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Research Newsletter-Fall/Winter 2009

RECENT PUBLICATIONS BY LPI SCIENTISTS

Selected summaries by Stephen Lawson

A comprehensive list of all LPI scientific papers published in 2007 to 2009 are posted online as a supplement to this article. Summaries of some representative papers appear below. LPI scientists are identified in boldface.



Cancer Chemoprotection


CARTER O, DASHWOOD RH, WANG R, DASHWOOD WM, ORNER GA, FISCHER KA, LOHR CV, PEREIRA CB, BAILEY GS, and WILLIAMS DE. Comparison of white tea, green tea, epigallocatechin-3-gallate, and caffeine as inhibitors of PhIP-induced colonic aberrant crypts. Nutr. Cancer 58:60-65, 2007.

In previous studies, the authors found that white tea—the least processed type of tea—inhibited the formation of lesions in rat colons induced by exposure to heterocyclic amines, frequently called "cooked-meat mutagens" because they are formed in proteinacious food grilled or fried at high temperatures. In the present study, the authors fed white tea or green tea to rats either before and during or after exposure to a heterocyclic amine. While both teas induced liver enzymes that metabolize and aid in the excretion of the mutagen, white tea afforded the greatest protection against colonic lesions, especially when given after exposure to the mutagen.

SIMONICH MT, EGNER P, ROEBUCK BD, ORNER G, JUBERT C, PEREIRA C, GROOPMAN JD, KENSLER TW, DASHWOOD RH, WILLIAMS D, and BAILEY GS. Natural chlorophyll inhibits aflatoxin B1 induced multiorgan carcinogenesis in the rat. Carcinogenesis 28:1294-1302, 2007.

Prolonged exposure to aflatoxin B1, a carcinogen produced by mold growing on damp grains, causes liver cancer in many people in Asia and Africa. The authors fed chlorophyll—the green pigment in plants—or its derivative, chlorophyllin, to rats treated with aflatoxin B1. Both compounds very substantially reduced DNA damage, a surrogate for liver and colon cancer, with chlorophyll slightly more effective than chlorophyllin. Chlorophyll and chlorophyllin bind to aflatoxin B1 in the gut, preventing its entry into the bloodstream and delivery to target organs.

CASTRO DJ, YU Z, L÷HR CV, PEREIRA CB, GIOVANINI J, FISCHER KA, ORNER GA, DASHWOOD RH, and WILLIAMS DE. Chemoprevention of dibenzo[a,l]pyrene transplacental carcinogenesis in mice born to mothers administered green tea: primary role of caffeine. Carcinogenesis 29:1581-1586, 2008.

The authors previously reported that feeding indole-3-carbinol—a phytochemical in cruciferous vegetables—to pregnant mice exposed to a carcinogenic polycyclic aromatic hydrocarbon called dibenzo[a,l]pyrene (DBP) protected the offspring from mortality due to lymphoma and also reduced lung tumor multiplicity. Polycyclic aromatic hydrocarbons are prevalent environmental carcinogens formed by the combustion of organic material. In the present study, the authors fed green tea, decaffeinated green tea, caffeine, or epigallocatechin-3-gallate (EGCG) from green tea to pregnant and nursing mice exposed to DBP. Only green tea and caffeine significantly protected the offspring from mortality due to lymphoma. All treatments, especially EGCG, reduced tumor multiplicity. The results show that transplacental carcinogenesis can be inhibited by the maternal consumption of green tea.

Debbie Mustacich and Maret Traber

CLARKE JD, DASHWOOD RH, and HO E. Multi-targeted prevention of cancer by sulforaphane. Cancer Lett. 269:291-304, 2008.

Isothiocyanates, including sulforaphane and indole-3-carbinol (I3C), are phytochemicals derived from glucosinolates in cruciferous vegetables that help protect against cancer. When cruciferous vegetables like broccoli are consumed, myrosinase enzymes in the plant and gut microbes convert the parent compounds into sulforaphane and I3C. Sulforaphane has been shown to induce Phase 1 and 2 enzymes in the liver that metabolize, detoxify, and help excrete carcinogens. New cancer chemoprotective functions for sulforaphane have been described, including cell-cycle arrest, apoptosis (programmed cell death), and histone deacetylase inhibition. When histone deacetylase is inhibited, tumor suppressor genes are turned on and cellcycle arrest and apoptosis occur, leading to the selective death of cancer cells. Clinical studies indicate that sulforaphane is absorbed into the bloodstream, accumulates in tissues, and appears to be safe and well tolerated.

