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Research Newsletter-Spring/Summer 2012

RECENT PUBLICATIONS BY LPI SCIENTISTS

SUMMARIES OF SELECTED PUBLICATIONS BY STEPHEN LAWSON

LPI scientists are identified in boldface.


Healthy Aging Program


GOMBART AF. The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Future Microbiol. 4:1151-1165, 2009

In the early 19th century, exposure to sunlight was found to be beneficial for tuberculosis patients, although the mechanism was unknown. Sunlight is required for the endogenous synthesis of vitamin D in the skin. Recent research has found that vitamin D regulates the synthesis of antimicrobial peptides in the body, including cathelicidin and defensin, involved in innate immunity. Cathelicidin and defensin punch holes in bacterial membranes, leading to their death. A study in hemodialysis patients by the author showed that high cathelicidin levels in the blood were associated with decreased mortality from infections. Some phytochemicals and dietary fats, such as curcumin and polyunsaturated fatty acids, may also stimulate anti- microbial peptide activity by binding to the vitamin D receptor on cells. The quantitative relationship between vitamin D and these antimicrobial peptides hasn’t yet been worked out.

SHAY KP, MOREAU RF, SMITH EJ, SMITH AR, and HAGEN TM. Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential. Biochim. Biophys. Acta 1790:1149-1160, 2009

In this review, the authors discuss the biochemical effects of supplemental lipoic acid, which is usually found as a racemic mixture of the S and R forms. The R form has greater bioavailability. About 20-40% of a dose of lipoic acid is absorbed into the blood stream and then fairly rapidly metabolized and excreted. It accumulates in the liver, heart, skeletal muscle, and, possibly, in the brain. In humans, oral doses as high as 600 mg twice a day for six months and intravenous infusions of 600 mg daily have not resulted in any significant side effects or toxicity. Both the oxidized and reduced forms of lipoic acid scavenge reactive oxygen species and each selectively chelates reactive metals like copper, iron, lead, and mercury. Lipoic acid induces the synthesis of glutathione—an important endogenous antioxidant—and may increase the absorption of vitamin C into the blood stream. Lipoic acid influences the transcription factor Nrf2, resulting in increased glutathione synthesis and phase 2 detoxification enzyme levels. Lipoic acid improves glucose handling, enhances vasodilation, lowers blood pressure, and has anti-inflammatory properties. Oral and intravenous lipoic acid have also been used to significantly attenuate diabetic neuropathy.

LI L, SMITH A, HAGEN TM,, and FREI B. Vascular oxidative stress and inflammation increase with age: Ameliorating effects of alpha-lipoic acid supplementation. Ann. N. Y. Acad. Sci. 1203:151-159, 2010

Age-related increases in oxidative stress and inflammation have been implicated in the development of cardiovascular diseases. In this study, the authors found that biomarkers of oxidative stress (e.g., superoxide radicals) and inflammation (e.g., NF-κB activation) were elevated in the aortas of old rats compared to young rats. The levels of superoxide dismutase—an important endogenous antioxidant enzyme—were decreased in old rats. Supplementing the diets of old rats with lipoic acid for two weeks reduced these biomarkers of oxidative stress and inflammation, increased levels of superoxide dismutase, and alleviated endothelial dysfunction.

scientist working in the lab

BARBEITO AG, MARTINEZ-PALMA L, VARGAS MR, PEHAR M, MAÑAY N, BECKMAN JS, BARBEITO L, and CASSINA P. Lead exposure stimulates VEGF expression in the spinal cord and extends survival in a mouse model of ALS. Neurobiol. Dis. 37:574-580, 2010

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurological disease in which the death of motor neurons leads inexorably to the patient’s death. Functional mutations in the gene coding for the endogenous antioxidant enzyme copper-zinc superoxide dismutase (SOD) are associated with a significant number of ALS cases. Such mutations cause the enzyme to lose its affinity for zinc, and the zinc-deficient SOD then becomes very reactive—leading to the generation of reactive oxygen and nitrogen species in astrocytes that damage motor neurons—and contributes to the development of ALS. Although environmental exposure to lead is a risk factor for ALS, the authors found that, paradoxically, small amounts of lead added to cultured astrocytes expressing the defective SOD increased the amount of vascular endothelial growth factor, which, in turn, protected motor neurons from death. Mice with the SOD mutation given low, non-toxic levels of lead lived longer than unsupplemented mice, suggesting that lead inhibits neuroinflammation. Recent studies have also associated low lead levels in ALS patients with longer survival.

