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Research Newsletter-Fall/Winter 2007

RECENT PUBLICATIONS BY LPI SCIENTISTS

Selected summaries by Stephen Lawson

For a comprehensive list of all LPI scientific papers published in 2006 and 2007, please contact the Institute. Summaries of some representative papers appear below. LPI scientists are identified in boldface.


Cancer Chemoprotection

COPE RB, LOEHR C, DASHWOOD R, and KERKVLIET N. Ultraviolet radiation-induced non-melanoma skin cancer in the Crl:SHK:hr-1 hairless mouse: augmentation of tumor multiplicity by chlorophyllin and protection by indole-3- carbinol. Photochem. Photobiol. Sci. 5:499-507, 2006.

The authors conducted experiments to determine the effect of dietary supplementation with high amounts of chlorophyllin (a derivative of chlorophyll) or indole-3-carbinol (I3C, a phytochemical in cruciferous vegetables) on non-melanoma skin cancer in hairless mice subjected to ultraviolet radiation. Mice supplemented with chlorophyllin exhibited more tumors than controls, whereas supplementation with I3C decreased tumor multiplicity. Neither treatment affected tumor incidence or immunosensitivity. The molecular mechanisms responsible for the observations remain obscure.

COLGATE EC, MIRANDA CL, STEVENS JF, BRAY TM, and HO E. Xanthohumol, a prenylflavonoid derived from hops, induces apoptosis and inhibits NF-kappaB activation in prostate epithelial cells. Cancer Lett. 246:201-209, 2006.

Xanthohumol is the major flavonoid in the hops used to make beer and has been shown to possess anticancer properties by inhibiting all stages of carcinogenesis (initiation, promotion, and progression). Therefore, the authors added xanthohumol or its oxidation product to cultured human non-malignant hyperplastic prostate cells and malignant prostate cells. Both compounds decreased cell viability in a dose-dependent manner and induced apoptosis (programmed cell death). In hyperplastic prostate cells, xanthohumol and its derivative substantially decreased NF-kappaB activity. NF-kappaB acts as a "pro-survival" factor, thereby inhibiting apoptosis. The effective dose of xanthohumol probably cannot be obtained by drinking beer. Animal studies have not demonstrated any toxicity of high doses of xanthohumol, but human studies are needed before xanthohumol can be recommended as a dietary supplement.

HIGDON JV, DELAGE B, WILLIAMS DE, and DASHWOOD RH. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmaco. Res. 55:224-236, 2007.

In this review article, the authors examined the evidence for a protective effect against cancer for the consumption of cruciferous vegetables, such as broccoli, Brussels sprouts, cabbage, cauliflower, turnips, collard greens, and kale. These vegetables contain phytochemicals called glucosinolates that produce isothiocyanates (e.g., sulforaphane) and indole-3-carbinol when chewed or chopped. Epidemiological evidence for the prevention of lung cancer, colorectal cancer, breast cancer, and prostate cancer has been inconsistent, suggesting that genetic variations, or polymorphisms, in how the glucosinolates are metabolized may influence their protective effects. For example, people who eliminate the compounds slowly may exhibit more protection against cancer. Additionally, cooking may inactivate myrosinase, an enzyme released during chopping or chewing that produces the active phytochemicals, resulting in diminished bioavailability. Boiling leeches glucosinolates from vegetables, and as much as 60% may be lost by boiling for 15 minutes.

YU Z, MAHADEVAN B, LOEHR CV, FISCHER KA, LOUDERBACK MA, KRUEGER SK, PEREIRA CB, ALBERSHARDT DJ, BAIRD WM, BAILEY GS, and WILLIAMS DE. Indole-3-carbinol in the maternal diet provides chemoprotection for the fetus against transplacental carcinogenesis by the polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene. Carcinogenesis 27:2116-2123, 2006.