FREI B and LAWSON S. Vitamin C and cancer revisited. Proc. Natl. Acad. Sci. U.S.A. 105:11,037-11,038, 2008.

The use of vitamin C to treat cancer has been controversial for many decades. In this commentary, the authors review the early work of Linus Pauling and Ewan Cameron, who treated terminal cancer patients with highdose intravenous and oral vitamin C, as well as recent mechanistic research. Cameron and Pauling reported that many patients derived benefit from vitamin C, ranging from an increased sense of well-being and prolonged survival to complete regression. In two clinical trials, the Mayo Clinic failed to find any benefit for vitamin C; however, vitamin C was given only orally. Recent work by Mark Levine at the National Institutes of Health has elucidated how very high concentrations of vitamin C attained only by intravenous administration generate hydrogen peroxide around cancer cells that then kills them. This mechanistic explanation should stimulate better-designed clinical trials using intravenous vitamin C.

NIAN H, DELAGE B, PINTO JT, and DASHWOOD RH. Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter. Carcinogenesis 29:1816-1824, 2008.

The authors screened several organosulfur compounds derived from garlic for their potential to inhibit histone deacetylase. Such inhibition turns on tumor suppressor genes and leads to cell cycle arrest, growth inhibition, and apoptosis in cancer cells. Allyl mercaptan, the most potent histone deacetylase inhibitor, arrested the cell cycle of human colon cancer cells, resulting in growth inhibition.

SIMONICH MT, MCQUISTAN T, JUBERT C, PEREIRA C, HENDRICKS JD, SCHIMERLIK M, ZHU B, DASHWOOD RH, WILLIAMS DE, and BAILEY GS. Low-dose dietary chlorophyll inhibits multi-organ carcinogenesis in the rainbow trout. Food Chem. Toxicol. 46:1014-1024, 2008.

The authors fed chlorophyll or its derivative chlorophyllin to trout treated with the environmental carcinogen dibenzo[a,l]pyrene. Chlorophyll or chlorophyllin were about equally effective in reducing the incidence of liver and stomach cancer by about half. Chlorophyllin given after exposure to the carcinogen slightly increased the incidence of cancer, although in other studies chlorophyll did not promote tumors post-initiation. Both compounds probably work by binding to the carcinogen and preventing its uptake into tissues. The chemoprotective amount of chlorophyll is within the range found in typically consumed portions of spinach.

CHUNG WG, MIRANDA CL, STEVENS JF, and MAIER CS. Hop proanthocyanidins induce apoptosis, protein carbonylation, and cytoskeleton disorganization in human colorectal adenocarcinoma cells via reactive oxygen species. Food Chem. Toxicol. 47:827-836, 2009.

Proanthocyanidins are polyphenols found in many fruits, vegetables, beverages, cocoa, and hops used in the production of beer. The authors tested the anticancer effect of proanthocyanidins from hops in human colon cancer cells, finding that the proanthocyanidins killed the cells in a dose-dependent manner by apoptosis (programmed cell death), cytoskeleton derangement, oxidative damage to proteins, and induction of the formation of hydrogen peroxide. Although the absorption of proanthocyanidins into the bloodstream may be very limited, there is evidence that high local concentrations in the colon can be attained. The anticancer concentrations cannot be achieved by drinking beer.

NIAN H, BISSON WH, DASHWOOD WM, PINTO JT, and DASHWOOD RH. α-Keto acid metabolites of organoselenium compounds inhibit histone deacetylase activity in human colon cancer cells. Carcinogenesis 30:21416-1423, 2009.

Low levels of selenium have been associated with an increased risk for cancer in several studies, but supplementation trials have yielded conflicting results. In this mechanistic study, the authors tested two organic forms of selenium (methylselenocysteine and selenomethionine) and their liver metabolites (β-methylselenopyruvate and α-keto-γ-methylselenobutyrate, respectively) for their ability to inhibit histone deacetylase in human colon cancer cells. Inhibition of histone deacetylase results in cell-cycle arrest and cell death. While the parent compounds did not appreciably affect histone deacetylase activity, the metabolites were inhibitory in a dose-dependent manner, resulting in apoptosis (programmed cell death).

SONG Y, CHUNG CS, BRUNO RS, TRABER MG, BROWN KH, KING JC, and HO E. Dietary zinc restriction and repletion affects DNA integrity in healthy men. Am. J. Clin. Nutr. 90:321-328, 2009.

