Caveolae and caveolin-1 as targets of dietary polyphenols for protection against vascular endothelial dysfunction.

Caveolae, consisting of caveolin-1 proteins, are ubiquitously present in endothelial cells and contribute to normal cardiovascular functions by acting as a platform for cellular signaling pathways as well as transcytosis and endocytosis. However, caveolin-1 is thought to have a proatherogenic role by inhibiting endothelial nitric oxide synthase activity and Nrf2 activation, or by promoting inflammation through NF-κB activation. Dietary polyphenols were suggested to exert anti-atherosclerotic effects by a mechanism involving the inhibition of endothelial dysfunction, by which they can regulate redox-sensitive signaling pathways in relation to NF-κB and Nrf2 activation. Some monomeric polyphenols and microbiota-derived catabolites from monomeric polyphenols or polymeric tannins might be responsible for the inhibition, because they can be transferred into the circulation from the digestive tract. Several polyphenols were reported to modulate caveolin-1 expression or its localization in caveolae. Therefore, we hypothesized that circulating polyphenols affect caveolae functions by altering its structure leading to the release of caveolin-1 from caveolae, and attenuating redox-sensitive signaling pathway-dependent caveolin-1 overexpression. Further studies using circulating polyphenols at a physiologically relevant level are necessary to clarify the mechanism of action of dietary polyphenols targeting caveolae and caveolin-1.

Lowering effect of combined sweet potato and onion intake on plasma quercetin concentration and underlying mechanism involving intestinal ß-glucosidase activity.

A combined intake of cooked sweet potato and fried onion in humans was found to suppress the increase of plasma quercetin metabolite concentration. Experiments using rat ß-glucosidase indicated that excess carbohydrate digestion products, especially glucose-containing saccharides, interfere with the deglycosylation of quercetin glucosides during intestinal epithelial uptake. Combined meals of sweet potato and onion may lower the bioavailability of onion quercetin glucosides.

Suppressive effects of quercetin on hydrogen peroxide-induced caveolin-1 phosphorylation in endothelial cells.

Caveolin-1 is a major protein of the caveolae structure in vascular endothelial cell membrane. Phosphorylation of caveolin-1 is one of the initial events leading to exacerbation of vascular permeability caused by oxidative stress. Although quercetin is known to be an anti-atherosclerosis factor that acts as a dietary antioxidant, little is known about its role in the regulation of caveolin-1 phosphorylation. In this study, we investigated the inhibitory effect of quercetin on hydrogen peroxide-induced caveolin-1 phosphorylation in human umbilical vein endothelial cells. Quercetin inhibited caveolin-1 phosphorylation in cells pretreated with quercetin for 24 h and then exposed to hydrogen peroxide. However, quercetin 3-O-ß-glucuronide, a conjugated metabolite of quercetin, did not exert this inhibitory effect. Exposure to hydrogen peroxide increased vascular permeability and reduced mRNA expression of the intercellular adhesion protein, vascular endothelial cadherin (VE-cadherin). By contrast, pretreatment with quercetin suppressed the increase in vascular permeability and decreased VE-cadherin expression. These results indicate that deconjugated quercetin can play a role in the prevention of altered vascular permeability under oxidative stress by suppressing caveolin-1 phosphorylation. Thus, dietary quercetin may be beneficial for the maintenance of endothelial cell function.

Role of Intestinal Microbiota in the Bioavailability and Physiological Functions of Dietary Polyphenols.

