress produces harmful effects such as (1) physical damage to biological membranes and lipoproteins through lipid peroxidation (2) modification of proteins, manifested by an inactivation of certain enzymes and (3) damage to DNA with the potential for causing mutations. The accumulated damage may form the basis of age-dependent diseases such as atherosclerosis, arthritis, neurodegenerative disorders and cancer. Animals have evolved mechanisms to deplete ROS, to limit their formation or to repair the damage caused by them. Many of these mechanisms arise through the direct activation of oxidative stress-inducible genes and the...

Neurotransmitters and Their Receptors

There are two basic types of glutamate receptors, NMDA and non-NMDA types. The latter type responds primarily to AMPA and kainate, and their stimulation releases the Mg+2 blockade of NMDA-receptor ion channels. This, in turn, allows glutamate to gate the NMDA receptors and permits Ca+2 influx from extracellular sources. Triggering both types of receptors normally raises the levels of free intra-cellular Ca+2, activating calmodulin-dependent protein kinases. Excessive stimulation by either receptor type may be deadly for cells. For example, the snake-derived neurotoxin, P-bungarotoxin, binds directly to NMDA receptors in primary cultures of cerebellar granule neurons and induces excessive Ca+2 influx, leading to ROS production, caspase-3 activation, and apoptosis 39 . Exceedingly high Ca+2 levels may trigger this cascade by overloading mitochondria, inducing overproduction of ROS, or by triggering production of xanthine oxidase and superoxide via proteolysis of xanthine dehydrogenase....

Celastrus paniculatus Willd

Withanolides Mechanisms

Memory processes, without inducing neurotoxic effects 171 . Administration of the seed oil to rats also reversed a scopolamine-induced task deficit, but this effect was not associated with anti-ChE activity 172 . Other studies have explored more polar extracts from the seeds of C. paniculatus rather than the seed oil. An aqueous seed extract showed an antioxidant effect in the CNS, which may provide some explanation for the reputed benefits on memory, since this extract enhanced cognition in vivo 173 . A seed extract is also reported to increase brain phospholipid content in vivo, possibly as a consequence of increased myelination 174 . Aqueous seed extracts protected neuronal cells against glutamate-induced toxicity 175 and H2O2-induced toxicity 176 , with methanol and ethanol extracts in addition to the seed oil also showing the latter effect 177 . Although the neuroprotective effect of the polar extracts was attributed to their antioxidant properties, the seed oil, which was the...

Reduction of peroxides

Reversal of oxidative damage is also affected by the antioxidant defence system, thereby arresting progression into oxidative stress and tissue damage. The dietary mineral element selenium is essential for this aspect of antioxi-dant protection and disease prevention, as it is a vital component of the two peroxidase enzymes, GPX, which reduces soluble peroxides and PHGPX, which removes lipid peroxides from biological membranes (Fig. 1.2). Dietary selenium, as selenomethionine, protects against ethanol-induced lipid peroxidation (Parke, 1994b), cirrhosis, cancer and cardiovascular disease. Selenium deficiency, through lower GPX and PHGPX activities, results in increased formation of thromboxanes (TXB2) at the expense of prostaglandin (PGy formation, leading to thrombotic and inflammatory episodes and vascular injury (Schoene et al., 1986).

Interventions refuted by evidence

Antioxidant vitamin and selenium supplements One systematic review evaluated antioxidants (nine trials, 567 patients) 19 . Seven trials examined vitamin E and other trials examined selenium ACE, vitamin A and vitamin C. The authors found no convincing evidence that selenium, vitamin A, vitamin C or the combination product selenium ACE was effective in the treatment of osteo-arthritis.

Therapeutic Manganese Related Agents

The first known therapeutic use of manganese was the treatment of psoriasis, in combination with vitamin Bi in 1966.30 Since that time, manganese salts, enzymes, related genes and synthetic antioxidants have been used to treat disorders involving arthritis, cancer, dermatitis, osteoporosis and ischemia reperfusion injury (lack return of blood) as reviewed below. Other possible therapeutic targets associated with manganese drugs in the future may involve treatment of cardiovascular diseases, diabetes, epilepsy, acquired immuno deficiency syndrome (AIDS), peritoneal adhesions (scars of membrane surrounding the abdominal cavity) and inflammatory pain. A more selective type of SODm is the low molecular weight Mn(II) (penta-azamacrocyclic ligands)-based complex. An example of the non-peptide SOD mimetic is M40403, a bis (cyclo-hexylpyridine-substituted) macrocyclic ligand as shown in Figure 9.2.33 This artificial antioxidant is more potent than natural forms of other antioxidants, with...

Takashi Okamoto Toshifumi Tetsuka Sinichi Yoshida and Takumi Kawabe

NF-kB is an inducible cellular transcription factor that activates various cellular and viral genes. In resting cells, NF-kB exists as a molecular complex with an inhibitory molecule IkB and is located in the cytosol. On stimulation of the cells by various agents, such as proinflammatory cytokines interleukin (IL)-l and tumor necrosis factor (TNF), IkB is dissociated and NF-kB is translocated to the nucleus and activates the expression of target genes. We found that the redox control mechanism is involved in the DNA-binding activity of NF-kB and that the cellular-reducing catalyst thioredoxin (Trx), together with kinases, is primarily involved as an effector molecule in this signaling pathway. Trx has been found to associate with the redox-sensitive cysteine within the DNA-binding loop of NF-kB. Effects of antioxidants in blocking NF-kB activation can be explained by the involvement of radical oxygen intermediates (ROI) in this pathway. These findings support the idea that redox...