It is estimated that about two billion people worldwide have inadequate zinc status, although specific and sensitive biomarkers for zinc deficiency have not been validated. In this study, the authors dietarily depleted nine healthy men of zinc for about six weeks, then repleted them with 11-20 mg/day of zinc for about four weeks. During the zinc-depletion part of the study, DNA damage in blood cells increased, and zinc repletion reversed DNA damage. Levels of F2-isoprostanes—markers of lipid peroxidation—were unaffected by zinc status throughout the study. The authors conclude that adequate zinc status maintains DNA integrity, which may reduce the risk for cancer.

Joe Beckman

YAN M, HARDIN K, and HO E. Differential response to zinc-induced apoptosis in benign prostate hyperplasia and prostate cancer cells. J. Nutr. Biochem. 2007 [Epub ahead of print].

The prostate has the highest concentration of zinc of all soft tissues in the body, but malignant prostate cells have low levels of zinc. The authors investigated the effect of zinc on prostate cancer cells and benign prostate hyperplasia (BPH) cells in vitro. Zinc added to the culture media at concentrations higher than those found in plasma but lower than levels found in the prostate induced apoptosis (programmed cell death) in BPH cells. Higher concentrations of zinc were required to kill the prostate cancer cells. Zinc affected molecular pathways in the BPH and prostate cancer cells differently. Overall, it appears that zinc helps prevent prostate cancer, including in men with BPH, but the therapeutic value in prostate cancer may be limited.

Cardiovascular and Metabolic Diseases


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, 2007.

In this study, the authors report that dietary restriction of zinc in rats resulted in an increase in oxidative stress as measured by F2-isoprostanes, which are formed from the oxidation of arachidonic acid, a polyunsaturated fat. The increased oxidative stress was associated with declines in levels of plasma uric acid and vitamin E in the liver, possibly because these antioxidants were used up by increased levels of oxidants. Plasma vitamin C was unaffected. Zinc appears to function as an antioxidant indirectly by enhancing the activity of liver enzymes that metabolize arachidonic acid and by maintaining the activity of glutathione, an important endogenous antioxidant. As many as 12% of Americans may be zinc deficient, thus compromising their antioxidant status.

LEONARD SW, JOSS JD, MUSTACICH DJ, BLATT DH, LEE YS, and TRABER MG. Effects of vitamin E on cholesterol levels of hypercholesterolemic patients receiving statins. Am. J. Health. Syst. Pharm. 64:2257-2266, 2007.

Based on studies of increased xenobiotic (drug) metabolism in mice fed vitamin E, the authors tested the hypothesis that vitamin E supplementation in hypercholesterolemic humans taking lovastatin or simvastatin to lower cholesterol would negate the beneficial effect of the statins. Surprisingly, vitamin E (400 IU/day for eight weeks) did not affect total or low-density cholesterol levels but did slightly lower HDL cholesterol levels.

TRABER MG and ATKINSON J. Vitamin E, antioxidant and nothing more. Free Rad. Biol. Med. 43:4-15, 2007.

The authors suggest that the sole role of vitamin E in humans is to act as a scavenger of peroxyl radicals, thus inhibiting lipid peroxidation. Preventing lipid peroxidation in membranes preserves their vital biological functions. The alpha-tocopherol transfer protein (alpha-TTP) recognizes only alpha-tocopherol (natural vitamin E) for distribution to tissues; thus, the vitamin E requirement for humans is based on alpha-tocopherol. Defects in alpha-TTP in humans cause severe vitamin E deficiency, leading to ataxia and neuropathy. The authors propose that the regulation of molecular signaling pathways often attributed to vitamin E is instead dependent on oxidative stress.

DEVARAJ S, LEONARD S, TRABER MG, and JIALAL I. Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome. Free Radic. Biol. Med. 44:1203-1208, 2008.

Metabolic syndrome increases the risk for diabetes and heart disease, probably due to increased oxidative stress and inflammation. The RDA for vitamin E is based on alpha-tocopherol, or natural vitamin E, an important fat-soluble antioxidant. Gamma-tocopherol, the most abundant form of vitamin E in the American diet, is also an antioxidant that prevents nitrative damage to proteins. The authors conducted a trial with 80 men and women with metabolic syndrome randomized to receive either 800 mg/day of alpha-tocopherol, 800 mg/day of gammatocopherol, 800 mg/day of each, or placebo for six weeks. The combination of alpha- and gamma-tocopherol significantly decreased levels of C-reactive protein, a marker of inflammation. Oxidative stress, as measured by lipid peroxides in blood, was diminished by either form of vitamin E and both forms in combination. Nitrative stress, assessed by urinary nitrotyrosine, was reduced only by gamma-tocopherol alone or in combination.