Polyphenols are categorized as plant secondary metabolites, and they have attracted much attention in relation to human health and the prevention of chronic diseases. In recent years, a considerable number of studies have been published concerning their physiological function in the digestive tract, such as their prebiotic properties and their modification of intestinal microbiota. It has also been suggested that several hydrolyzed and/or fission products, derived from the catabolism of polyphenols by intestinal bacteria, exert their physiological functions in target sites after transportation into the body. Thus, this review article focuses on the role of intestinal microbiota in the bioavailability and physiological function of dietary polyphenols. Monomeric polyphenols, such as flavonoids and oligomeric polyphenols, such as proanthocyanidins, are usually catabolized to chain fission products by intestinal bacteria in the colon. Gallic acid and ellagic acid derived from the hydrolysis of gallotannin, and ellagitannin are also subjected to intestinal catabolism. These catabolites may play a large role in the physiological functions of dietary polyphenols. They may also affect the microbiome, resulting in health promotion by the activation of short chain fatty acids (SCFA) excretion and intestinal immune function. The intestinal microbiota is a key factor in mediating the physiological functions of dietary polyphenols.

Inhibitory effect of catecholic colonic metabolites of rutin on fatty acid hydroperoxide and hemoglobin dependent lipid peroxidation in Caco-2 cells.

To determine the preventive effect of dietary rutin on oxidative damages occurring in the digestive tract, 13-hydroperoxyoctadecadienoic acid and hemoglobin were exposed to Caco-2 intestinal cells after the pretreatment with colonic rutin metabolites. Among four catechol-type metabolites, quercetin and 3,4-dihydroxytoluene exerted significant protection on 13-hydroperoxyoctadecadienoic and hemoglobin-dependent lipid peroxidation of this epithelial cell. Compared with quercetin, a much lower concentration allowed 3,4-dihydroxytoluene to maximize the protective effect, though it needed a longer pre-incubation period. Neither quercetin nor 3,4-dihydroxytoluene affected the expression of peroxiredoxin-6 protein, which comprises the cellular antioxidant defense system. It is concluded that 3,4-dihydroxytoluene is a plausible rutin colonic metabolite that can suppress oxidative damages of intestinal epithelial cells by directly inhibiting lipid peroxidation. This result may illuminate the preventive role of dietary rutin against colorectal cancer incidence in relation to the consumption of red and processed meat.

8-Prenylnaringenin promotes recovery from immobilization-induced disuse muscle atrophy through activation of the Akt phosphorylation pathway in mice.

8-Prenylnaringenin (8-PN) is a prenylflavonoid that originates from hop extracts and is thought to help prevent disuse muscle atrophy. We hypothesized that 8-PN affects muscle plasticity by promoting muscle recovery under disuse muscle atrophy. To test the promoting effect of 8-PN on muscle recovery, we administered an 8-PN mixed diet to mice that had been immobilized with a cast to one leg for 14 days. Intake of the 8-PN mixed diet accelerated recovery from muscle atrophy, and prevented reductions in Akt phosphorylation. Studies on cell cultures of mouse myotubes in vitro demonstrated that 8-PN activated the PI3K/Akt/P70S6K1 pathway at physiological concentrations. A cell-culture study using an inhibitor of estrogen receptors and an in vivo experiment with ovariectomized mice suggested that the estrogenic activity of 8-PN contributed to recovery from disuse muscle atrophy through activation of an Akt phosphorylation pathway. These data strongly suggest that 8-PN is a naturally occurring compound that could be used as a nutritional supplement to aid recovery from disuse muscle atrophy.

Effect of quercetin and its metabolite on caveolin-1 expression induced by oxidized LDL and lysophosphatidylcholine in endothelial cells.