MONETTE JS, GOMEZ LA, MOREAU RF, DUNN KC, BUTLER JA, FINLAY LA, MICHELS AJ, SHAY KP, SMITH EJ, and HAGEN TM. (R)-α-Lipoic acid treatment restores ceramide balance in aging rat cardiac mitochondria. Pharmacol. Res. 63:23-29, 2011

Ceramides are sphingolipids found in cell membranes that have structural and signaling functions in cells. Ceramides are also associated with oxidative stress and programmed cell death (apoptosis) and accumulate upon exposure of cells to inflammatory stimuli. Such accumulation may lead to altered function of mitochondria—cellular organelles that generate chemical energy. The authors found that ceramides increased by over 30% in the heart mitochondria from old rats compared to young rats. Supplementing old rats with lipoic acid for two weeks lowered ceramide levels to those observed in young rats and restored mitochondrial energy metabolism.

BOWMAN GL, SILBERT LC, HOWIESON D, DODGE HH, TRABER MG, FREI B, KAYE JA, SHANNON J, and QUINN JF. Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. Neurology 78:241-249, 2012

The Oregon Brain Aging Study began in 1989 with nearly 300 men and women aged 65 years and older to investigate the link between diet and brain aging. Blood samples were obtained and various nutrients were measured, including vitamins, fatty acids, and carotenoids (beta-carotene, lycopene, lutein, etc.). Additionally, neuropsychological tests were administered, and the subjects’ brain volumes were assessed by MRI. Several nutrient biomarker patterns emerged from the analysis that were associated with cognitive function and brain volume. In particular, those subjects who scored highest in plasma values for the B vitamins and vitamins C, D, and E performed best on cognitive function tests and had greater total cerebral brain volume. Subjects who had the highest levels of plasma trans fats (partially hydrogenated fats found in many processed foods) had worse cognitive function and less total cerebral brain volume. Omega-3 fatty acids and higher lutein plus HDL cholesterol scores were associated with better cognitive and memory function, respectively.

GOMEZ LA, HEATH SH,, and HAGEN T. Acetyl-L- carnitine supplementation reverses the age-related decline in carnitine palmitoyltransferase 1 (CPT1) activity in interfibrillar mitochondria without changing the L-carnitine content in the rat heart. Mech. Ageing Dev. 133:99-106, 2012

Research has shown that supplementation with the non-protein amino acid acetyl-L-carnitine (L-carnitine to which an acetyl chemical group has been added) improves memory performance and increases physical activity in old rats. In this study, the authors investigated the specific biochemical mechanisms that may explain these observations. There are two subpopulations of mitochondria—the organelles that produce chemical energy in cells. The authors found that acetyl-L-carnitine increases the activity of the enzyme carnitine palmitoyltransferase 1 (CPT1) in one mitochondrial subpopulation in heart cells of old rats. CPT1 controls the oxidation of fatty acids, a crucial process in mitochondrial energy metabolism, and declines with age. While these relationships are complex and not fully understood, the authors propose that age-related oxidative modifications of CPT1 may be reversed by acetyl-L-carnitine supplementation, leading to improved cardiac function in old animals.