Industrial prospects and relevance of biotechnology

Capsaicin is fast becoming a number one plant based pharmaceutical in the world due to its benefits as a pain reliever for arthritis and as a nutraceutical owing to its natural antioxidant properties. Similarly, carotenoids of paprika have been useful as natural colourants and as potent antioxidants for use in designer foods. It is estimated that the world market for food colourants is US 7000 million annually, of which US 2000 million is for natural colours for food applications. The use of paprika carotenoid is for both direct use as a carotenoid colourant in processed foods, but also as colourant for meat, especially chicken by way of feeding it to the poultry birds. Since the use of chemical methods of colouring processed foods is diminishing, scope for the application of a natural colourant is enormous.

Other activities and effects

A protective effect by aerial parts of lavender flowers against enzyme-dependent lipid peroxidation is described by Hohmann et al. (1999). Plant volatile oils have been found to exert certain beneficial effects on the human body in maintaining the level of polyunsaturated acids (PUFAs), to protect them from becoming oxidised (Deans et al., 1995). These EOs show a greater anti-hydrolytic effect than commercial preservatives, such as BHT, on butter, thus reducing its oxidation (Singh et al, 1998). Linalool, on the contrary, showed only marginal inhibitory effects, even at high concentrations, on lipid peroxidation of PUFA's (Reddy et al, 1992). Natural concentrations of some EOs were examined for effects on the system lipid-peroxidation-antioxidant-defense and lipid metabolism in 150 patients with chronic bronchitis. Lavender oil promoted normalisation of the level of total lipids and the ratio of total cholesterol to its a-fraction (Siurin, 1997). Inhalation of lavender oil volatiles,...

Few Extra Nutrients

Antioxidants (Vitamins C and E and Coenzyme Q10) These powerful antioxidants lend their electrons to free radicals in your body, making the radicals more stable and preventing them from destroying cells. This can prevent a host of problems from general aging to heart disease to cancer to arthritis. Your best defense against free radicals is a multilevel approach, and that's why I suggest all the above antioxidants rather than just one. You can get all these antioxidants, plus a dose of other helpful vitamins and minerals, from a few commercially available multivitamin and mineral supplements sold in health food stores. See Chapter 8, Resources.

Polyunsaturated Fatty Acids And Lymphocyte Functions

Inflammatory-type diseases are amenable to fatty-acid replacement therapies because the composition of fatty acids in lymphocytes and other immune cells are modified by both bodily-fat amounts and types of fatty acids available for eicosanoid production. Fatty acids such as arachidonic, alpha-linolenic, eicosapentaenoic, oleic, linoleic, conjugated linoleic, gamma-linolenic, dihomo-gamma-linolenic, and docosahexaenoic all have the ability to influence inflammatory responses that are associated with lymphocyte proliferation and cytokine production, as well as natural-killer (NK) cell activity.9 Pro-inflammatory cytokine production is reduced by omega-3 PUFAs, decreasing the severity of the inflammatory cytokine-related disease processes. Because cytokine production and function are part of a normal host defense, they are necessary. Consumption of PUFAs in excess of 3- 4 g per day may lead to impairment of the immune response. Increased consumption of PUFAs may also lead to increased...


Exactly how MSM may be of benefit in joint disease is not certain, but it may well function by providing a source of sulfur for the formation of the cartilage matrix or the antioxidant systems N-acetylcysteine and glutathione.33 This parallels the suggestion that compounds such as glucosamine and chondroitin sulfate may function by overcoming dietary deficiencies in sulfur amino acids.15

Dual Coxlox Inhibitors

Several chemically distinct dual inhibitors are in different stages of development and deployment. For example, the di-tert-butylphenol class has antioxidant and radical scavenging properties in addition to inhibiting both COX and LOX, in vitro and in vivo examples of this class include darbufelone, tebufelone, and R-830 (Leval, Julemont, Delarge, Pirotte, & Dogne, 2002). Other classes include pyrazoles (FPL-62064, tepoxalin, ER-34122), thiophenes (RWJ-34122, L-652,343), and the pyrrolizines (licofelone or ML 3000) (Leval et al., 2002).

Prevention Of Physical Wear And Tear

Glucosamine is comprised of glucose and glutamine, is the key precursor for the manufacture of joint glycosaminoglycans, and comprises 50 of hyaluronic acid, the core protein from which cartilage and proteolglycans are formed. The three most common commercial forms are glucosamine sulfate (as the sodium or potassium salts), glucosamine hydrochloride, and N-acetylglucosamine, the acetylated derivative. The majority of clinical trials have used a chemically bonded glucosamine sulfate. In vitro studies have revealed that glucosamine increases sulfate uptake by cartilage and stimulates glycosaminoglycan synthesis by cartilage cells (chondrocytes).10 Glucosamine has been shown to have both anti-inflammatory and antioxidant activities. Its anti-inflammatory activity is independent of an effect on cyclooxygenase (COX) or the inflammatory mediators bradykinin or histamine.11 In a three-year study of glucosamine sulfate in subjects with osteoarthritis of the knee, radiography was used to...