Oxidized low-density lipoprotein contributes to atherosclerotic plaque formation, and quercetin is expected to exert anti-atherosclerotic effects. We previously reported accumulation of conjugated quercetin metabolites in the aorta of rabbits fed high-cholesterol diets with quercetin glucosides, resulting in attenuation of lipid peroxidation and inhibition of lipid accumulation. Caveolin-1, a major structural protein of caveolae in vascular endothelial cells, plays a role in atherosclerosis development. Here we investigated effects of oxidized low-density lipoprotein, quercetin and its metabolite, quercetin 3-O-ß-glucuronide, on caveolin-1 expression. Oxidized low-density lipoprotein significantly upregulated caveolin-1 mRNA expression. An oxidized low-density lipoprotein component, lysophosphatidylcholine, also induced expression of both caveolin-1 mRNA and protein. However, lysophosphatidylcholine did not affect the location of caveolin-1 proteins within caveolae structures. Co-treatment with quercetin or quercetin 3-O-ß-glucuronide inhibited lysophosphatidylcholine-induced caveolin-1 expression. Quercetin and quercetin 3-O-ß-glucuronide also suppressed expression of adhesion molecules induced by oxidized low-density lipoprotein and lysophosphatidylcholine. These results strongly suggest lysophosphatidylcholine derived from oxidized low-density lipoprotein contributes to atherosclerotic events by upregulating caveolin-1 expression, resulting in induction of adhesion molecules. Quercetin metabolites are likely to exert an anti-atherosclerotic effect by attenuating caveolin-1 expression in endothelial cells.

Extracellular metabolism-dependent uptake of lysolipids through cultured monolayer of differentiated Caco-2 cells.

Glycerophospholipids are known to be hydrolyzed in the intestinal lumen into free fatty acids and lysophospholipids that are then absorbed by the intestinal epithelial cells. A monolayer of enterocyte-differentiated Caco-2 cell is often used to assess the intestinal bioavailability of nutrients. In this study, we examined how differentiated Caco-2 cells process lysoglycerolipids such as lysophosphatidylcholine (LPC). Our findings were twofold. (1) Caco-2 cells secreted both a lysophospholipase A-like enzyme and a glycerophosphocholine-phosphodiesterase enzyme into the apical, but not basolateral, lumen, suggesting that food-derived LPC is converted to a free fatty acid, sn-glycerol-3-phosphate, and choline through two sequential enzymatic reactions in humans. The release of the latter enzyme was differentiation-dependent. (2) Fatty acid-releasing activities toward exogenous fluorescent LPC, lysophosphatidic acid and monoacylglycerol were shown to be higher on the apical membranes of Caco-2 cells than on the basolateral membranes. These results suggest that human intestinal epithelial cells metabolize lysoglycerolipids by two distinct mechanisms involving secreted or apical-selective expression of metabolic enzymes.

N-myristoylated ubiquitin ligase Cbl-b inhibitor prevents on glucocorticoid-induced atrophy in mouse skeletal muscle.

A DGpYMP peptide mimetic of tyrosine(608)-phosphorylated insulin receptor substrate-1 (IRS-1), named Cblin, was previously shown to significantly inhibit Cbl-b-mediated IRS-1 ubiquitination. In the present study, we developed N-myristoylated Cblin and investigated whether it was effective in preventing glucocorticoid-induced muscle atrophy. Using HEK293 cells overexpressing Cbl-b, IRS-1 and ubiquitin, we showed that the 50% inhibitory concentrations of Cbl-b-mediated IRS-1 ubiquitination by N-myristoylated Cblin and Cblin were 30 and 120 µM, respectively. Regarding the DEX-induced atrophy of C2C12 myotubes, N-myristoylated Cblin was more effective than Cblin for inhibiting the DEX-induced decreases in C2C12 myotube diameter and IRS-1 degradation. The inhibitory efficacy of N-myristoylated Cblin on IRS-1 ubiquitination in C2C12 myotubes was approximately fourfold larger than that of Cblin. Furthermore, N-myristoylation increased the incorporation of Cblin into HEK293 cells approximately 10-folds. Finally, we demonstrated that N-myristoylated Cblin prevented the wet weight loss, IRS-1 degradation, and MAFbx/atrogin-1 and MuRF-1 expression in gastrocnemius muscle of DEX-treated mice approximately fourfold more effectively than Cblin. Taken together, these results suggest that N-myristoylated Cblin prevents DEX-induced skeletal muscle atrophy in vitro and in vivo, and that N-myristoylated Cblin more effectively prevents muscle atrophy than unmodified Cblin.

Cholesterol hydroperoxides and their degradation mechanism.

