LINUS PAULING INSTITUTE RESEARCH REPORT

Recent Publications by LPI Scientists

Selected summaries by Stephen Lawson

A comprehensive list of all LPI scientific papers published in 2004 and 2005 appears on pages 14 and 15. Summaries of some representative papers appear below. LPI scientists are identified in boldface.

Aging

MICHELS AJ and HAGEN TM. Vitamin C status declines with age. In Vitamin C (Asard H, May JM, and Smirnoff N, eds.), pp. 203-227, BIOS Scientific Publishers Ltd., Oxford, UK, 2004.

This book chapter reviews the effect of age on vitamin C levels in the body. Animals and humans exhibit decreased vitamin C levels in plasma and tissues with age. This decrease in animals capable of manufacturing vitamin C in the liver does not appear to be caused by decreased synthesis, but possibly by diminished cellular uptake. Gender also affects vitamin C status—men tend to have lower vitamin C plasma levels than women and exhibit accentuated declines in plasma vitamin C with age, whereas plasma vitamin C in women does not decline substantially with age. Many studies have found that the elderly require about twice as much vitamin C as young people to achieve similar plasma concentrations. The authors of this chapter note that vitamin C is involved in many critical biochemical functions affecting immune surveillance, gene expression, collagen synthesis, vascular function, and mitochondrial energy production, all of which can become impaired with age. High vitamin C intake, mainly from the diet, is associated with decreased risk for overall mortality and age-related diseases like heart disease, cancer, cataracts, and diabetic complications. The chapter concludes with a discussion of age-related changes in the molecules that transport vitamin C into cells that may account for the decline in vitamin C status with age. For more detailed information, please see the article by Michels in the Fall/Winter 2002 LPI Research Report.


SMITH AR, SHENVI SV, WIDLANSKY M, SUH JH, and HAGEN TM. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr. Med. Chem. 11: 1135-1146, 2004.

Lipoic acid is synthesized in the body and serves many functions, including a critical role in energy production in the cells’ mitochondria. In this review, the authors note that 20-40% of an oral dose of lipoic acid is absorbed and peaks in plasma in about two hours, followed by its rapid disappearance. It is almost undetectable in plasma after four hours. Despite its short biological life, lipoic acid has several therapeutic applications, including the treatment of diabetic polyneuropathy. Case studies have also reported that lipoic acid improves glycemic control, although this has not yet been confirmed by clinical trials. Lipoic acid has also been used in animals to detoxify heavy metals like mercury and cadmium and may have value in chelating and removing excess iron and copper from the body, thereby decreasing oxidative stress. Since lipoic acid crosses the blood brain barrier, its potential amelioration of oxidative stress in the brain may affect neurodegenerative diseases. Lipoic acid also boosts levels of glutathione, an endogenous antioxidant with important detoxification functions.

LPI faculty, staff, students, and advisors
SUH JH, MOREAU R, HEATH S-H, and HAGEN TM. Dietary supplementation with (R)-a-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex. Redox Report 10: 52-60, 2005.

The authors note that the accumulation of reactive metals like iron or copper in the brain may contribute to an increase in oxidative stress that is associated with aging and neurodegenerative disease. Reactive metals may contribute to the formation of free radicals that damage biomolecules and brain tissue from old rats were 80% higher than those in young rats. Levels of vitamin C and glutathione, an endogenous antioxidant, were diminished in the brains of old rats. After the old rats were supplemented with lipoic acid—a potent metal chelator that helps remove excess metals from the body—for two weeks, iron levels in their brains were found to be similar to those in young, unsupplemented rats. Lipoic acid did not deplete iron levels, but rather restored normal iron status and had no effect on iron levels in the brains of young rats.

Antioxidants and oxidative stress

FREI B and HIGDON JV. Antioxidant activity of tea polyphenols in vivo: Evidence from animal studies. J. Nutr. 133: 3275S-3284S, 2003.