Polycyclic aromatic hydrocarbons (PAHs), formed by the combustion of organic material like coal, cigarettes, cooking oil, and wood, are environmental carcinogens. Maternal exposure to PAHs (transplacental carcinogenesis) has been implicated in childhood and adult cancers, including leukemias and lymphoma. The authors supplemented pregnant mice exposed to one PAH called dibenzo[a,l]pyrene (DBP) with indole-3-carbinol (I3C), a phytochemical in cruciferous vegetables that protects against cancer. They found that maternal supplementation with I3C significantly reduced mortality due to aggressive lymphoma in offspring and decreased lung tumor multiplicity in offspring that survived ten months after birth.

PRATT MM, REDDY AP, HENDRICKS JD, PEREIRA C, KENSLER TW, and BAILEY GS. The importance of carcinogen dose in chemoprevention studies: quantitative interrelationships between dibenzo[a,l]pyrene dose, chlorophyllin dose, target organ DNA adduct biomarkers, and final tumor outcome. Carcinogenesis 28:611-624, 2006.

In a study with over 12,000 trout, the authors determined dose-response curves for a carcinogen and a chemoprotective compound. The carcinogen dibenzo[a,l]pyrene (DBP)—a polycyclic aromatic hydrocarbon formed from the combustion of organic material—caused a dose-dependent formation of tumors in the liver, stomach, and swim bladder. Co-administration of chlorophyllin—a derivative of natural chlorophyll—dose-dependently inhibited tumor formation except in the liver at the highest dose of DBP. At that dose, much higher concentrations of chlorophyllin were required for tumor inhibition. These results emphasize the need to choose the experimental carcinogen dose carefully, since the choice of a very high dose might lead to the erroneous conclusion that the putative chemoprotective compound is ineffective. In other words, one cannot extrapolate from high dose-response relationships often selected for experimental studies to low dose-response relationships frequently encountered in human carcinogen exposure.

MYZAK MC, TONG P, DASHWOOD WM, DASHWOOD RH, and HO E. Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects. Exp. Biol. Med. 232:227-234, 2007.

Sulforaphane is an isothiocyanate found in cruciferous vegetables, such as broccoli, Brussels sprouts, cauliflower, and cabbage. Broccoli sprouts contain particularly high amounts of sulforaphane, which has been identified as an anticarcinogen based on its induction of Phase 2 liver enzymes involved in the detoxification and metabolism of carcinogens. The authors have identified another anticancer role of sulforaphane: the inhibition of histone deacetylase (HDAC). DNA is wrapped around proteins called histones, and changes in the conformation of histones determine when genes are turned on or off. When acetyl groups are added to histones, genes are turned on, and removal of the acetyl groups inactivates genes. HDAC removes acetyl groups from histones, which results in gene inactivation. In cancer cells, this process inactivates tumor suppressor genes. If HDAC could be inhibited, then the tumor suppressor genes could be turned back on to block cancerous cell growth. In the present study, the authors found that feeding a sulforaphane-supplemented diet to mice implanted with human prostate cancer cells significantly inhibited tumor growth. HDAC activity was also suppressed. When healthy humans were given a dose of sulforaphane as broccoli sprouts, HDAC activity in peripheral blood mono-nuclear cells was significantly inhibited. Each subject consumed about 105 mg of sulforaphane in the 68-gram serving (about one cup) of broccoli sprouts. An equivalent amount of sulforaphane is present in about 570 grams of mature broccoli.

Heart Disease

WIDLANSKY ME, DUFFY SJ, HAMBURG NM, GOKCE N, WARDEN BA, WISEMAN S, KEANEY JF JR, FREI B, and VITA JA. Effects of black tea consumption on plasma catechins and markers of oxidative stress and inflammation in patients with coronary artery disease. Free Rad. Biol. Med. 38:499-506, 2005.

The authors previously reported that consumption of black tea improved endothelial function in patients with heart disease, as measured by brachial artery blood flow. In this study, the authors measured catechins from tea in the plasma of those subjects to determine which may have been responsible for the beneficial effect. Individual catechins did not affect plasma antioxidant status, endothelial function, or C-reactive protein (a marker of inflammation), suggesting that other flavonoids in tea and the diet are responsible for the observed improvement in endothelial function.