The Major Players in Apoptosis

Box 17.1 Inflammatory Diseases, Oxidative Stress, Antioxidants and Redox Modulators While the generation of reactive species by immune cells is therefore beneficial to the human body under normal conditions, an accidental activation of this defense in the absence of an (external) threat is counterproductive, as human diseases, such as rheumatoid arthritis, dramatically illustrate. There have been various attempts to alleviate this kind of attack. First, nonsteroidal antiinflammatory drugs (NSAIDs) are available, which inhibit cyclooxygenase (COX) enzymes and hence disrupt the cellular processes leading to inflammation. As an alternative, antioxidants have been considered that chemically sequester the dangerous cocktail of reactive species formed by immune cells. The uses of NSAIDs and antioxidants cover a whole range of events, from the first step of trying to prevent the occurrence of inflammation to a situation where antioxidants are used to fight off the chemical weapons after they...

Gut Microflora Influences

An epidemiologic study involving a Finnish cohort of 18,709 subjects, of whom 122 developed RA, found that both low selenium and alpha-tocopherol could be risk markers for RA.34 The interesting findings showed that low selenium was probably a risk factor specifically for Rf negative RA, while low alpha-tocopherol levels probably represented a risk factor that was independent of Rf status. An additional report on 1,400 people whose levels of the key antioxidants beta-carotene, vitamin E, and selenium were measured before any of the volunteers had symptoms of RA indicated a significantly reduced antioxidant status in the 14 patients who later developed RA.35

Botanical Medicines

One of the most supportive botanical medicines for the patient with RA may well be cur-cumin or turmeric (Curcuma longa). Notable for its ability to act as an antioxidant and antiinflammatory,59-61 curcumin seems well suited for treating this condition. More recent research suggests that curcumin is a potent inhibitor of the signaling pathway utilized by a specific type of IL-6, called oncostatin M.62 Specifically, curcumin decreases the proinflammatory pathways induced by oncostatin M. If not inhibited via this pathway, oncostatin M signaling results in the transcription translation of metalloproteinases and their inhibitors. An imbalance between metalloproteinases and their inhibitors may represent one of the mechanisms of joint damage in RA. To be able to slow down metalloproteinase expression may represent one of the many recently discovered mechanisms of efficacy of an ancient herb. demonstrated significant increases in the activity of the antioxidant enzymes superoxide...

Bottomline Bodybuilding

TMG works in the liver in helping to metabolize fat as well as increasing detoxifying liver enzymes and increasing glutathione levels. (Glutathione is considered by many Life Extension practitioners to be the very best antioxidant and anti-aging nutrient.) It shows no side effects even in dosages as high as 6 grams a day yet produces many of its benefits with as little as 500mgs daily. It's also a bargain. A weekly dose will run you about a buck.

Therapeutic Applications

However, these approaches have also had limited success 136 . Low-molecular-mass nonprotein-based SOD mimetics that could overcome some of the limitations of the native enzyme have been designed 137 . One such mimetic is M40403, which is currently in phase I clinical trials. In addition, the use of recombinant EC-SOD as a therapeutic enzyme in many of the conditions associated with free radicals is now being assessed. EC-SOD has a much longer half-life (20 h) than intracellular SOD, and is targeted to endothelial cells by its heparin affinity. The targeting of EC-SOD to the endothelial cells would be very beneficial in the treatment of atherosclerosis and ischemia reperfusion injury. This beneficial effect has been demonstrated in animal models of these conditions 138 . To date, no SOD-based therapeutic has been approved in the United States.

Degradation by Nonenzymatic Means

In contrast to being a chemical compound stable under normal physiological conditions, chain scission of the HA polymer can be induced in an unspecific manner by chemical reactions other than enzyme-catalyzed degradation as well as by physical stresses such as freeze-drying, shearing or stirring at critical conditions. Moreover, irradiation can cause depolymerization. In line with this, it was found that free radicals can interact with HA and cause degradation of the polymer (53).

Development Of A Working Hypothesis Relating Parp And Inflammation

NAD depletion induced by PARP activation is likely to accelerate this positivefeedback cycle by preventing the energy-dependent reduction of oxidized glu-tathione, the chief intracellular antioxidant and most abundant thiol in eukaryotic cells.82 NAD is the precursor for NADP, a cofactor that plays a critical role in bioreductive synthetic pathways and the maintenance of reduced glutathione pools.83 Depletion of reduced glutathione, as a consequence of intracellular energetic failure or overwhelming oxidant exposure,84 leaves further oxidant stress unopposed, resulting in greater DNA strand breakage.

Hyaluronan Structures in Solution Relevance to Tissue Biologic Functions and Aging

The reason (or reasons) for the loss of HA with aging has not been elucidated. Some studies suggest that it is due to depolymerization caused by natural free radicals produced during metabolism (62). The finding that free radical scavengers inhibit HA fragmentation in vitro suggests that its depolymerization in vivo follows a free radical pathway (63). HA has also been described as a free radical scavenger and antioxidant (64,65). Its cleavage in vitro upon exposure to irradiation (66-68) also supports the free radical pathway for its depolymerization. the skin from endogenous and exogenous, free radicals. Hydrolytic enzymes, whose catalytic activity is known to increase with aging, may cleave HA into small fragments that are then removed from the tissues (72).