Epidemiological evidence suggests that tea may help protect against cancers of the gastrointestinal tract. Tea has also been studied extensively in vitro and in animals, with much focus on its antioxidant flavonoids, called catechins. Catechins in vitro scavenge free radicals and chelate reactive metals, rendering them unable to generate free radicals. Catechins in rats have been found to induce phase 2 enzymes that detoxify carcinogens and toxins. Tea also inhibits atherosclerosis in some experimental animal models and, as measured by several types of assays, can inhibit the oxidation of lipids, proteins, and DNA. Tea and/or catechin administration to animals has consistently decreased DNA damage induced by carcinogens and has inhibited many types of cancers. Many of the salubrious effects observed for tea in animals have not been observed in humans, possibly because of the higher doses relative to body weight given to animals, greater genetic variability among humans, and differences in chemical carcinogen exposure.

TRABER MG. Vitamin E, nuclear receptors and xenobiotic metabolism. Arch. Biochem. Biophys. 423: 6-11, 2003.

Vitamin E is a widely consumed supplement in the U.S., but the clinical trials on the prevention of heart attacks, strokes, and death in heart disease patients have been largely disappointing. Since most heart disease patients enrolled in these trials also took a panoply of drugs, a possible explanation for vitamin E’s failure concerns the ability of vitamin E to indirectly affect the regulation of cytochrome P450 phase 2 enzymes in the liver that are responsible for drug detoxification. The author of this review notes that various members of the vitamin E family interact differently with the molecules that affect P450 enzymes, which themselves also metabolize vitamin E. In several of the clinical trials, vitamin E was given to patients who also took simvastatin or other drugs that have been shown to be metabolized by P450 enzymes, so supplemental vitamin E may have interfered with the effectiveness of the drugs. Vitamin E has often been given in combination with other antioxidants, so it is difficult to tease apart their respective effects.

SOWELL J, FREI B, and STEVENS JF. Vitamin C conjugates of genotoxic lipid peroxidation products: Structural characterization and detection in human plasma. Proc. Natl. Acad. Sci. USA 101: 17964-17969, 2004.

A study published in 2001 by a group at the University of Pennsylvania found that vitamin C reacted with oxidized, or rancid, fat to produce DNA-damaging compounds. Although it was only a test-tube study, the authors speculated that vitamin C might promote DNA damage and increase the risk of cancer. The authors of the present study confirmed that vitamin C does indeed react with lipid hydroperoxides to form reactive products, but then continues to react with these products to form harmless conjugates. This newly discovered “ascorbylation” reaction occurs in the body when vitamin C concentrations are high relative to those of lipid hydroperoxides. Thus, the authors speculate that vitamin C may protect against cancer and inflammatory diseases through this mechanism, rather than increasing the risk of cancer as hypothesized in 2001. For more detailed information, please see the article by Dr. Stevens in the Spring/Summer 2005 LPI Research Report.

LOTITO SB and FREI B. The increase in human plasma antioxidant capacity after apple consumption is due to the metabolic effect of fructose on urate, not apple-derived antioxidant flavonoids. Free Radic. Biol. Med. 37: 251-258, 2004.

Many scientists believe that the health benefits of consuming lots of fruits and vegetables may be due to flavonoids—compounds in plants that are often pigmented and have antioxidant properties. While flavonoids exhibit potent antioxidant effects in vitro, they are poorly absorbed and present in plasma in very low concentrations. In the experiments reported in this paper, the authors fed apples, which contain flavonoids mainly in the peel, and flavonoid free bagels to volunteers. The antioxidant capacity of the volunteers’ plasma was then measured. Apples, but not bagels, increased the antioxidant capacity of plasma. Further analysis revealed that uric acid—not flavonoids or vitamin C from apples—was responsible for the increase in antioxidant activity in plasma and that the fructose, or fruit sugar, in apples increased the amount of uric acid in plasma. This was confirmed by giving the volunteers a fructose drink, which increased plasma uric acid and, concomitantly, increased antioxidant capacity. Flavonoids in fruit and vegetables may have other important biochemical roles related to health, but it now appears that they do not serve as meaningful antioxidants in the body. For more detailed information, please see the article by Dr. Lotito in the Fall/Winter 2004 LPI Research Report.

MASTALOUDIS A, MORROW JD, HOPKINS DW, DEVARAJ S, and TRABER MG. Antioxidant supplementation prevents exercise-induced lipid peroxidation, but not inflammation, in ultramarathon runners. Free Radic. Biol. Med. 36: 1329-1341, 2004.