Cardiovascular and Metabolic Diseases


MICHELS AJ, HAGEN TM, and FREI B. A new twist on an old vitamin: Human polymorphisms in the gene encoding the sodium-dependent vitamin C transporter 1. Am. J. Clin. Nutr. 92:271-272, 2010

In this commentary, the authors reflect on a paper by Timpson et al. discussing variations among humans in the gene coding for one of the vitamin C transporters (SVCT1) on cells. These transporters control the amount of vitamin C that gets into the blood stream and into cells. Analysis of a cohort of 15,000 people in the United Kingdom found that people with a single nucleotide polymorphism (SNP) in the SVCT1 gene have significantly reduced concentrations of vitamin C in blood. SVCT1 is especially important in the reabsorption of vitamin C in the kidneys, and alterations in its gene affect the level of vitamin C in the blood. The glucose transporter may compensate for the inefficient SNP in the affected SVCT1 gene since it takes up oxidized vitamin C, which may be increased by supplementation. Since the incidence of the SNP may be about 3% in Caucasians and over 9% in African-Americans, studies assessing the effect of vitamin C intake on health and disease outcomes should take SNPs among subjects into account.

TRABER MG. Regulation of xenobiotic metabolism, the only signaling function of alpha-tocopherol? Mol. Nutr. Food Res. 54:1-8, 2010

Studies on vitamin E supplementation and mortality have been conflicting. Vitamin E is a family of eight isomers, but only one—RRR-alpha-tocopherol (natural vitamin E)—is selectively recognized by transport mechanisms for distribution to the body’s tissues. Vitamin E is metabolized by cytochrome P450s, the same enzymes that metabolize xenobiotics like drugs. Thus, the non-RRR-alpha-tocopherol isoforms are metabolized for excretion in the urine or bile and do not accumulate in the body, unlike RRR-alpha-tocopherol, which does accumulate—but not excessively—due to its slower metabolism. Results from the Women’s Health Study showing that vitamin E reduces the incidence of venous thromboembolism may be explained by vitamin E’s interference with the conversion of active vitamin K, which is critical in blood clotting.

KUIPER HC, BRUNO RS, TRABER MG, and STEVENS JF. Vitamin C supplementation lowers urinary levels of 4-hydroperoxy-2-nonenal metabolites in humans. Free Radic. Biol. Med. 50:848-853, 2011

Oxidative stress has been implicated in age-related diseases, but intervention trials with antioxidants have had conflicting results for myriad reasons. It would be useful to validate biomarkers of oxidative stress that can help identify people who might benefit from antioxidant supplementation. The authors found that the levels of lipid peroxidation (LPO) products in urine can be affected by vitamin C intake. LPO products are derived from polyunsaturated fatty acids and can damage proteins and DNA; they are associated with Alzheimer’s disease and cancer. Specifically, supplementation with 500 mg of vitamin C twice per day for 17 days in volunteers reduced levels of urinary LPO products by 20-30%. These LPO products may be more sensitive biomarkers of oxidative stress than the commonly used F2-isoprostanes, which are also products of lipid peroxidation.

scientist working in the lab

JUMP DB. Fatty acid regulation of hepatic lipid metabolism. Curr. Opin. Clin. Nutr. Metab. Care 14:115-120, 2011

In this review, the author summarizes findings from studies on the role of dietary fatty acids in the metabolism of fats in the liver. People with diabetes or metabolic syndrome typically have low levels of polyunsaturated fatty acids (PUFA). In mice, high-fat diets lead to hyperglycemia, insulin resistance, and fatty liver—conditions that are associated with decreased levels of enzymes that synthesize PUFA in the liver. Fatty acid elongase is a liver enzyme involved in the synthesis of PUFA that regulates carbohydrate metabolism and liver lipid content.

LOTITO SB, ZHANG WJ,, YANG CS, CROZIER A, and FREI B. Metabolic conversion of dietary flavonoids alters their anti-inflammatory and antioxidant properties. Free Radic. Biol. Med. 51:454-463, 2011

Flavonoids are pigmented compounds found in fruits, vegetables, and tea that protect them from UV light and pathogens. They are believed to have health benefits in humans, but their mode of action has been unclear because they are poorly absorbed and then chemically modified before being rapidly excreted. The authors studied the anti-inflammatory and antioxidant activity of two flavonoids—quercetin (found in apples) and catechins (found in tea) and their metabolites—in human aortic endothelial cells in culture. The antioxidant and anti- inflammatory behavior of metabolites differed significantly from the parent compounds depending on the type of chemical modification, illustrating that the biological activity of metabolites of the dietary flavonoids cannot be predicted. Cell culture studies have limited utility in evaluating the activity of dietary flavonoids in the body.