Cholesterol is one of the oxidizable lipids constituting biomembranes and plasma lipoproteins. Cholesterol hydroperoxides (Chol-OOH) are the primary products if cholesterol is subjected to attack by reactive oxygen species. In particular, singlet molecular oxygen reacts with cholesterol to yield cholesterol 5α-hydroperoxide as the major hydroperoxide species. Chol-OOH may accumulate in biological systems because of its resistance to glutathione-dependent enzymatic detoxification reactions. Their degradation products (including hydroxycholesterol and 7-ketocholesterol) participate in the pathophysiological functions of oxysterols. Highly reactive cholesterol 5,6-secosterol present in atherosclerotic lesions can be derived from the degradation of cholesterol 5α-hydroperoxide. Chol-OOH themselves may affect the lipid rafts of biomembranes, thereby leading to the modification of signal transduction pathways.

Biological impacts of resveratrol, quercetin, and N-acetylcysteine on oxidative stress in human gingival fibroblasts.

In periodontitis, production of reactive oxygen species (ROS) by neutrophils induces oxidative stress and deteriorates surrounding tissues. Antioxidants reduce damage caused by ROS and are used to treat diseases involving oxidative stress. This study summarizes the different effects of resveratrol, quercetin, and N-acetylcysteine (NAC) on human gingival fibroblasts (HGFs) under oxidative stress induced by hydrogen peroxide. Real-time cytotoxicity analyses reveals that resveratrol and quercetin enhanced cell proliferation even under oxidative stress. Of the antioxidants tested, resveratrol is the most effective at inhibiting ROS production. HGFs incubated with resveratrol and quercetin up-regulate the transcription of type I collagen gene after 3 h, but only resveratrol sustained this up-regulation for 24 h. A measurement of the oxygen consumption rate (OCR, mitochondrial respiration) shows that resveratrol generates the highest maximal respiratory capacity, followed by quercetin and NAC. Simultaneous measurement of OCR and the extracellular acidification rate (non-mitochondrial respiration) reveals that resveratrol and quercetin induce an increase in mitochondrial respiration when compared with untreated cells. NAC treatment consumes less oxygen and enhances more non-mitochondrial respiration. In conclusion, resveratrol is the most effective antioxidant in terms of real-time cytotoxicity analysis, reduction of ROS production, and enhancement of type I collagen synthesis and mitochondrial respiration in HGFs.

Prenylation modulates the bioavailability and bioaccumulation of dietary flavonoids.

Prenylflavonoids are distributed widely in the plant kingdom and have attracted appreciable attention because of their potential benefits for human health. Prenylation may be a promising tool for applying the biological functions of flavonoids to clinical uses. The bioavailability and bioaccumulation of prenylflavonoids have not been clarified, but extensive studies have been accomplished on their biological functions. This review provides current knowledge on the bioavailability of prenylflavonoids, including their absorption and metabolism in the intestine, as well as their bioaccumulation in specific tissues. Despite higher uptake into epithelial cells of the digestive tract, the bioavailability of single-dose prenylflavonoids seems to be lower than that of the parent flavonoids. Efflux from epithelial cells to the blood circulation is likely to be restricted by prenyl groups, resulting in insufficient increase in the plasma concentration. Rodent studies have revealed that prenylation enhances accumulation of naringenin in muscle tissue after long-term feeding; and that prenylation accelerates accumulation of quercetin in liver tissue. Efflux from hepatocytes to blood and enterohepatic circulations may be restricted by prenyl groups, thereby promoting slow excretion of prenylflavonoids from the blood circulation and efficient uptake to tissues. The hepatotoxicity and other deleterious effects, taken together with beneficial effects, should be considered because unexpectedly high accumulation may occur in some tissues after long-term supplementation.

Specific localization of quercetin-3-O-glucuronide in human brain.