While it is well established that extreme exercise increases oxidative stress and inflammation, studies on the effect of antioxidants in attenuating these responses have had inconsistent results. In this study, the authors supplemented male and female runners with a placebo or with a combination of 1,000 mg/day of vitamin C and 400 IU/day of natural vitamin E for six weeks prior to running a 50-kilometer ultramarathon. Plasma levels of vitamins C and E, and markers of oxidative stress (F2-isoprostanes) and inflammation, such as interleukin-6 and C-reactive protein, were measured before, during, and after the race. As expected, F2-isoprostanes increased during the race only in runners given placebos. In the placebo group, the levels of F2-isoprostanes in women quickly returned to baseline shortly after the race, whereas they were still elevated in men six days later. Antioxidant supplementation had no effect on markers of inflammation, which increased substantially during the race. The authors concluded that antioxidant supplementation was beneficial because it inhibited the formation of F2-isoprostanes, which are involved in proatherogenic activities, and did not interfere with the inflammatory response that aids in the recovery from strenuous exercise by stimulating the repair of damaged tissues.

POLIDORI MC, MECOCCI P, LEVINE M, and FREI B. Short-term and long-term vitamin C supplementation in humans dose-dependently increases the resistance of plasma to ex vivo lipid peroxidation. Arch. Biochem. Biophys. 423: 109-115, 2004.

Several previous in vitro studies have shown that vitamin C is the most important antioxidant in human plasma— oxidation of lipids was inhibited as long as vitamin C was present. In this two-part study, the authors investigated the effect of vitamin C on the oxidation of lipids in blood taken after the subjects ingested vitamin C. The short-term study involved ten young men and ten young women who were given an oral dose of 2,000 mg of vitamin C. Blood was taken two hours later and the rate of lipid oxidation was measured. In the second study, eight young women were given increasing daily doses of vitamin C up to a maximum of 2,500 mg/day over a period of months, and plasma samples were taken periodically. The rate of lipid oxidation in these samples was also measured. The authors found that vitamin C dose- dependently increased the protection of lipids in plasma from oxidation and suggested that a high concentration of vitamin C in plasma might help prevent oxidative stress observed in patients with chronic diseases like heart disease, cancer, and dementia.

LEONARD SW, GOOD CK, GUGGER ET, and TRABER MG. Vitamin E bioavailability from fortified breakfast cereal is greater than that from encapsulated supplements. Am. J. Clin. Nutr. 79: 86-92, 2004.

Vitamin E is fat soluble and must be taken with fat to be absorbed. In this study, the authors gave either capsules containing 400 IU of vitamin E, wheat cereal specially coated with 30 IU of vitamin E, or cereal coated with 400 IU of vitamin E to volunteers with non-fat milk and then measured the amount of vitamin E in plasma at various times. The bioavailability of the vitamin E from vitamin E-enriched cereal was much greater than that of vitamin E capsules. Even the 30-IU dose of vitamin E in cereal produced plasma concentrations of vitamin E six times those of the capsules, and the cereal enriched with 400 IU of vitamin E resulted in plasma levels 20 times higher than the capsules produced. These results suggest that the physical dispersion of vitamin E in cereal aids absorption and may help explain why some clinical trials with vitamin E had negative results. For example, if subjects in such trials were not instructed to take vitamin E capsules with a fat-containing meal, absorption may have been extremely limited and, therefore, no effect on health would be observed.

LEONARD SW, PATERSON E, ATKINSON JK, RAMAKRISHNAN R, CROSS CE, and TRABER MG. Studies in humans using deuterium labeled a- and g-tocopherols demonstrate faster plasma g-tocopherol disappearance and greater g-metabolite production. Free Radic. Biol. Med. 38: 857-866, 2005.

While a special protein is synthesized in the liver to distribute alpha-tocopherol to tissues, indicating that this is the form of vitamin E preferred by the body, gamma-tocopherol is the form of vitamin E that predominates in the American diet. Gamma-tocopherol has more potent anti-inflammatory activity and scavenges nitrogen radicals better than alpha-tocopherol. The authors conducted experiments to determine the plasma levels and metabolism of these forms of vitamin E. Volunteers were given equal amounts of specially labeled alpha- and gamma-tocopherol with a meal, and the plasma level of each form was measured over 72 hours. Both forms peaked in plasma after 12 hours, with significantly more alpha-tocopherol detected. Gamma-tocopherol disappeared from plasma much faster than alpha-tocopherol, indicating increased metabolism and urinary excretion. Half of the gamma-tocopherol had disappeared 13 hours after ingestion, whereas half of the alpha-tocopherol disappeared in 57 hours.