JUMP DB. N-3 polyunsaturated fatty acid regulation of hepatic gene transcription. Curr. Opin. Lipidol. 19:242-247, 2008.

In this review, the author notes that omega-3 polyunsaturated fats, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) commonly found in fish, regulate genes in the liver that control carbohydrate and fat metabolism. For example, omega-3 fatty acids increase the oxidation of fats while inhibiting their synthesis and storage. Omega-3 fats affect glucose utilization and do not contribute to insulin resistance. Therefore, they may help prevent metabolic syndrome.

TRABER MG, FREI B, and BECKMAN JS. Vitamin E revisited: do new data validate benefits for chronic disease prevention? Curr. Opin. Lipidol. 19:30-38, 2008.

Vitamin E prevents the propagation of lipid peroxidation and inhibits platelet aggregation, although results of studies investigating the role of vitamin E in disease prevention have been conflicting. In this review, the authors suggest that several problems have plagued the observational and clinical studies: 1) plasma levels of vitamin E (influenced by whether fat-soluble supplements are taken with food) were seldom measured, and 2) levels of oxidative stress in subjects were rarely determined to identify the cohort that might respond to antioxidant supplementation. Nevertheless, there are several good studies showing health benefits for vitamin E in protecting neurological function and decreasing the risk of mortality from heart disease or cancer.

ZHANG W-J, BIRD K, MCMILLEN T, LEBOEUF R, HAGEN TM, and FREI B. Dietary alpha-lipoic acid supplementation inhibits atherosclerotic lesion development in apolipoprotein E-deficient and apolipoprotein E/low-density lipoprotein receptor-deficient mice. Circulation 117:421-482, 2008.

Mice specially bred as a model of atherosclerosis were fed a Western-type diet containing cholesterol and saturated fat with and without alpha-lipoic acid supplements for ten weeks. Supplementation significantly reduced artherosclerotic lesion formation and triglyceride levels. Alpha-lipoic acid also inhibited the expression of pro-inflammatory molecules and adhesion molecules in the aorta that are associated with the development of atherosclerotic lesions. Additionally, supplemented mice gained 40% less body weight than unsupplemented mice.

Scott Leonard

BUTLER JA, HAGEN TM, and MOREAU R. Lipoic acid improves hypertriglyceridemia by stimulating triacylglycerol clearance and down regulating liver triacylglycerol secretion. Arch. Biochem. Biophys. 485:63-71, 2009.

Elevated levels of triglycerides in blood (hypertriglyceridemia) are causally related to diabetes and heart disease. In this study, the authors fed chow supplemented with alpha-lipoic acid for five weeks to rats bred as a model of diabetes. They found that alpha-lipoic acid inhibited the expression of genes in the liver involved in the synthesis of fatty acids and triglycerides and decreased the secretion of triglycerides from the liver. In a related experiment, they determined that intravenously administered alpha-lipoic acid stimulated clearance of triglycerides from blood. The results suggest that alpha-lipoic acid may have utility in treating hypertriglyceridemia and diabetic dyslipidemia in humans.

MIRANDA CL, REED RL, KUIPER HC, ALBER S, and STEVENS JF. Ascorbic acid promotes detoxification and elimination of 4-hydroxy-2(E)-nonenal in human monocytic THP-1 cells. Chem. Res. Toxicol. 22:863-874, 2009.

Reactive oxygen species can induce the formation of lipid hydroperoxides like 4-hydroxy-2(E)-nonenal, or HNE, which can, in turn, generate oxidants and protein carbonyls that damage cells, leading to cell death. The authors report that vitamin C protects cells from damage by HNE by increasing the formation of glutathione conjugates of HNE and then clearing the conjugates from cells. Glutathione is an endogenous antioxidant that detoxifies cellular toxicants like HNE. This pathway represents yet another healthpromoting mechanism of vitamin C.

MUSTACICH DJ, GOHIL K, BRUNO RS, YAN M, LEONARD SW, HO E, CROSS CE, and TRABER MG. Alpha-tocopherol modulates genes involved in hepatic xenobiotic pathways in mice. J. Nutr. Biochem. 20:469-476, 2009.