In recent years, many papers have suggested that dietary flavonoids may exert beneficial effects in the brain tissue for the protection of neurons against oxidative stress and inflammation. However, the bioavailability of flavonoids across the blood-brain barrier and the localization in the brain remain controversial. Thus, we examined the localization of quercetin-3-O-glucuronide (Q3GA), a major phase-II metabolite of quercetin, in the human brain tissues with or without cerebral infarction by immunohistochemical staining using anti-Q3GA antibody. A significant immunoreactivity was observed in the epithelial cells of the choroid plexus, which constitute the structural basis of the blood-cerebrospinal fluid (CSF) barrier, and in the foamy macrophages of recent infarcts. The cellular accumulation of Q3GA was also reproduced in vitro in macrophage-like RAW264, microglial MG6, and brain capillary endothelial RBEC1. It is of interest that a common feature of these cell lines is the deconjugation of Q3GA, resulting in the cellular accumulation of non-conjugated quercetin and the methylated forms. We then examined the anti-inflammatory activity of Q3GA and the deconjugated forms in the lipopolysaccharide-stimulated macrophage cells and revealed that the deconjugated forms (quercetin and a methylated form isorhamnetin), but not Q3GA itself, exhibited inhibitory effects on the inflammatory responses through attenuation of the c-Jun N-terminal kinase pathway. These results suggested that a quercetin glucuronide can pass through the blood-brain barrier, perhaps the CSF barrier, accumulate in specific types of cells, such as macrophages, and act as anti-inflammatory agents in the brain through deconjugation into the bioactive non-conjugated forms.

Prenylation enhances quercetin uptake and reduces efflux in Caco-2 cells and enhances tissue accumulation in mice fed long-term.

Prenyl flavonoids are widely distributed in plant foods and have attracted appreciable attention in relation to their potential benefits for human health. Prenylation may enhance the biological functions of flavonoids by introducing hydrophobic properties in their basic structures. Previously, we found that 8-prenyl naringenin exerted a greater preventive effect on muscle atrophy than nonprenylated naringenin in a mouse model. Here, we aimed to estimate the effect of prenylation on the bioavailability of dietary quercetin (Q). The cellular uptake of 8-prenyl quercetin (PQ) and Q in Caco-2 cells and C2C12 myotube cells was examined. Prenylation significantly enhanced the cellular uptake by increasing the lipophilicity in both cell types. In Caco-2 cells, efflux of PQ to the basolateral side was <15% of that of Q, suggesting that prenylation attenuates transport from the intestine to the circulation. After intragastric administration of PQ or Q to mice or rats, the area under the concentration-time curve for PQ in plasma and lymph was 52.5% and 37.5% lower than that of Q, respectively. PQ and its O-methylated form (MePQ) accumulated at much higher amounts than Q and O-methylated Q in the liver (Q: 3400%; MePQ: 7570%) and kidney (Q: 385%; MePQ: 736%) of mice after 18 d of feeding. These data suggest that prenylation enhances the accumulation of Q in tissues during long-term feeding, even though prenylation per se lowers its intestinal absorption from the diet.

Influence of fatty acid patterns on the intestinal absorption pathway of quercetin in thoracic lymph duct-cannulated rats.

Since it is known that dietary fats improve the bioavailability of the flavonol quercetin, we purposed to investigate whether this effect is due to increased lymphatic transport of quercetin. In rats with implanted catheters in the thoracic lymph duct, we administered quercetin into the duodenum with TAG emulsions containing either long-chain fatty acids (LCT) or medium-chain fatty acids (MCT). Controls received quercetin together with a glucose solution. LCT administration increased the lymphatic output of quercetin (19.1 (SEM 1.2) nmol/8 h) as well as the lymph-independent bioavailability of the flavonol, determined as area under the plasma concentration curve (1091 (SEM 142) microM x min). Compared with glucose administration, MCT neither increased the lymphatic output (12.3 (SEM 1.5) nmol/8 h) nor the bioavailability of quercetin (772 (SEM 99) microM x min) significantly (glucose group: 9.8 (SEM 1.5) nmol/8 h and 513 (SEM 55) microM x min, respectively). Because LCT are released within chylomicrons into the intestinal lymph while MCT are mainly released into the portal blood, we conclude from the present results that dietary fats that are mainly composed of LCT improve quercetin bioavailability by increasing its transport via the lymph, thereby circumventing hepatic first-pass metabolism of the flavonol. In addition, LCT could enhance quercetin absorption by improving its solubility in the intestinal tract.