DIETRICH M, TRABER MG, JACQUES PF, CROSS CE, HU Y, and BLOCK G. Does gamma-tocopherol play a role in the primary prevention of heart disease and cancer? A review. J. Am. Coll. Nutr. 25:292-299, 2006.

The vitamin E family consists of eight isomers, including gamma-tocopherol and alpha-tocopherol. The American diet provides mainly gamma-tocopherol from soybean and canola oils, which has been shown in vitro and in vivo to possess anti-inflammatory and antioxidant properties. The authors reviewed epidemiological studies to determine whether gamma-tocopherol provides protection against heart disease or cancer. They found no evidence for a protective effect of gamma-tocopherol against heart disease and stroke, except in post-menopausal women. In men, gamma-tocopherol intake was associated with decreased risk of prostate cancer. Despite the rapid clearance of gamma-tocopherol from the body, its anti-inflammatory properties remain of great interest.

TRABER MG. Heart disease and single-vitamin supplementation. Am. J. Clin. Nutr. 85:293S-299S, 2007.

Vitamin E is a powerful fat-soluble antioxidant and anti-inflammatory agent. It becomes oxidized when it acts as an antioxidant but can be regenerated by vitamin C. Since oxidative stress is believed to play a role in the development of heart disease, the potential protective effect of vitamin E has been extensively studied. Results of intervention studies in patients with heart disease have been conflicting. Those results are difficult to interpret because actual levels of oxidative stress were not usually measured, nor were plasma levels of vitamin E. We know that vitamin E decreases biomarkers of oxidative stress and needs adequate vitamin C for optimal function, but we still lack precise knowledge about optimal intakes. In one large-scale, long-term primary prevention trial in healthy women, the daily intake of 600 IU of vitamin E was found to decrease mortality from heart disease by 24% and by 49% in women over 65 years old.

MCMACKIN CJ, WIDLANSKY ME, HAMBURG NM, HUANG AL, WELLER S, HOLBROOK M, GOKCE N, HAGEN TM, KEANEY JF JR, and VITA JA. Effect of combined treatment with alpha-lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease. J. Clin. Hypertens. 9:249-255, 2007.

Based on evidence that mitochondrial dysfunction may contribute to the development of heart disease and recognizing that alpha-lipoic acid and acetyl-L-carnitine improve mitochondrial function and reduce oxidant stress, the investigators conducted a small, short-term clinical trial with patients with coronary artery disease. Patients were supplemented with 200 mg of alpha-lipoic acid and 500 mg of acetyl-L-carnitine twice daily for eight weeks. Such treatment resulted in a 2% increase in brachial artery diameter, a non-statistically significant decrease in blood pressure, and a significant decrease in systolic blood pressure in patients with initially elevated systolic blood pressure or with metabolic syndrome.

BLUMBERG JB and FREI B. Why clinical trials of vitamin E and cardiovascular disease may be fatally flawed. Commentary on "The Relationship Between Dose of Vitamin E and Suppression of Oxidative Stress in Humans". Free Radic. Biol. Med. 43:1374-1376, 2007.

Oxidative stress has long been implicated in the development of heart disease, but results of clinical studies designed to test the effectiveness of supplemental vitamin E in preventing heart attacks, stroke, or death from heart disease in patients with heart disease have been equivocal. Many epidemiological studies have reported associations between supplemental vitamin E intake and decreased incidence of heart disease, and in vitro and animal studies have identified several putative mechanisms of action, including antioxidant function, inhibition of smooth muscle cell proliferation, and prevention of platelet adhesion and aggregation. Conflicting results of clinical trials may be due to poor bioavailability—vitamin E must be taken with fat-containing food for absorption—or inappropriate duration or dose. In this commentary, the authors note that a recent study demonstrated that doses of vitamin E required to ameliorate oxidative stress in hypercholesterolemic patients, as measured by markers of lipid oxidation called F2 isoprostanes, are four to eight times greater (1,600-3,200 IU) than doses commonly used in clinical trials. Hence, clinical trials may have failed simply because the vitamin E doses were inadequate to significantly lower oxidative stress. Levels of plasma vitamin E and biomarkers of oxidative stress were typically not measured in clinical trials.