Phase 1 and 2 liver enzymes help detoxify xenobiotics, including drugs and some phytochemicals, by chemically modifying them to aid in their excretion. In this study, mice were fed large amounts of vitamin E for four months and their liver enzymes were measured. Supplemental vitamin E increased the expression of several enzymes involved in xenobiotic metabolism, suggesting that high intakes of vitamin E in humans may affect drug metabolism.

ROBERTS LJ 2ND, TRABER MG, and FREI B. Vitamins E and C in the prevention of cardiovascular disease and cancer in men. Free Radic. Biol. Med. 46:1558, 2009.

The authors wrote this letter in response to the Physicians' Health Study II, which reported that long-term use of vitamin C (500 mg daily) and vitamin E (400 IU every other day) had no effect on the incidence of heart attacks and strokes, deaths from cardiovascular disease, the risk of prostate or total cancers, or cancer mortality in a group of 14,641 U.S. male physicians in a ten-year period. The letter notes several flaws in the study, including the lack of measurements of oxidative stress or blood levels of the antioxidants. The "healthy enrollee effect" may have also lessened the chance for finding any effect, since the physicians had a lower risk for heart disease and cancer compared to non-enrollees. Furthermore, the amount and type of vitamin E may have been inadequate to substantially lower oxidative stress.

Healthy Aging


MILGRAM NW, ARAUJO JA, HAGEN TM, TREADWELL BV, and AMES BN. Acetyl-L-carnitine and α-lipoic acid supplementation of aged beagle dogs improves learning in two landmark discrimination tests. FASEB J. 21: 3756-3762, 2007.

In a group of 12 old beagles (7.6-8.8 years old), six dogs supplemented twice daily with alpha-lipoic acid and acteyl-L-carnitine performed significantly better than unsupplemented dogs in sensitive tests of complex learning and spatial abilities. Similar results were previously obtained with rodents, but this was the first test with dogs. The authors propose that the results were due to improved mitochondrial activity in the brain and, possibly, enhanced synthesis of the neurotransmitter acetylcholine.

CASSINA P, CASSINA A, PEHAR M, CASTELLANOS R, GANDELMAN M, DE LE”N A, ROBINSON KM, MASON RP, BECKMAN JS, BARBEITO L, and RADI R. Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J. Neurosci. 28:4115-4122, 2008.

Astrocytes provide structural and metabolic support for motor neurons. Mutations in the endogenous antioxidant copper-zinc superoxide dismutase (SOD), resulting in its loss of zinc, cause the altered SOD to help generate damaging reactive oxygen and nitrogen species. Astrocytes that express the mutated SOD become highly reactive and damage motor neurons, contributing to the development of amyotrophic lateral sclerosis (ALS). In this in vitro study, the authors report that mitochondrial dysfunction in astrocytes with the mutant SOD cause astrocyte activation leading to motor neuron death and that this can be prevented by incubating the astrocytes with the antioxidant ubiquinone, or coenzyme Q.

PETERSEN SHAY K, MOREAU RF, SMITH EJ, and HAGEN TM. Is alpha-lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity. IUBMB Life 60:362-367, 2008.

Acting as an antioxidant, lipoic acid scavenges reactive oxygen and nitrogen species. However, an oral dose of lipoic acid is quickly cleared from the blood, suggesting that lipoic acid does not function primarily as a physiological antioxidant. The authors review evidence that supports the role of lipoic acid as an indirect antioxidant through its induction of the endogenous antioxidant glutathione. Lipoic acid also inhibits the activation of NF-κB, a transcription factor that increases gene expression of pro-inflammatory cytokines. Lipoic aid improves glycemic handling and has been used in Europe to treat diabetic neuropathy for over 30 years. Lipoic acid exerts these favorable effects by altering cell-signaling pathways and by acting as a weak hormetic agent that induces stress responses. In aging studies in rats and dogs, lipoic acid has been found to improve mitochondrial function, reversing age-related declines in cognitive ability and physical activity.

SMITH AR, VISIOLI F, FREI B, and HAGEN TM. Lipoic acid significantly restores, in rats, the age-related decline in vasomotion. Brit. J. Pharamcol. 153:1615-1622, 2008.

Cellular ceramides—membrane lipids composed of fatty acids and sphingosine that serve as signaling molecules—increase with age. This increase is associated with decreases in glutathione, an important endogenous antioxidant, and loss of proper arterial relaxation dependent on nitric oxide activity, leading to a "stiffening" of the arteries and impaired function. The authors found that injecting lipoic ceramide levels, and reversed vasomotor decline. Since agerelated vasomotor dysfunction is a feature of heart disease, lipoic acid may provide a therapeutic intervention.