HATHCOCK JN, AZZI A, BLUMBERG J, BRAY T, DICKINSON A, FREI B, JIALAL I, JOHNSTON CS, KELLY FJ, KRAEMER K, PACKER L, PARTHASARATHY S, SIES H, and TRABER MG. Vitamins E and C are safe across a broad range of intakes. Am. J. Clin. Nutr. 81: 736-745, 2005.

Based on in vitro studies and clinical trials, some investigators have speculated that supplemental vitamins C and E may pose health hazards. The authors of this review examined the relevant studies carefully and concluded that vitamin E in amounts less than 1,600 IU/day—about the same as the “tolerable upper intake level” of 1,500 IU/day of alpha-tocopherol set by the U.S. Institute of Medicine in 2000—is safe for most adults. Over 20 clinical trials investigating the effect of vitamin E supplementation on diabetes, heart disease, eye diseases, and neurodegenerative diseases in over 80,000 subjects have been conducted. While the results have been inconsistent, no serious toxicity at doses less than 2,000 IU/day has been documented. A few trials reported more adverse effects among the supplemented subjects compared to those taking placebos, but the differences were not statistically significant. Fewer vitamin C supplementation studies have been conducted, but no evidence of risk for healthy adults has emerged. Some recent epidemiological evidence suggests that men with a tendency to form oxalate kidney stones may want to restrict their intake of supplemental vitamin C. Otherwise, the only documented side effect for high-dose vitamin C in healthy adults involves a transient laxative effect that occurs at variable intakes in different individuals. Consequently, the U.S. Institute of Medicine set the tolerable upper intake level for vitamin C at 2,000 mg/day based solely on this side effect. The authors of this review concur that intakes of vitamin C up to 2,000 mg/day are safe for the general population. Trials that combined vitamins C and E often included other antioxidants, so it is impossible to ascertain the independent effects of the vitamins in those studies.

BRUNO RS, RAMAKRISHNAN R, MONTINE TJ, BRAY TM, and TRABER MG. a-Tocopherol disappearance is faster in cigarette smokers and is inversely related to their ascorbic acid status. Am. J. Clin. Nutr. 81: 95-103, 2005.

Cigarette smoking increases oxidative stress. In this study, smokers and non-smokers were given vitamin E and their plasma was analyzed for vitamin E, vitamin C, and F2- isoprostanes, which are markers of lipid peroxidation or oxidative stress. As was expected, the plasma of smokers had higher levels of F2-isoprostanes—by about 40%—and lower levels of vitamin E compared to that of non-smokers. Plasma levels of vitamin C were not significantly different between smokers and non-smokers, but there was a broader range of vitamin C levels in the plasma of smokers. The disappearance of vitamin E from the plasma of smokers correlated with vitamin C concentration. In vitro evidence suggests that vitamin C is able to regenerate vitamin E from its oxidized form, but the present study is the first to report this activity in humans. Thus, low vitamin C levels in conditions of oxidative stress result in the faster utilization of vitamin E, which is decreased by smoking.

Cancer and Toxicology

MYZAK MC, KARPLUS PA, CHUNG FL, and DASHWOOD RH. A novel mechanism of chemoprotection by sulforaphane: Inhibition of histone deacetylase. Cancer Res. 64: 5767-5774, 2004.

As the lead author of this study explained in the LPI Spring/Summer 2004 Research Report, the intake of cruciferous vegetables like broccoli and Brussels sprouts is associated with protection against cancer. A phytochemical called sulforaphane in broccoli has been found to induce phase 2 enzymes in the liver that detoxify toxins and carcinogens, thereby inhibiting tumor formation in animals. The present study describes a newly discovered mechanism by which sulforaphane may inhibit cancer. DNA is wrapped around proteins called histones, and changes in the conformation, or shape, of these histones determines when genes are turned on or off. Specifically, when acetyl groups are added to histones, genes are turned on, and removal of the acetyl groups inactivates genes. Histone deacetylases remove acetyl groups from histones, which results in gene inactivation. In cancer cells, deacetylated histones are associated with tumor suppressor genes, resulting in their inactivation. If the histone deacetylase could be inhibited, then the tumor suppressor genes could be turned on to block cancerous cell growth. In this study, the authors discovered that a sulforaphane metabolite inhibited histone deacetylation in cultured human kidney cells and increased the activity of tumor suppressor gene p21 in cultured human cancer cells.