Antioxidants

TRABER MG. How much vitamin E? ... Just enough! Am. J. Clin. Nutr. 84:959-960, 2006.

In this editorial, the author comments on a recent study (ATBC) showing that men with the highest serum concentration of vitamin E (alpha-tocopherol) had decreased risk of mortality from heart disease and cancer. The RDA for vitamin E (15 mg or 22.5 IU per day for adult men and women), set by the Food and Nutrition Board, is based on in vitro lysis of red blood cells taken from vitamin E-depleted men, not on the prevention of chronic disease. The new study of over 29,000 men followed for 19 years adds to the evidence that vitamin E helps prevent chronic disease. Based on other studies, an intake of about 100 IU/day may be necessary to increase the serum concentration of vitamin E to the protective levels described in the ATBC study. It is estimated that over 90% of Americans consume less than the RDA of vitamin E.

BRUNO RS, SONG Y, LEONARD SW, MUSTACICH DJ, TAYLOR AW, TRABER MG, and HO E. Dietary zinc restriction in rats alters antioxidant status and increases plasma F2 isoprostanes. J. Nutr. Biochem. 18:509-518, 2006.

Over ten percent of Americans do not consume the RDA of zinc, an abundant trace element involved in many critical cellular functions. It has been proposed that zinc functions as an antioxidant in vivo, leading the authors to conduct experiments with rats to determine potential antioxidant functions of zinc. Rats fed a zinc-deficient diet exhibited elevated levels of plasma F2 isoprostanes, which are markers of lipid oxidation, and decreased levels of plasma uric acid— an important endogenous antioxidant—and hepatic vitamin E. The zinc-deficient diet did not appreciably affect levels of plasma vitamins C or E but did increase cytochrome P450 activity, which is involved in the metabolism of arachidonic acid. Oxidized arachidonic acid generates F2 isoprostanes. Hence, it appears that the observed in vivo antioxidant function of zinc is indirect and related to its influence on plasma levels of uric acid and hepatic vitamin E, as well as on cytochrome P450 activity.

LOTITO SB and FREI B. Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon? Free Rad. Biol. Med. 41:1727-1746, 2006.

Flavonoids are polyphenolic compounds in fruit and vegetables that exhibit potent antioxidant properties in vitro, and many scientists have assumed that they function as potent antioxidants in vivo as well. The authors previously showed that apple consumption by human subjects increased the antioxidant capacity of their plasma, but the observed effect was not due to vitamin C or flavonoids in apples, but rather to increased levels of plasma uric acid influenced by fructose in apples. Flavonoids are poorly absorbed into the bloodstream, extensively metabolized, and quickly excreted after absorption. In this review article, the authors examined the antioxidant effect of flavonoids in fruit and vegetables. It is estimated that the total daily intake of flavonoids is about 1,000 mg, with apples contributing over 20% of the flavonoid intake from fruit. One serving of apples, blueberries, red wine, or dark chocolate provides about 400 mg, 200-400 mg, 200-500 mg, or about 340 mg of flavonoids, respectively. Coffee and tea are also good sources of flavonoids, providing about 150-180 mg and 150-250 mg per serving, respectively. The authors note that it is possible that flavonoids may accumulate in certain tissues where they might act as antioxidants but that their health effects are more likely related to cell signaling, gene regulation, and other biological functions.

MUSTACICH DJ, LEONARD SW, DEVEREAUX MW, SOKOL RJ, and TRABER MG. alpha-Tocopherol regulation of hepatic cytochrome P450s and ABC transporters in rats. Free Radic. Biol. Med. 41:1069-1078, 2006.

The authors studied the metabolism and other effects of vitamin E (alpha-tocopherol) injected subcutaneously in rats. Daily injections elevated hepatic vitamin E levels, which then began to decline (although remaining higher than baseline levels), suggesting that excess vitamin E was being eliminated by increased metabolism. This was confirmed by measurement of vitamin E metabolites, which increased over time. Certain cytochrome P450 enzymes involved in liver metabolism were found to be elevated in response to vitamin E injections. These same enzymes are critically involved in the metabolism of xenobiotics, including drugs. Therefore, the authors hypothesize that pharmacological intakes of vitamin E in humans may induce the P450 detoxification enzymes, consequently affecting the efficacy of pharmaceutical drugs.