LEGETTE L, MA L, REED RL, MIRANDA CL, CHRISTENSEN JM, RODRIGUEZ-PROTEAU R, and STEVENS JF. Pharmacokinetics of xanthohumol and metabolites in rats after oral and intravenous administration. Mol. Nutr. Food Res. 55:1-9, 2011

In vitro and rodent studies have shown that xanthohumol, a flavonoid in hops used to make beer, has antioxidant, anti-inflammatory, antimicrobial, and cancer chemo- protective properties. However, not much is known about the uptake of xanthohumol into the blood stream from the gut, its distribution to tissues, or its metabolism in vivo. The authors gave low, medium, and high doses of xanthohumol to rats and determined that peak plasma concentrations were achieved about four hours after dosing and that half of the xanthohumol was gone from the plasma in 18-30 hours.

Bioavailability correlated inversely with the dose; it was highest for the low dose and lowest for the high dose. The levels of metabolites peaked in plasma about 15-25 hours after initial xanthohumol dosing. Scaling from rats to humans on the basis of body weight suggests that the dietary intake of xanthohumol by humans is insufficient to achieve its postulated health benefits.

TRABER MG and STEVENS JF. Vitamins C and E: Beneficial effects from a mechanistic perspective. Free Rad. Biol. Med. 51:1000-1013, 2011

Vitamin C, required for collagen synthesis to prevent scurvy, plays a number of other crucial biochemical roles in the body. It regulates hypoxia-inducible factor-1 (HIF-1), which is involved in cell growth, metal transport, programmed cell death (apoptosis), blood vessel formation (angiogenesis), and energy metabolism. Vitamin C lowers levels of the HIF-1alpha subunit, high levels of which have been associated with aggressive cancer. Vitamin C accumulates in immune cells called neutrophils when they attack bacteria, presumably to protect the neutrophils from damage by the reactive oxygen species they produce to kill pathogens. The suppression of HIF-1 by vitamin C also regulates the death and removal of neutrophils when they have completed their function. Importantly, vitamin C is the premier water-soluble antioxidant in blood and protects against damaging free radicals and, with vitamin E, the formation of oxidized lipids. In cultured cells, vitamin C reacts with the lipid peroxidation product acrolein—a toxic and potentially carcinogenic substance primarily formed by heating food—assisting in its metabolic degradation and elimination. Vitamin C also exerts beneficial effects on blood pressure and vascular function by indirectly improving nitric oxide activity.

Vitamin E is a family of eight fat-soluable antioxidant molecules, only one of which, RRR-alpha-tocopherol, is selected for distribution to tissues. Deficiency of vitamin E causes hemolysis (rupture of red blood cells) and peripheral neuropathy. The degeneration of sensory neurons—leading to ataxia—has been observed in infants deficient in vitamin E due to fat malabsorption problems. There also seems to be a role for vitamin E in preserving proper immune function in elderly people. Vitamin E terminates the chain reaction of lipid peroxidation and is regenerated from its oxidized form by vitamin C. In some populations studied, such as elderly women, supplemental vitamin E decreased cardiovascular mortality, heart attacks, and strokes. While adequate vitamin E intake over a lifetime may help protect against chronic diseases, about 95% of Americans did not meet the Estimated Average Requirement some years ago (12 mg/d [17.9 IU/d] for adult men and women). Vitamin E may also ameliorate abnormally high levels of oxidative stress. Furthermore, vitamin E interferes with the synthesis of vitamin K, which is involved in blood clotting, possibly preventing thrombosis.