YU TW, XU M, and DASHWOOD RH. Antimutagenic activity of spearmint. Environ. Mol. Mutagen. 44: 387-393, 2004.

Spearmint (Mentha spicata) is a popular additive in foods and beverages and is used to make an herbal tea. The authors tested the antimutagenic activity of spearmint in vitro using the Salmonella, or Ames, test. Spearmint tea did not inhibit the mutagenicity of the dye 4-nitro-1,2-phenylenediamine, but did inhibit the mutagenicity of two cooked-meat mutagens, including IQ, which is formed in proteinaceous food cooked at high temperatures. This observation led the authors to test spearmint tea in rats treated with IQ, a mutagen that stimulates the formation in the colon of aberrant crypt foci (ACF), which are precancerous lesions that can develop into colon cancer. Rats given IQ plus spearmint tea developed less than half the number of ACF per colon compared to rats given IQ alone, demonstrating that spearmint possesses anticancer potential.

HO E, BOILEAU TW-M, and BRAY TM. Dietary influences on endocrine-inflammatory interactions in prostate cancer development. Arch. Biochem. Biophys. 428: 109-117, 2004.

Prostate cancer is exceedingly common in American men and has been linked to high levels of the hormones estrogen and testosterone, chronic inflammation, and cell proliferation. The authors of this review suggest that dietary strategies that target these processes may be effective in inhibiting prostate cancer. They present the hypothesis that elevated estrogen combined with high testosterone levels activates proinflammatory molecules that cause immune cells to enter the prostate and generate oxidants. These oxidants, in turn, damage DNA and disturb molecular pathways, leading to uncontrolled cell proliferation. Epidemiological evidence indicates that the consumption of tomato products offers some protection against prostate cancer. The authors propose a “whole food” approach to prostate cancer prevention that includes tomatoes, soy, and tea, which are good sources of anti-inflammatory, antioxidant, and antiproliferative substances.

KRUEGER SK, SIDDENS LK, MARTIN SR, YU Z, PEREIRA CB, CABACUNGAN ET, HINES RN, ARDLIE KG, RAUCY JL, and WILLIAMS DE. Differences in FMO2*1 allelic frequency between Hispanics of Puerto Rican and Mexican descent. Drug Metabol. Dispos. 32: 1337-1340, 2004.

This group previously reported that many African Americans and Hispanics have differences in the flavin-containing monooxygenase (FMO) gene system in the lung, which codes for enzymes that metabolize drugs and xenobiotics. These differences, or polymorphisms, may affect the determination of medicinal drug dosage. About 26% of African Americans have the FMO isoform known as FMO2*1. This isoform has not been detected in non-Hispanic whites. In this study, the authors investigated the occurrence of FMO2*1 in 632 Hispanics of Puerto Rican and Mexican origin. About 7% of Hispanics of Puerto Rican origin and 2% of Hispanics of Mexican origin exhibited the FMO2*1 isoform. Therefore, a significant percentage of African Americans and Hispanics may exhibit increased or decreased sensitivity to environmental toxicants or drugs that enter through the lung.

ORNER GA, DASHWOOD WM, and DASHWOOD RH. Tumor-suppressing effects of antioxidants from tea. J. Nutr. 134: 3177S-3178S, 2004.

The authors studied the effect of tea and a non-steroidal anti-inflammatory drug, sulindac, on tumor formation in two strains of mice: one that develops spontaneous polyps in the colon and another that develops colon polyps in response to carcinogen treatment. A hallmark of the transformation of many normal cells into cancer cells is a disruption in a cell-signaling pathway that increases the synthesis of the b-catenin protein, leading to the increased expression of oncogenes. The authors previously showed that whole tea and polyphenolic antioxidants isolated from tea strongly inhibited b-catenin in cultured human kidney cells. In this report, the authors found that white tea, green tea, or sulindac inhibited colon tumors in the mice that spontaneously develop polyps and that the combination of white tea and sulindac resulted in the greatest tumor inhibition. b-Catenin was reduced in the treated mice and almost eliminated in mice treated with both tea and sulindac. White tea or sulindac alone did not inhibit tumor formation in the mice that develop polyps after exposure to carcinogens. However, the combination of white tea and sulindac strongly inhibited tumor formation in these mice and reduced b-catenin levels.