Interleukin1 and Tumor Necrosis Factora

In addition to inducing the synthesis of MMPs and other proteinases by chondrocytes, IL-1 and TNF-a increase the synthesis of other proinflammatory cytokines such as IL-6, leukemia inhibitory factor (LIF), IL-17, and IL-18, and chemokines, including IL-8 (see, for review, 70,74 ). They also upreg-ulate the production of nitric oxide (NO) via inducible nitric oxide synthetase (iNOS, or NOS2) and prostaglandin E2 (PGE2) by stimulating the expression or activities of cyclooxygenase (cOx)-2, microsomal PGE synthase-1 (mPGES-1), and soluble phospho-lipase A2 (sPLA2). Although PGE2 and NO have been well characterized as proinflamma-tory mediators, they may also act protectively in chondrocyte survival and in responses to mechanical stress 57,110 . The mechanisms of crosstalk between prostaglandins and NO that regulate chondrocyte function have been reviewed recently 70 . In the production of prostaglandins, mPGES-1, which is increased in OA cartilage, is a major player 108,118, 136 . In...

Tocopherols and Other Diseases Epidemiological Evidence

Vitamin E appears to act as an immunosuppressant due to its ability to suppress both humoral and cellular immune responses. Tocopherol supplementation significantly enhances lymphocyte proliferation, interleukin-2 production, and delayed-type hypersensitivity skin response and decreases prosta-glandin E2 production by inhibiting cyclooxygenase activity. There appears to be compelling evidence that intervention with dietary antioxidants, such as vitamin E, may help maintain the well-preserved immune function of 'very healthy' elderly, restore the age-related decrease in immune function, and reduce the risk of several age-associated chronic diseases. Epidemiological evidence suggests an Among the most common neurologic diseases are neurodegenerative disorders such as Alzheimer's and Parkinson's disease, which may be caused by oxida-tive stress and mitochondrial dysfunction leading to progressive neural death. An increasing number of studies show that antioxidants (vitamin E and...

Pharmacological effects

Rosmarinic acid (RA) is an important caffeoyl ester (phenolic depside) with proven medicinal properties and well characterized physiological functions. Rosmarinic acid is found in substantial sources in the family Lamiaceae (1,2). Salvia lavandulifolia is used as choleretic, antiseptic, astringent, and hypoglycemic drug in Southern Europe and contains high levels of RA (3). Rosmarinic acid-containing Ocimum sanctum (holy basil) is used to reduce fevers and against gastrointestinal disorders in India and has antioxidant properties (2,4). In Mexico, high RA-containing Hyptis verticillata is widely used by Mixtec Indians against gastrointestinal disorders and skin infections (5). In Indonesia and several countries in Southeast Asia, RA-containing Orthosiphon aristatus is known for diuretic properties and is also used against bacterial infections of the urinary system (6). Salvia cavaleriei, a high RA-containing species is used in China for treatment of dysentery, boils, and injuries (7)....

Ginger Research Umudike

Ahmad, N., Katiyar, S.K., and Mukhtar, H. (2001) Antioxidants in chemoprevention of skin cancer. Curr. Probl. Dermatol. (Oxidants & Anti-oxidants in Cutaneous Biology) 29, 128-139. Cho, K.J. Kim, J.W. Choi, I.L. Kim, J.B., and Hwang, YS. (2001) Isolation, identification and determination of antioxidant in ginger (Zingiber officinale) rhizome. Agric. Chem. Biotechnol. (Engl. Edn.), 44, 12-15. He, W., Wei, X., Li, L., Li, Y, Guo, S., and Guo, B. (2001b) A new antioxidant cyclic diaryl heptanoid from rhizomes of Zingiber officinale.' Zhiwu Xuebao, 43, 757-759.

Arthritis In Bloodvessel To The Brain

Coronal Plane

Just as changes at the tissue level cause organ-level signs of aging, certain biochemical changes fuel cellular aging. Lipofuscin and ceroid pigments accumulate as the cell can no longer prevent formation of damaging oxygen free radicals. A protein called beta amyloid may build up in the brain and blood vessels, contributing, in some individuals, to the development of Alzheimer disease. A generalized metabolic slowdown results from a dampening of thyroid gland function, impairing glucose utilization, the rate of protein synthesis, and production of digestive enzymes. At the whole body level, we notice slowed metabolism as diminished tolerance to cold, weight gain, and fatigue.

Organs and Systems Cardiovascular

When penicillamine is started in patients with Wilson's disease, pre-existing neurological involvement can acutely worsen convulsions, muscle spasms, and coma can occur and death can follow (76-81). Worsening of neurological symptoms after starting therapy with penicillamine can occur in up to 50 of neurologically affected patients with Wilson's disease (79,80) and penicillamine can precipitate serious neurological injury in previously asymptomatic patients (82,83). It is uncertain if this results from alterations of copper distribution at submolecular, subcel-lular, transcellular, or transorganic levels, or whether it results from some other property of penicillamine (for example its capacity to donate sulfhydryl groups). Since the initial damage may be caused by copper decompart-mentalization, it has been suggested that pretreatment with lipid-soluble antioxidants, such as vitamin E, may be useful (77), whereas at least some of these effects may reflect secondary pyridoxine...

[4 Assay of Proteoglycan Degradation

The turnover of proteoglycans is a normal physiological process of removal and replacement. Removal appears to involve the fragmentation of the protein core by the action of proteolytic enzymes or oxygen free radicals, with hydrolysis of the glycosaminoglycan side chains occurring later. Any increase in the rate of removal or decrease in biosynthesis of proteoglycans may have pathological consequences, such as in the development of arthritis. Thus, proteinases involved in the degradation of proteoglycans could be contributing to the pathology of disease, and methods for determining rates of proteoglycan breakdown are important indicators of the process.