Cancer Chemoprotection Program


HO E, CLARKE JD, and DASHWOOD RH. Dietary sulforaphane, a histone deacetylase inhibitor for cancer prevention. J. Nutr. 139:2393-2396, 2009

In the cell’s nucleus, DNA is wrapped around proteins called histones. Acetylation (addition of acetyl chemical groups) of histones results in genes being turned on, and the deacetylation of histones causes genes to be turned off. Histone deacetylase (HDAC) inhibitors, therefore, keep genes, including tumor suppressor genes, active. Cancer cells seem to be especially sensitive to acetylation, which triggers differentiation and apoptosis (programmed cell death). Sulforaphane—found in cruciferous vegetables like broccoli—is an isothiocyanate whose metabolites act as HDAC inhibitors. Sulforaphane also induces Phase 2 enzymes that detoxify carcinogens, which is important in the early stage of carcinogenesis. It has also been found to induce cell-cycle arrest in cultured human prostate cancer cells and to slow tumor growth in xenografts of human prostate cancer cells in mice. In a mouse model of colon cancer, sulforaphane inhibited the development of polyps. About 74% of sulforaphane from broccoli extracts are absorbed in the intestine and have a biological half-life of about two hours.

scientist working in the lab

HSU A, BRAY TM, and HO E. Anti-inflammatory activity of soy and tea in prostate cancer prevention. Exp. Biol. Med. (Maywood) 235:659-667, 2010

Chronic inflammation has been implicated in prostate cancer, which is responsible for about 10% of cancer deaths in men. In this review, the authors focus on the effects of diet on prostate cancer, since environmental factors play an important role in cancer development. Historically, the incidence of prostate cancer has been lower in Asian countries, where soy products and tea are commonly consumed, than in Western countries. Inflammation, as indicated by activation of the transcription factor NF-κB, is associated with benign prostatic hyperplasia, which often precedes prostate cancer. Epigallocatechin-3-gallate (EGCG), a catechin in green tea, attenuates NF-κB activity in vitro and inhibits carcinogen activation and tumor growth in mice.

Isoflavones are found in soy and act as phytoestrogens. Consumption of soy in Asia is associated with a low incidence of prostate cancer, presumably due to its isoflavone content. Through cell-signaling effects, isoflavones, especially genistein, inhibit angiogenesis (blood vessel formation) needed to support tumor growth and cancer cell pro- liferation. High dietary intakes of soy also inversely correlate with testosterone levels in Japanese men, illustrating the hormone-like effects of soy. In the authors’ studies, only supplementation with both green tea and soy—but not with either alone—suppressed inflammation and inhibited prostatic hyperplasia in hormone-treated rats. The authors argue that a “whole foods” approach that relies on modest concentrations of these compounds lacking toxicity may be most effective against prostate cancer.

BOBE G, MURPHY G, ALBERT PS, SANSBURY LB, LANZA E, SCHATZKIN A, and CROSS AJ. Dietary lignan and proanthocyanidin consumption and colorectal adenoma recurrence in the Polyp Prevention Trial. Int. J. Cancer 130:1649-1659, 2012

Lignans and proanthocyanidins are polyphenols that have attracted interest because of their anti-inflammatory and anticancer properties. Lignans are found in the fibrous portion of plants, especially whole grains and flax, and are metabolized by gut bacteria to compounds that have estrogenic activity. Primary dietary sources of proanthocyanidins are tea, chocolate, and apples. The authors evaluated the association between lignan and proanthocyanidin intake—estimated from databases linked to a food frequency questionnaire—and adenoma recurrence in 1,859 participants in a four-year, randomized, nutritional intervention study that encouraged the consumption of a high-fiber, high-fruit, and vegetable-enriched diet. Overall, no association between lignan and proanthocyanidin intake and adenoma recurrence was observed; however, lignan intake was associated with adenoma recurrence in women, indicating that high lignan intake may increase the risk of adenoma recurrence in women.

CASTRO DJ, LÖHR CV, FISCHER KA, WATERS KM, WEBB-ROBERTSON BJ, DASHWOOD RH, BAILEY GS,, and WILLIAMS DE. Identifying efficacious approaches to chemoprevention with chlorophyllin, purified chlorophylls, and freeze-dried spinach in a mouse model of transplacental carcinogenesis. Carcinogenesis 30:315-320, 2009