Neurodegenerative Disease

PEHAR M, VARGAS MR, ROBINSON KM, CASSINA P, ENGLAND P, BECKMAN JS, ALZARI PM, and BARBEITO L. Peroxynitrite transforms nerve growth factor into an apoptotic factor for motor neurons. Free Radic. Biol. Med. 41:1632-1644, 2006.

Nerve growth factor (NGF) plays a critical role in neuronal development and maintenance. The investigators found that when NGF is exposed to peroxynitrite—an oxidant formed when superoxide reacts with nitric oxide—at physiologically relevant conditions, NGF is chemically modified and induces apoptosis (programmed cell death) of motor neurons in vitro. The authors further discovered that peroxynitrite caused oxidative damage to tyrosine, an amino acid in protein present in NGF, which was the mechanism for motor neuron apoptosis initiated by altered NGF. Urate, a physiological antioxidant present in blood, prevented the damage to tyrosine by peroxynitrite.

YE Y, QUIJANO C, ROBINSON KM, RICART KC, STRAYER AL, SAHAWNEH MA, SHACKA JJ, KIRK M, BARNES S, ACCAVITTI-LOPER MA, RADI R, BECKMAN JS, and ESTEVEZ AG. Prevention of peroxynitrite-induced apoptosis of motor neurons and PC12 cells by tyrosinecontaining peptides. J. Biol. Chem. 282:6324-6337, 2007.

Peroxynitrite, formed from the reaction between nitric oxide and superoxide, is a strong oxidant that can damage biomolecules. It has been implicated in the development of inflammatory conditions and can damage cells by interfering with mitochondrial function and by damaging DNA and proteins through a process called nitration. In this paper, the authors report that peroxynitrite-derived radicals modify tyrosine residues in proteins, leading to the death of motor neurons in vitro. Tyrosine-containing peptides added to the culture medium scavenged peroxynitrite-derived radicals and protected motor neurons from death. These results offer new possibilities in neutralizing the damaging effects of peroxynitrite.

Aging

JUDGE S, JANG YM, SMITH A, HAGEN T, and LEEUWENBURGH C. Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging. FASEB J. 19:419-421, 2005.

Mitochondria are intracellular organelles in which fatty acids are oxidized to produce chemical energy. There are two types of mitochondria in heart muscle cells (myocytes): subsarcolemmal (SSM) and interfibrillar (IFM). The authors investigated age-related changes in antioxidant status and oxidative stress in cardiac SSM and IFM in young and old rats. Many markers of oxidative stress were elevated in IFM with age, whereas only one such marker, protein carbonyls, was elevated in SSM with age. Antioxidant enzyme levels in both SSM and IFM increased with age, although catalase activity declined in SSM. Catalase is an antioxidant enzyme that scavenges hydrogen peroxide. Thus, hydrogen peroxide levels increased in SSM with age due to diminished catalase activity. Levels of glutathione, another endogenous antioxidant, were lower in IFM regardless of age. Since cardiac myocytes are postmitotic cells (i.e., incapable of cell division) and have a high demand for oxygen, they may be especially vulnerable to oxidative stress and damage. When mitochondrial dysfunction implicated in the age-related decline of cardiac function is examined, special attention should be given to the different characteristics of the two populations of mitochondria in cardiac myocytes. Conflicting results of previous studies may be due to isolation procedures that do not effectively separate SSM and IFM.

SMITH AR, VISIOLI F, FREI B, and HAGEN TM. Age-related changes in endothelial nitric oxide synthase phosphorylation and nitric oxide dependent vasodilation: evidence for a novel mechanism involving sphingomyelinase and ceramide-activated phosphatase 2A. Aging Cell 5:391-400, 2006.