Fermented Wheat Germ Extract

TNF-a plays an important role in local inflammatory and adhesion processes. TNF-a can destroy tumor cells by directly inducing apoptosis or by producing free radicals, and indirectly by inhibiting tumor angiogenesis or by enhancing other cellular antitumor processes. In order to activate their own antitumor capabilities, macrophages need to reach and then penetrate into the tumor, aided by the protein ICAM-I, an intracellular adhesion molecule (CD54). ICAM-I helps TNF-a to cross the vessel wall and also to transport them to the target. Avemar is capable of increasing the level of ICAM-I molecules, an effect synergistic with its TNF-a-like effect. In this way, Avemar enhances ICAM-I production in two distinct ways - on its own and through the enhancement of TNF-a production in macrophages - thereby helping the leukocytes to reach tumor cells. Cancerous tumors that have undergone angio-genesis are characterized by an almost complete lack of ICAM-I.

Rheumatoid Arthritis Hydrogen Peroxide

A continuous and long-term deficiency in antioxidants is believed to be responsible for the etiology of many diseases,1-3 including the neurodegenerative disorders Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's chorea, as well as a variety of inflammatory diseases such as atherosclerosis, diabetes, arthritis, and the aging process itself. Even diseases such as cancer and certain viral infections are exacerbated by a deficiency in antioxidants. Human papilloma virus (HPV) can cause genital warts, various types of cancer, and is a major risk factor in squamous cell carcinoma. The multiplication and possibly the transformation of HPV is inhibited by high levels of antioxidants, both in vitro and in vivo. , These diseases are linked to oxidative stress, a term coined by Seis,6 which is an imbalance in the ratio of oxidants to antioxidants, where oxidants predominate in the body. Raising the level of different antioxidants can provide some protection...

Recent Studies on Glucosamine Chondroitin and Vitamin C

Several recent studies, using similar combinations of supplements, clearly convey the benefits of glucosamine, chondroitin, and vitamin C in people with osteoarthritis. In particular, glucosamine and chondroitin help rebuild articular cartilage and also have anti-inflammatory properties, which may explain why they reduce joint pain. These two actions likely reduce the influx of white blood cells into joints, where they would release inflammation-promoting free radicals.

Antiinflammatory Effects of Chondroitin Sulfate

ChS-A decreased matrix proteoglycan loss and erosion in a mouse model of collagen-induced arthritis 14 . This is again attributed to a decrease in NF-kB nuclear translocation and decreased degradation of IKB-a protein, which leads to decreased expression of proinflammatory molecules. A decrease in MMP-13 expression and synthesis, lipid peroxidation and neutrophil activation is also seen in the presence of ChS. Finally, endogenous antioxidant levels increased with ChS treatment. Together, these anti-inflammatory responses in the presence of ChS contribute to the observed decrease in the degradation of cartilage tissue. Oxidative stresses are present in arthritic knees and those stresses are in part responsible for the observed cartilage degeneration 78 . ChS increases the production of endogenous antioxidants 13, 14 and acts as an antioxidant itself 21 . The polysaccharide is able to reduce membrane damage by ROS 74 . For more information on the protective effects of ChS against ROS,...

What You Can Do to Plug the Leaks

Most flavonoids, as we have seen, are powerful and versatile antioxidants and inhibitors of lipid peroxidation. They also bind excess iron and reduce inflammation. This makes them very important for treatment of inflammatory bowel disease. Flavonoids from green tea extract, primarily catechins, not only reduce inflammation and protect against free radicals, but also inhibit the growth of Clostridium, a very bad bacteria, and promote the growth of Lactobacillus and Bifidobacterium, both good bacteria.445

Rheumatoid Arthritis

Rheumatoid arthritis affects approximately 1 of the adult population in a female male ratio ranging from 2 1 to 4 1 (Grossman and Brahn, 1997). Production of free radicals at inflammation sites has been suggested to play a significant role in the pathogenesis of rheumatoid arthritis (Araujo et al, 1998 Mapp et al, 1995 Maurice et al, 1998). Adhesion molecules facilitate the migration of cells to the joint as well as the attachment of synovium to bone and cartilage (Cunnane et al, 1998). Monocyte and lymphocyte traffic into the rheumatoid arthritis synovium is mediated by adhesion molecules such as ELAM-1, VCAM-1, ICAM-1, and ICAM-2, as well as by monocyte chemotactic protein 1 and 32 integrins (CD11 a,b,c CD18) (Cutolo etal., 1993 Veale and Maple, 1996). Anti-ICAM-1 therapy has shown beneficial effects in the treatment of rheumatoid arthritis (Rothlein and Jaeger, 1995).

Acute Intermittent Porphyria

In CCD, normal phagocytosis of bacteria occurs, but the patient cannot form peroxide and consequently hypochlorite as an antibacterial mechanism. CGD is causcd by a deficiency in NADPH oxidase, which converts molecular oxygen into superoxide free radicals in neutrophils ( RESPIRATORY BURST) superoxide dismutase then acts on superoxide to produce peroxide, which, combined with chloride via the myeloperoxidase system, forms hypochlorite, a powerful bacteria killer (due to degradation of the bacterial wall). Patients with CGD have increased susceptibility to infections caused by S. aureus, E. coli, and Aspergillus.

Muscle Joint and Soft Tissue Complications of Diabetes

Several studies have found that a vegan or vegetarian diet resulted in a modest improvement in RA, but the scientific evidence is not strong enough to recommend this as a useful component of routine treatment. Many dietary supplements such as yeast, cider vinegar, honey, copper, zinc, magnesium, garlic, ginger, alfalfa, and shark cartilage have been used to treat arthritis without adequate evidence available to support or refute claims for their efficacy. oxidative stress resulting in increased production of free radicals appears to be increased in many types of arthritis. Antioxidant vitamins, particularly vitamin E and vitamin C, have therefore been suggested as treatments for arthritis. in some studies, high doses of vitamin E improved the symptoms of RA. Vitamin C did not appear to improve symptoms of RA or osteoarthritis (OA) but was associated with a slower progression of OA in one study.