BECKMAN JS. Understanding peroxynitrite biochemistry and its potential for treating human diseases. Arch. Biochem. Biophys. 484:114-116, 2009.

The author and his colleagues established peroxynitrite, which is formed from reactions between the superoxide radical and nitric oxide, as a biological oxidant. Peroxynitrite can nitrate the amino acid tyrosine in proteins, leading to functional impairment. In the case of acetaminophen poisoning, the therapeutic reduction of peroxynitrite formation decreases tyrosine nitration correlated with liver damage. Additionally, motor neuron death in amyotrophic lateral sclerosis (ALS) can be initiated by peroxynitrite. Peroxynitrite chemistry is very complex, but as more is learned, the possibility of therapeutic interventions increases. For example, urate, a physiological antioxidant that causes gout in very high concentrations, blocks tyrosine nitration without scavenging peroxynitrite and is associated with a reduced risk for multiple sclerosis and Parkinson's disease.

Tory Hagen

BOWMAN GL, DODGE H, FREI B, CALABRESE C, OKEN BS, KAYE JA, and QUINN JF. Ascorbic acid and rates of cognitive decline in Alzheimer's disease. J. Alzheimers Dis. 16:93-98, 2009.

Alzheimer's disease is related to oxidative damage in the brain. The authors analyzed the vitamin C content in plasma and cerebrospinal fluid (CSF) from 32 patients with mild to moderate Alzheimer's disease, finding that the highest ratio of vitamin C in CSF to vitamin C in plasma was associated with the slowest decline in cognitive function. They also reported that patients with impaired blood-brain barrier function, which provides a junction between blood and CSF—protecting the brain by permitting only small molecules to pass—exhibited lower CSF to plasma vitamin C levels. Therefore, blood-brain barrier dysfunction may accelerate decline in Alzheimer's disease.

GOMBART AF, BHAN I, BORREGAARD N, TAMEZ H, CAMARGO JR CA, KOEFFLER HP, and THADHANI R. Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis. Clin. Infect. Dis. 48:418-424, 2009.

Death from infections is the second most common cause of mortality among patients with end-stage renal disease undergoing hemodialysis. In this study, the authors analyzed the levels of cathelicidin, an antimicrobial protein whose synthesis is dependent on vitamin D, in 279 renal patients undergoing hemodialysis. They found that those patients with the lowest levels of cathelicidin in plasma had a twofold increased risk of death from infections compared to those patients with the highest levels. Since the development of microbial resistance to antimicrobial peptides is rare, strategies that enhance cathelicidinís activity, such as vitamin D supplementation, may be useful in decreasing mortality.

GOMBART AF, SAITO T, and KOEFFLER HP. Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates. BMC Genomics 10:321, 2009.

The authors showed that the cathelicidin antimicrobial peptide gene, controlled by vitamin D, has been evolutionarily conserved in primates for 55-60 million years. Its persistence in primates, including humans, but not in other mammals has been mediated by Alu genetic elements in so-called "junk" DNA. The authors propose that cathelicidin helps regulate the delicately balanced immune response, optimizing innate immunity while minimizing damage to the host by suppressing inflammation. The biological importance of cathelicidin activity is demonstrated by its evolutionary conservation for many millions of years.

TRUMBULL KA and BECKMAN JS. A role for copper in the toxicity of zinc-deficient superoxide dismutase to motor neurons in amyotrophic lateral sclerosis. Antioxid. Redox Signal. 11:1627-1639, 2009.

In this review, the authors revisit the hypothesis that the loss of zinc from the endogenous antioxidant copper-zinc superoxide dismutase (SOD) causes the mutant protein to become toxic to motor neurons, leading to amyotrophic lateral sclerosis, or ALS. Mutations to SOD account for 20-25% of ALS cases. Zinc is not as tightly bound to SOD as copper, and if zinc is lost, the resultant copper SOD helps to generate peroxynitrite and other radicals that kill motor neurons. Scientists have observed that SOD aggregates are associated with ALS, but the authors suggest that the protein aggregation is merely a means to remove the mutant SOD rather than a causal factor in motor neuron death. In mouse models of ALS, copper chelators and appropriate zinc supplementation delayed the progression of the disease.


Last updated November 2009