The authors examined the age-related decline in nitric oxide activity in rats. Nitric oxide is a signaling molecule critically involved in the function of smooth muscle cells that line blood vessels. Impairment of nitric oxide activity leads to increased rigidity of vessels, which is a hallmark of aging and heart disease. The authors found that age-related post-translational modifications (phosphorylation) of proteins involved in nitric oxide synthesis partly explain this phenomenon. They found that ceramides—lipids composed of sphingosine and fatty acids that are found in cell membranes—accumulate with age, resulting in disruptions in cell signaling that interfere with nitric oxide synthesis. A compound that inhibits the abnormal increase in ceramides was found to improve endothelial function and relaxation in aged aortas. The authors speculated that age-related declines in glutathione—an endogenous antioxidant—may be responsible for the increased ceramide activity in aged endothelium.

VISIOLI F and HAGEN TM. Nutritional strategies for healthy cardiovascular aging: Focus on micronutrients. Pharmacol. Res. 55:199-206, 2007.

The authors note that age is the major risk factor for heart disease and that over 40% of elderly people in developed countries have inadequate nutrition. Socioeconomic and lifestyle factors, as well as age-related physiological changes, play a role in this malnutrition. For example, atrophic gastritis inhibits the absorption of vitamin B12, which can lead to hematological diseases and neuropsychiatric disorders, and iatrogenic illness caused by the use of multiple medications can also impair nutrient intake. B vitamins lower homocysteine levels, improve cell function in blood vessels, and exert anti-inflammatory effects. With age, oxidative stress increases as the production of oxidants increases and as stress response enzymes and other antioxidants diminish. One consequence of these phenomena is the deterioration of cardiac function. Many studies have found that the consumption of fatty fish or the use of omega-3 fatty acid supplements helps protect against heart disease and sudden death from cardiac failure, possibly through anti-arrhythmic and anti-inflammatory activity or by stabilization of atherosclerotic plaque. Vitamin E may be helpful in preventing heart disease, but studies have reported conflicting results. Low vitamin C intake in the elderly is associated with higher mortality from stroke, and high vitamin C intake lowers mortality from heart disease. A meta-analysis concluded that the elderly need more vitamin C to attain plasma levels achieved in younger adults with much lower intakes. This may be due to age-related changes in one of the cellular uptake mechanisms for vitamin C. In clinical trials, vitamin C has been shown to lower blood pressure and to improve vasodilation. Additionally, dietary flavonoids from fruit and vegetables may help attenuate inflammation and inhibit platelet aggregation.

Nutrition and Other Topics

POPKIN BM, ARMSTRONG LE, BRAY GM, CABALLERO B, FREI B, and WILLETT WC. A new proposed guidance system for beverage consumption in the United States. Am. J. Clin. Nutr. 83:529-542, 2006.

We are familiar with the food pyramid established by the U.S. Department of Agriculture to encourage better dietary habits. In this paper, the authors propose a “beverage guidance system” to help us choose healthful beverages. Presently, caloric intake from beverages represents about 20% of total energy intake for most Americans and contributes to the obesity trend among children and adults. Calorically sweetened beverages are mainly responsible for an increase in caloric intake, and the proposed guidelines rank beverages in value based on caloric and nutrient content and on health benefits and risks. The authors ranked beverages in the following order based on those parameters: water, tea and coffee, low-fat and skim milk and soy beverages, noncalorically sweetened drinks, beverages with some heath benefits (fruit and vegetable juices, whole milk, alcoholic drinks, and sports drinks), and, lastly, calorically sweetened beverages, which should be avoided. Although it is not possible to recommend specific amounts of these beverages, it may be possible to reduce caloric intake from beverages to about 15% of daily total energy intake by following the guidelines. The authors suggest drinking 20-50 fluid ounces of water each day, which accounts for about 20-50% of the recommended total daily fluid intake of about 100 fluid ounces.

HIGDON JV and FREI B. Coffee and health: a review of recent human research. Crit. Rev. Food Sci. Nutr. 46:101-123, 2006.