Muscarinic Receptor Stimulation

15.2.6 Antioxidant Activity Antioxidants have been suggested to reduce the risk of developing dementia, although evidence to support this hypothesis is under review 71 . Free-radical reactions, which are reported to initiate cell injury, have been implicated in the pathology of various diseases including ageing processes, atherosclerosis, ischemic heart disease and neurodegenerative diseases which involve cognitive impairment 72-74 . Antioxidants have therefore been considered as a means to modify and minimise neuronal degeneration in cognitive disorders. A wide variety of plants have been associated with antioxidant effects 75-77 . It is therefore not surprising that many different and structurally diverse phyto-chemicals have also shown antioxidant activity, including some cinnamic acids, coumarins, diterpenoids, flavonoids, monoterpenoids, phenylpropanoids and tannins 78-84 . The antioxidant properties of Camellia sinensis Kuntze (Theaceae), commonly known as green tea, are well...

Functional properties

Allspice is not only valued as a spice to add flavour to food but has medicinal, antimicrobial, insecticidal, nematicidal, antioxidant and deodorizing properties. The powdered fruit of allspice is used in traditional medicine to treat flatulence, dyspepsia, diarrhoea and as a remedy for depression, nervous exhaustion, tension, neuralgia and stress. In small doses it can also help to cure rheumatism, arthritis, stiffness, chills, congested coughs, bronchitis, neuralgia and rheumatism. It has anaesthetic, analgesic, antioxidant, antiseptic, carminative, muscle relaxant, rubefacient, stimulant and purgative properties (Rema and Krishn-amoorthy, 1989). It is also useful for oral hygiene and in cases of halitosis. An aqueous suspension of allspice is reported to have anti-ulcer and cytoprotective activity by protecting gastric mucosa against indomethacin and various other necrotizing agents in rats (Rehaily et al., 2002) 7.6.6 Antioxidant Antioxidants help to preserve food from oxidation...

Alzheimers Disease and Alzheimers Dementia

The oxidative stress hypothesis of neurodegeneration holds that free radical generation from metabolism is neurotoxic, and there is some evidence that Abeta may promote free radical formation. 1 This has led some to propose the use of antioxidants clinically and in experimental trials in patients with clinically diagnosed AD. y use of a large family of growth factor compounds that normally function during embryogenesis, some of which promote neuronal growth and retard neuronal death use of antioxidants to interfere with the generation of free radicals that cause cellular damage. Strategies for symptomatic therapy include

Oroxylum indicum L Vent

Pharmaceutical interest Oroxylin A (5, 7-hydroxy-6-methoxyflavone) and chrysin and ursolic acid characterized from the fruits of Oroxylum indicum (L.) Vent. are antioxidant in the xanthine-xanthine oxidase assay system (Jiwajinda S et a ., 2002). Note that Oroxylum indicum (L.) Vent. contains

Human Nutrition References

Chanez, P. et al., Generation of oxygen free radicals from blood eosinophils from asthma patients after stimulation with PAF or phorbol ester, Eur. Respir. J, 3, 1002, 1990. 49. Kumazawa, H. et al., The role free radicals in airway obstruction in asthmatic patients, Chest, 100, 1319, 1991. Soutar, A., Seaton, A., and Brown, K., Bronchial reactivity and dietary antioxidants, Thorax, 52, 166, 1997.

Asian Herbal Medicine

Fu-zheng therapy, a type of Chinese herbal medicine, is believed to improve the ability of the body to defend itself. Two herbs used in Fu-zheng therapy, astragalus and Ligustrum lucidum, have been shown to activate immune cells. Licorice and Asian ginseng, which are present in many different types of Chinese herbal medicine, have diverse effects on the immune system, including stimulating effects. Green tea contains potent antioxidant compounds, which also may produce immune-stimulating activity this is discussed elsewhere in this book (see Coffee and Other Caffeine-Containing Herbs ).

Arachidonic Acids Profound Growth Impact

Stress stimuli, such as that induced during exercise or a physical injury, increases arachidonic acid release from the cell membrane through phosphorylation of the cytosolic enzyme phospholipase A2. This enzymatic activation is induced by stress-activated protein kinases (SAPKs). These SAPKs are activated during inflammatory processes by cytokines (which are AA derivatives), phospholipids, polysaccharides, and stress stimuli such as heat and free radicals (mostly considered bad guys ). Generally, SAPK is a growth inhibitor that is likely to balance other stress-related growth-stimulating agents. However, SAPK 2 helps induce phosphorylation and activation of heat-shock protein 27, a fact that may play an important role in the mechanism that repairs damaged muscle tissues and thereby helps cell survival and muscular maintenance under stress.

Flavonoids and Neurological Diseases

The difficulty with all these studies is that they are either in vitro with regard to mechanisms, or only investigate a few flavonoid classes in vivo with questionnaires to determine intake use of rather inaccurate or incomplete flavonoid databases. As we mentioned before, many factors can confound the determination of true flavonoid intake. None of these studies have investigated flavonoid supplements because they are a relatively new occurrence in the marketplace. A great deal of research has been sponsored commercially for products such as pycnogenol. Marketed as an antioxidant, pycnogenol is promoted as lowering blood pressure. Pycnogenol, made from the bark of a white pine, has been purported to be fifty times more powerful than vitamin E in its antioxidant properties and twenty times more powerful than vitamin C. These results are from in vitro studies. Pycnogenol is also marketed as exceptionally useful for fighting against capillary fragility and varicose veins, diabetic...