Blueberry intervention improves vascular reactivity and lowers blood pressure in high-fat-, high-cholesterol-fed rats.

Growing evidence suggests that intake of flavonoid-containing foods may exert cardiovascular benefits in human subjects. We have investigated the effects of a 10-week blueberry (BB) supplementation on blood pressure (BP) and vascular reactivity in rats fed a high-fat/high-cholesterol diet, known to induce endothelial dysfunction. Rats were randomly assigned to follow a control chow diet, a chow diet supplemented with 2 % (w/w) BB, a high-fat diet (10 % lard; 0·5 % cholesterol) or the high fat plus BB for 10 weeks. Rats supplemented with BB showed significant reductions in systolic BP (SBP) of 11 and 14 %, at weeks 8 and 10, respectively, relative to rats fed the control chow diet (week 8 SBP: 107·5 (SEM 4·7) v. 122·2 (SEM 2·1) mmHg, P= 0·018; week 10 SBP: 115·0 (SEM 3·1) v. 132·7 (SEM 1·5) mmHg, P< 0·0001). Furthermore, SBP was reduced by 14 % in rats fed with the high fat plus 2 % BB diet at week 10, compared to those on the high-fat diet only (SBP: 118·2 (SEM 3·6) v. 139·5 (SEM 4·5) mmHg, P< 0·0001). Aortas harvested from BB-fed animals exhibited significantly reduced contractile responses (to L-phenylephrine) compared to those fed the control chow or high-fat diets. Furthermore, in rats fed with high fat supplemented with BB, aorta relaxation was significantly greater in response to acetylcholine compared to animals fed with the fat diet. These data suggest that BB consumption can lower BP and improve endothelial dysfunction induced by a high fat, high cholesterol containing diet.

Potential Role of Quercetin Glycosides as Anti-Atherosclerotic Food-Derived Factors for Human Health.

Quercetin is a monomeric polyphenol of plant origin that belongs to the flavonol-type flavonoid subclass. Extensive studies using cultured cells and experimental model animals have demonstrated the anti-atherosclerotic effects of dietary quercetin in relation to the prevention of cardiovascular disease (CVD). As quercetin is exclusively present in plant-based foods in the form of glycosides, this review focuses on the bioavailability and bioefficacy of quercetin glycosides in relation to vascular health effects. Some glucose-bound glycosides are absorbed from the small intestine after glucuronide/sulfate conjugation. Both conjugated metabolites and deconjugated quercetin aglycones formed by plasma ß-glucuronidase activity act as food-derived anti-atherogenic factors by exerting antioxidant, anti-inflammatory, and plasma low-density lipoprotein cholesterol-lowering effects. However, most quercetin glycosides reach the large intestine, where they are subject to gut microbiota-dependent catabolism resulting in deglycosylated aglycone and chain-scission products. These catabolites also affect vascular health after transfer into the circulation. Furthermore, quercetin glycosides may improve gut microbiota profiles. A variety of human cohort studies and intervention studies support the idea that the intake of quercetin glycoside-rich plant foods such as onion helps to prevent CVD. Thus, quercetin glycoside-rich foods offer potential benefits in terms of cardiovascular health and possible clinical applications.

Revisiting carotenoids as dietary antioxidants for human health and disease prevention.