Coffee contains over one thousand chemical compounds, including caffeine, chlorogenic acid, and diterpenes (cafestol and kahweol). Caffeine content in brewed coffee ranges from 72-130 mg per eight-ounce (about 240 ml) serving but can be as high as 282 mg per eight-ounce serving, depending on variations in roasting, grinding, type of bean, brewing time, etc. Chlorogenic acid is a polyphenol that is converted to caffeic acid and quinic acid in the gut. These acids may act as physiological antioxidants. A number of studies have found that diterpenes in boiled coffee raise serum total and LDL cholesterol levels. Diterpenes are removed by paper filters during brewing. Coffee also contains magnesium and potassium and is a significant source of niacin. Epidemiological studies found that coffee may help protect against type 2 diabetes, Parkinson’s disease, colorectal and liver cancer, and cirrhosis. On the other hand, high coffee consumption has been associated in some epidemiological studies with increased risk of heart disease, while other studies have not found that association, despite the observations that coffee consumption increases plasma homocysteine levels and raises blood pressure in nonhypertensive subjects and that boiled coffee raises cholesterol levels. Coffee may also impair iron and zinc absorption and increase the risk of osteoporotic fractures in older adults. The maternal intake of more than three cups per day may increase the risk of spontaneous abortion and impair fetal growth.

PACHER P, BECKMAN JS, and LIAUDET L. Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87: 315-424, 2007.

In this lengthy review, the authors provide comprehensive information on the research history of nitric oxide and peroxynitrite and their roles in health and disease. Nitric oxide is the first gas found to have a role as a physiological signaling molecule. Over 25 years ago investigators found that an uncharacterized molecule called endothelium-derived relaxing factor (EDRF) played an important role in relaxing smooth muscle cells around blood vessels, permitting dilation and normal function. Years later, EDRF was identified as nitric oxide, and a number of researchers shared the Nobel Prize for identifying its cell-signaling properties. Nitric oxide is synthesized in the body from the amino acid arginine by nitric oxide synthases. It diffuses through tissues and is converted to nitrate in red blood cells. Nitric oxide can combine with the superoxide radical to form peroxynitrite, which is a very powerful oxidant used by immune cells to destroy pathogens. However, excess peroxynitrite can damage biomolecules like proteins, lipids, and DNA, as well as mitochondria, often resulting in cell death. The body synthesizes an antioxidant enzyme called superoxide dismutase to convert superoxide to hydrogen peroxide and stable oxygen so that production of excess peroxynitrite is partly mitigated. Peroxynitrite itself decomposes into radicals capable of damaging biomolecules. Peroxynitrite has been implicated in cardiovascular dysfunction and pathology, including heart failure, atherosclerosis, and hypertension; inflammatory diseases like arthritis and inflammatory bowel disease; diabetes; stroke and reperfusion injury; cancer; and neurodegenerative diseases like multiple sclerosis, Parkinson's disease, Alzheimer's disease, and ALS. Antioxidants like urate, vitamins C and E, and polyphenolic compounds found in fruit and vegetables may help protect against peroxynitrite damage. Urate is an endogenous antioxidant formed in the body from DNA breakdown products called purines, which are also found in foods like sardines and organ meat.

ZHANG W-J, WEI H, HAGEN T, and FREI B. alpha-Lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. Proc. Natl. Acad. Sci. USA 104:4077-4082, 2007.

Monocytes are immune system cells that circulate in the blood. When they migrate into tissues, they become macrophages and engulf pathogens. When macrophages ingest oxidized cholesterol in the arterial wall, they become foam cells and contribute to the development of atherosclerotic lesions. When monocytes are activated by bacterial toxins, they elicit a pro-inflammatory response that can lead to sepsis (septic shock) and its sequelae, including organ failure and death. The authors exposed monocytes in vitro to a bacterial toxin and found that alpha-lipoic acid added to the culture medium inhibited the acute inflammatory response by activating a specific biochemical signaling pathway (PI3K/Akt). The effect of alpha-lipoic acid on this pathway was confirmed in vivo using mice. The authors also found that mice injected with alpha-lipoic acid prior to exposure to the bacterial toxin were significantly protected from death.


Last updated December 2007