CARTER O, BAILEY GS, and DASHWOOD RH. The dietary phytochemical chlorophyllin alters E-cadherin and b-catenin expression in human colon cancer cells. J. Nutr. 134: 3441S-3444S, 2004.

Chlorophyllin, a derivative of the ubiquitous plant pigment chlorophyll, has been reported to attenuate biomarkers of aflatoxin-induced liver cancer in both trout and humans by binding to the carcinogen and preventing its metabolic activation. Therefore, chlorophyllin is expected to help prevent liver cancer in those exposed to aflatoxin in moldy food. Studies with rats have found that chlorophyllin also inhibits carcinogenesis caused by cooked-meat mutagens. In the present study, the authors investigated the effect of chlorophyllin on human colon cancer cells in culture to learn more about the underlying molecular mechanisms. Colon cancer cells treated with chlorophyllin underwent programmed cell death, or apoptosis. The amounts of two proteins, E-cadherin and alkaline phosphatase, related to cell differentiation in these cells were increased. Differentiation is a normal cellular process that is lost in cancer cells. Chlorophyllin also decreased the amount of b-catenin, a protein associated with the induction of oncogenes, in the cell nucleus.

Neurodegenerative disease

CASSINA P, PEHAR M, VARGAS MR, CASTELLANOS R, BARBEITO AG, ESTEVEZ AG, THOMPSON JA, BECKMAN JS, and BARBEITO L. Astrocyte activation by fibroblast growth factor-1 and motor neuron apoptosis: implications for amyotrophic lateral sclerosis. J. Neurochem. 93: 38-46, 2004.

Cell growth factors play important roles in many cellular processes. Fibroblast growth factor (FGF) may be induced in cells by oxidative stress, which is increased in motor neurons in amyotrophic lateral sclerosis (ALS) patients because of mutations to the antioxidant enzyme superoxide dismutase. The authors found that FGF added to cultured spinal cord astrocytes—cells that provide structural and metabolic support to motor neurons—caused the astrocytes to become reactive. Astrocytes thus activated release nerve growth factor and nitric oxide, which may lead to the production of the destructive oxidant peroxynitrite and ultimately cause the death of motor neurons. The authors also found that antioxidants, such as urate, prevented the toxicity of activated astrocytes.

VARGAS MR, PEHAR M, CASSINA P, ESTEVEZ AG, BECKMAN JS, and BARBEITO L. Stimulation of nerve growth factor expression in astrocytes by peroxynitrite. In Vivo 18: 269-274, 2004.

Nitric oxide is an important signaling molecule that helps maintain proper blood vessel function. However, it can combine with the superoxide radical to form peroxynitrite, a powerful oxidant. In the experiments reported in this paper, the authors found that peroxynitrite activated cultured spinal cord astrocytes, resulting in the production of nerve growth factor and altered morphology. These events, in turn, can lead to the death of motor neurons as observed in ALS and suggest that strategies to decrease oxidative stress may have value against this neurodegenerative disease.

ERMILOVA IP, ERMILOV VB, LEVY M, HO E, PEREIRA C, and BECKMAN JS. Protection by dietary zinc in ALS mutant G93A SOD transgenic mice. Neurosci. Lett. 379: 42-46, 2005.

The authors note that mutations to an endogenous antioxidant enzyme, copper, zinc superoxide dismutase (SOD), are associated with some cases of ALS. These mutations result in the loss of zinc from SOD, causing the defective SOD to become toxic to motor neurons. In this study, mice with defective SOD were given different doses of supplemental zinc. High doses of zinc resulted in more rapid death, whereas moderate doses delayed death. Further analysis revealed that the high zinc doses inhibited the absorption of copper, resulting in fatal anemia. This was surmounted by giving supplemental copper with zinc, which prevented the early death caused by high zinc treatment alone.

Last updated November, 2005


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