The authors previously reported that indole-3-carbinol— a phytochemical in cruciferous vegetables—green tea, or caffeine fed to pregnant mice exposed to a carcinogenic polycyclic aromatic hydrocarbon called dibenzo[a,l] pyrene (DBP) protected the offspring from mortality due to lymphomas and decreased the number of lung tumors per mouse. Exposure to DBP is widespread because it is formed from the combustion of coal, petroleum products, tobacco, and other organic material. The authors have also demonstrated that chlorophyll or its derivative chlorophyllin protected trout from liver cancer caused by exposure to aflatoxin B1 formed by molds on grain and nuts. In the present study, oral co-administration of chlorophyllin and DBP to pregnant mice significantly protected their offspring from carcinogenesis, even though the offspring had no direct exposure to either compound. This provides another example of the utility of phytochemical chemoprotection against transplacental carcinogenesis.

scientist working in the lab

CLARKE JD, HSU A, RIEDL K, BELLA D, SCHWARTZ SJ, STEVENS JF,, and HO E. Bioavailability and interconversion of sulforaphane and erucin in human subjects consuming broccoli sprouts or broccoli supplement in a cross-over study design. Pharmacol. Res. 64:456-463, 2011

It has long been known that consumption of cruciferous vegetables like broccoli, Brussels sprouts, and cabbage confers some protection against cancer. Glucosinolates in these vegetables are converted by myrosinase—an enzyme in the vegetables released by chopping or chewing—into isothiocyanates like sulforaphane and erucin, as well as other compounds. Sulforaphane has demonstrated anticancer properties in cell culture and animal studies. The authors examined the bioavailability of sulforaphane in humans consuming broccoli sprouts or broccoli supplements by measuring sulforaphane and erucin in the blood. Both compounds were measured because sulforaphane can be converted to erucin and erucin to sulforaphane in the blood. The bioavailability of sulforaphane and erucin in the broccoli supplement was much lower than in fresh broccoli sprouts, probably because the supplements lack the enzyme myrosinase.

MCQUISTAN TJ, SIMONICH MT, PRATT MM, PEREIRA CB, HENDRICKS JD, DASHWOOD RH, WILLIAMS DE, and BAILEY GS.. Cancer chemoprevention by dietary chlorophylls: A 12,000-animal dose-dose matrix biomarker and tumor study. Food Chem. Toxic. 50:341-352, 2012

Dibenzo(def,p)chrysene (DBC, formerly known as DBP), a polycyclic aromatic hydrocarbon formed by the combustion of organic substances like coal, wood, and oil, is a potent carcinogen in animals. Because people are unavoidably exposed to DBC in urban areas, they may be at increased risk for cancer. The authors exposed trout to DBC and observed a linear dose-response increase in the incidence and multiplicity of liver tumors up to the dose of maximum effect. Co-treatment of the trout with chlorophyll-enriched spinach extracts at human dietary intake levels significantly inhibited the incidence and multiplicity of tumors, except at the highest DBC doses. This suggests that chemoprevention studies in animals conducted with very high carcinogen doses may not have much relevance to people. Chlorophyll’s likely protective mechanism is its binding to DBC in the gut, thereby preventing DBC uptake into the blood stream and delivery to target tissues.

WONG CP and HO E. Zinc and its role in age-related inflammation and immune dysfunction. Mol. Nutr. Food Res. 56:77-87, 2012

In this paper, the authors review the role of zinc deficiency in age-related immune dysfunction—leading to increased susceptibility to infections—and inflammation, which contributes to chronic diseases like heart disease and certain cancers. Over 40% of older Americans do not consume the daily Estimated Average Requirement for zinc (9.4 mg/d and 6.8 mg/d for men and women over 50, respectively), and there is an unexplained age-related decline in zinc levels that does not appear to be due to decreased dietary intake or absorption. Zinc inhibits the activation of NF-κB, a molecule that regulates the inflammatory response. Zinc supple- mentation has been shown to improve immune response and to lower inflammation.

Epigenetics refers to changes in gene expression without corresponding alterations in the underlying DNA. Zinc plays an epigenetic role in the methylation of DNA required for normal development and the suppression of carcinogenesis. Additionally, rodent experiments have shown that maternal zinc deficiency impairs immune function and glucose handling in offspring through epigenetic mechanisms.


Last updated May 2012