Bendich And Cohen 1996

Journal of Nurition 127, 966S-970S. Bendich, A. (1990) Antioxidant micronutrients and immune responses. In Bendich, A. and Chandra, R.K. (eds) Micronutrients and Immune Functions, Vol. 587. New York Academy of Sciences, New York, pp. 168-180. Bendich, A. (1991) Carotenoids and immunity. CJinics in AppJied Nutrition Nutrition Bendich, A. (1994b) Role of antioxidants in the maintenance of immune functions. In Frei, B. (ed.) Natural Antioxidants in Human Health and Disease. Academic Press, New York, pp. 447-467. Bendich, A. (1996) Antioxidant vitamins and the immune response. Vitamins and Hormones 52, 35-62. Bendich, A. et al. (1986) The antioxidant role of vitamin C. Advances in Free Radical Biology and Medicne 2, 419-444. Burton, G.W. et al. (1983) Is vitamin E the only lipid-soluble, chain-breaking antioxidant in human blood plasma and erythrocyte membranes Archives of Biochemistry and Biophyics 221, 281-290. Duthie, S.J. et al. (1996) Antioxidant...

Inflammatory Diseases

Although ROS generation is a physiological defense process, for example, antimicrobial, the inappropriate generation of ROS may result in tissue damage. Such damage is due to the chemical reactivity of certain ROS with biomolecules, such as DNA, lipids and proteins. McCord and Fridovich 31 were the first to report a mammalian enzyme activity that was able to remove O2 . The activity was due to superoxide dismutase (SOD), and the discovery of this enzyme, which counteracts O2 , suggested that ROS play important physiological and pathophysiological roles. Since the discovery of the antioxidant enzyme SOD, a number of other human antioxidant enzymes have been identified. These include the enzymes glutathione peroxidase, Trx, TR and Prdx. Glutathione peroxidase and TR require the presence of the essential element selenium for activity 32 . In addition to antioxidant enzymes, small molecule antioxidants, often derived from the diet, provide protection from ROS-mediated tissue damage by...

Phytochemicals of Interest

Antioxidant Antioxidants that reduce plaque formation, and promote cell differentiation Antioxidants that block carcinogens, anti-inflammatory Antioxidant arthritis relief, deters ulcers Antioxidant carotenoid prostate cancer preventive Antioxidant anti-inflammatory inhibits carcinogen-induced cell proliferation

Diseases Involving Insulin Alterations

Insulin production secretion occurs in P cells of the islets of Langerhans of the pancreas. This hormone regulates the entry of glucose into cells, and its secretion is regulated in part by glucose, amino acids, free intracellular Ca+2, and glutamate dehydroxygenase (GDH). GDH dysregulation is associated with hyperin-sulinemia hyperammonemia (HI HA) syndrome, a genetic disorder involving hypo-glycemia. EGCG inhibits GDH in a reversible, allosteric manner at nanomolar levels independently of its antioxidant activities 43 . This only occurs under conditions in which GDH is not inhibited by high-energy metabolites. EGCG also effectively inhibits mutant forms of GDH found in HI HA. While EGCG blocks the enhancement of glutamine oxidation by GDH by an activating compound, it does not affect basal levels of glutaminolysis or glucose-stimulated insulin secretion.

The functional role of spices

Herbs and spices are not just valuable in adding flavour to foods. Their antioxidant activity also helps to preserve foods from oxidative deterioration, increasing their shelf- Table 1.6 Antioxidants isolated from herbs and spices Table 1.6 Antioxidants isolated from herbs and spices life. There has been increasing research in the role of herbs and spices as natural preservatives. As an example, ground black pepper has been found to reduce the lipid oxidation of cooked pork. Table 1.6 illustrates the range of antioxidants isolated from herbs and spices. Antioxidants also play a role in the body's defence against cardiovascular disease, certain (epithelial) cancers and other conditions such as arthritis and asthma. Phenolic compounds such as flavonoids may help to protect against cardiovascular disease and intestinal cancer (black pepper, oregano, thyme and marjoram). Gingerol in ginger is also an intestinal stimulant and promoter of the bioactivity of drugs. Capsaicin in chilli pepper...

Pharmacological Activities of Turmeric

Generation of free radicals inhibition has been observed in paw and 107,113 liver of treated rats turmeric and curcumin act by interacting with certain transcription factors, a property that is important for the treatment of arthritis and cancer HCC is predominantly due to the chronic inflammation by virus, bacteria, or chemical and curcumin may prevent HCC Exhibits antibacterial, antimycotic, and antiviral activity this property 109,111 has been associated with sesquiterpenes, hydrocarbones, monoterpenes, and oxygenated monoterpenes, all with excellent antioxidant activities Inhibits the mutagenicity of several agents such as benzo(a)pyrene and 97,98 dimethylbenzanthracene, among others evaluations have been carried out using the Ames test Inhibits the formation of colon adenomas and adenocarcinomas 99

Iron a Double Edged Sword

Iron is essential not only for proper hemoglobin function but also for the production of cellular energy, immune function, and brain function. It is especially important for learning and memory in growing children. Iron supplementation may also be necessary in endurance athletes, pregnant women, those taking arthritis medication regularly, and for those taking an aspirin a day. Later in life, it becomes less essential. Low iron levels are known to increase the likelihood of infection and can increase the generation of free radicals in tissues. Low levels are also responsible for poor wound healing.