Humans are unique indiscriminate carotenoid accumulators, so the human body accumulates a wide range of dietary carotenoids of different types and to varying concentrations. Carotenoids were once recognized as physiological antioxidants because of their ability to quench singlet molecular oxygen (1O2). In the 1990s, large-scale intervention studies failed to demonstrate that supplementary ß-carotene intake reduces the incidence of lung cancer, although its antioxidant activity was supposed to contribute to the prevention of oxidative stress-induced carcinogenesis. Nevertheless, the antioxidant activity of carotenoids has attracted renewed attention as the pathophysiological role of 1O2 has emerged, and as the ability of dietary carotenoids to induce antioxidant enzymes has been revealed. This review focuses on six major carotenoids from fruit and vegetables and revisits their physiological functions as biological antioxidants from the standpoint of health promotion and disease prevention. ß-Carotene 9',10'-oxygenase-derived oxidative metabolites trigger increases in the activities of antioxidant enzymes. Lutein and zeaxanthin selectively accumulate in human macular cells to protect against light-induced macular impairment by acting as antioxidants. Lycopene accumulates exclusively and to high concentrations in the testis, where its antioxidant activity may help to eliminate oxidative damage. Dietary carotenoids appear to exert their antioxidant activity in photo-irradiated skin after their persistent deposition in the skin. An acceptable level of dietary carotenoids for disease prevention should be established because they can have deleterious effects as prooxidants if they accumulate to excess levels. Finally, it is expected that the reason why humans are indiscriminate carotenoid accumulators will be understood soon.

Theophylline Prevents Dexamethasone-Induced Atrophy in C2C12 Myotubes.

Skeletal muscle mass is maintained by a balance between the synthesis and degradation of muscle proteins, the collapse of which causes muscle wasting. The prevention of muscle wasting improves the quality of life and extends a healthy life. The methyl xanthine theophylline showed strong preventive activity against dexamethasone-induced muscle atrophy, as determined using the expression level of myosin heavy chain in C2C12 myotubes. Mechanistically, theophylline inhibited the expression of ubiquitin ligases MuRF1 and Cbl-b, but not that of atrogin-1. Furthermore, theophylline inhibits glucocorticoid receptor translocation to the nucleus. A pull-down assay using a theophylline probe revealed that theophylline and dexamethasone competitively interacted with the glucocorticoid receptor, suggesting an antagonistic activity of theophylline on glucocorticoid receptors. Additionally, theophylline inhibited the dexamethasone-induced phosphorylation of p38 and FoxO3a in C2C12 myotubes. These findings suggest that theophylline is an effective food ingredient in the prevention of glucocorticoid-induced skeletal muscle atrophy.

Self-reported seafood intake and atopy in Japanese school-aged children.

BACKGROUND: The effects of fish consumption and n-3 poly-unsaturated fatty acid (PUFA) levels on atopic disorders are inconsistent in previous reports, but few studies have investigated the effects of both fish and n-3 PUFA. The aim of the present study was to investigate whether erythrocyte fatty acids and the consumption of fish are associated with atopic diseases in pre- and early adolescents. METHODS: A total of 135 students with eczema, 136 students with asthma, and 137 healthy control students were selected from fifth and eighth grades in Shunan, Japan. Atopic disorders and dietary intake were evaluated with questionnaires, and total serum IgE was measured using an enzyme-linked immunosorbent assay. In addition, erythrocyte membrane levels of PUFA were assessed via gas chromatography. RESULTS: Total IgE was significantly elevated in the atopic subjects (P < 0.001). The intake of fatty and dried fish or seafood was significantly associated with eczema (odds ratios of the highest quartiles: 0.46, 95% confidence interval (95%CI): 0.22-0.94; 0.34, 95%CI: 0.16-0.71, respectively). Additionally, only erythrocyte eicosapentaenoic acid (EPA) level had a negative association with eczema (P= 0.048). For asthma, the effect of fish consumption was not significant. CONCLUSIONS: Fish consumption was related to a low prevalence of eczema, but not asthma in Japanese pre- and early adolescents. EPA may be involved in this mechanism.