Recent Clinical Developments

Vitamin C is also necessary for vitamin E to function at full effectiveness as an antiaging agent. In the aging process free radicals (peroxidation of essential fatty acids) go about the body destroying tissue and changing the shape of cell organization as a result, sagging skin occurs. When the diet contains jtoo many fats that overbalance the vitamin E in the body, damage is done. Furthermore, when collagen fiber gets old, it chokes off tissue and becomes anoxic (lacking in oxygen), thereby causing wrinkles. Vitamin C is very important to healthy collagen and, if taken in sufficient amounts, will help hold off the aging process considerably.

Dmso Arthritis Swelling

Effects It works, not by lubricating joints or by deadening pain, but by scavenging free radicals. It has been shown to increase circulation protect against the effects of radiation and freezing reduce keloids, scars, and the effects of burns help protect against fungus, bacteria, and viruses be a beneficial supplement to cancer therapy stimulate immunity stimulate wound healing and useful in treating such eye problems as cataracts, macular degeneration, and glaucoma, among others. Most of the industrial grade, or solvent grade, solutions contain acetone, which is readily carried into the blood by DMSO, and which can cause liver damage and death. According to Pearson and Shaw, much of the DMSO sold over the counter or by mail order contains unwanted impurities such as dimethylsulfone, dimethylsufide, nitrogen oxides, and benzene. In addition, after it has scavenged the hydroxyl radicals from the body, it converts to a sulfoxide free radical. While this new free radical is less...

Role of Diet in the Management and Prevention of Degenerative Arthritis

Much less is known about the role of diet in the treatment of OA and other degenerative arthritides. The above discussion regarding n-3 PUFAs in RA also may pertain to OA, although the strength of the effect has not been studied as thoroughly. However, the same eicosanoid metabolism occurs in OA as in RA, with the exception that the disorder is limited to the joint rather than involving the whole body. Thus, fish oils may well be of benefit in OA. Antioxidant intervention with vitamin E may also be effective in OA, with several studies showing an effect comparable with NSAIDs. Although not strictly nutrients, glucosa-mine and chondroitin sulfate, which are two of the constituents of normal cartilage that decline with arthritis, have been shown to be useful when given as an oral supplement, especially in patients with early OA.

Excitotoxins and the Elderly

There is overwhelming evidence that aging is the result of destruction caused by free radicals, which damage cell membranes, DNA, and proteins. Of particular importance is damage to proteins, which make up enzymes, structural proteins, information molecules, and cell membranes. Damage to enzymes interferes with metabolism, particularly energy production, and growing evidence suggests that damage to DNA-repair enzymes increases risk for developing numerous degenerative diseases including cancer. Once the calcium channel gets stuck open, the cell is in real danger. Free radicals of every sort begin to accumulate inside and outside the cell, triggering the release of even more glutamate. Recent evidence indicates that when glutamate begins to accumulate outside the cell, the brain's immune system is activated. The brain's immune cells, microglia, then begin to secrete a host of immune-activating chemicals called cytokines, which stimulate inflammation of the brain, in turn generating...

Ginger Zingiber officinale

Herbalist Paul Schulick, author of an exhaustive treatise on ginger's remarkable healing powers, Ginger - Common Spice & Wonder Drug, cites among its medicinal properties the prevention and amelioration of such conditions as heart attacks, arthritis and ulcers it is a potent aid to improved digestion, and is a powerful anti-inflammatory. Ginger contains a substance known as zingibain, a potent protein-digesting enzyme, one gram of which is capable of tenderizing 20 pounds of meat. More effective than all non-steroidal anti-inflammatory drugs on the market today, ginger is capable of counteracting arthritic and rheumatoid inflammation. Extremely potent in its antioxidant properties (having more than 12 constituents superior to Vitamin E), enzymatic properties (it is considered the

Hypokinetic Movement Disorders

Hydrogen peroxide, superoxide anions, and hydroxyradicals. Interaction between these chemicals and membrane lipids leads to lipid peroxidation, membrane disruption, and, potentially, cell death. In support of this hypothesis, several observations are pertinent (1) glutathione peroxidase, a tripeptide normally present in brain that is reduced with oxidative stress, is markedly reduced in the SN of patients with PD (2) elemental iron, which can facilitate the formation of free radicals in the nervous system, is increased in the brains of PD patients (3) the iron-chelating protein ferritin is decreased or of normal concentration in PD, so that compensatory increases to handle elemental iron do not occur and (4) specific enzymatic activity defects in complex 1 of the mitochondrial respiratory chain appear to occur in the SN of the brains of patients with PD. Whereas all these events develop and probably reflect or provoke oxidative stress in the SN, the actual precipitant, whether...

Acanthopanax senticosus

The root and stem bark of Acanthopanax senticosus Harms (Araliaceae), also called Siberian ginseng, have been used as a tonic and adaptogen to strengthen qi in TEM and to treat rheumatic arthritis and stress-induced disease 51 . A. senticosus includes eleutheroside, chiisanoside, senticoside, triterpenic saponin, syringin, and flavones in its compounds 52 , and it has sedative, antioxidant, antihistamine, hypolipidemic, antistress, and immunomodulatory effects 14 .