Showing papers in "Journal of Nutritional Biochemistry in 2006"
TL;DR: Recent studies on the effects of CLA and individual isomers on body composition, cardiovascular disease, bone health, insulin resistance, mediators of inflammatory response and different types of cancer, obtained from both in vitro and animal studies are discussed.
Abstract: Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of octadecadienoic acid [linoleic acid (LA), 18:2n-6] commonly found in beef, lamb and dairy products. The most abundant isomer of CLA in nature is the cis-9, trans-11 (c9t11) isomer. Commercially available CLA is usually a 1:1 mixture of c9t11 and trans-10, cis-12 (t10c12) isomers with other isomers as minor components. Conjugated LA isomer mixture and c9t11 and t10c12 isomers alone have been attributed to provide several health benefits that are largely based on animal and in vitro studies. Conjugated LA has been attributed many beneficial effects in prevention of atherosclerosis, different types of cancer, hypertension and also known to improve immune function. More recent literature with availability of purified c9t11 and t10c12 isomers suggests that t10c12 is the sole isomer involved in antiadipogenic role of CLA. Other studies in animals and cell lines suggest that the two isomers may act similarly or antagonistically to alter cellular function and metabolism, and may also act through different signaling pathways. The effect of CLA and individual isomers shows considerable variation between different strains (BALB/C mice vs. C57BL/6 mice) and species (e.g., rats vs. mice). The dramatic effects seen in animal studies have not been reflected in some clinical studies. This review comprehensively discusses the recent studies on the effects of CLA and individual isomers on body composition, cardiovascular disease, bone health, insulin resistance, mediators of inflammatory response and different types of cancer, obtained from both in vitro and animal studies. This review also discusses the latest available information from clinical studies in these areas of research.
658 citations
TL;DR: Modulation of the arginine-NO pathway through dietary supplementation with L-arginine or L-citrulline may aid in the prevention and treatment of the metabolic syndrome in obese humans and companion animals, and in reducing unfavorable fat mass in animals of agricultural importance.
Abstract: Nitric oxide (NO) is synthesized from L-arginine by NO synthase in virtually all cell types. Emerging evidence shows that NO regulates the metabolism of glucose, fatty acids and amino acids in mammals. As an oxidant, pathological levels of NO inhibit nearly all enzyme-catalyzed reactions through protein oxidation. However, as a signaling molecule, physiological levels of NO stimulate glucose uptake as well as glucose and fatty acid oxidation in skeletal muscle, heart, liver and adipose tissue; inhibit the synthesis of glucose, glycogen, and fat in target tissues (e.g., liver and adipose); and enhance lipolysis in adipocytes. Thus, an inhibition of NO synthesis causes hyperlipidemia and fat accretion in rats, whereas dietary arginine supplementation reduces fat mass in diabetic fatty rats. The putative underlying mechanisms may involve multiple cyclic guanosine-3',5'-monophosphate-dependent pathways. First, NO stimulates the phosphorylation of adenosine-3',5'-monophosphate-activated protein kinase, resulting in (1) a decreased level of malonyl-CoA via inhibition of acetyl-CoA carboxylase and activation of malonyl-CoA decarboxylase and (2) a decreased expression of genes related to lipogenesis and gluconeogenesis (glycerol-3-phosphate acyltransferase, sterol regulatory element binding protein-1c and phosphoenolpyruvate carboxykinase). Second, NO increases the phosphorylation of hormone-sensitive lipase and perilipins, leading to the translocation of the lipase to the neutral lipid droplets and, hence, the stimulation of lipolysis. Third, NO activates expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, thereby enhancing mitochondrial biogenesis and oxidative phosphorylation. Fourth, NO increases blood flow to insulin-sensitive tissues, promoting substrate uptake and product removal via the circulation. Modulation of the arginine-NO pathway through dietary supplementation with L-arginine or L-citrulline may aid in the prevention and treatment of the metabolic syndrome in obese humans and companion animals, and in reducing unfavorable fat mass in animals of agricultural importance.
634 citations
TL;DR: This study suggests that the anticarcinogenic effect of dietary ETs could be mainly due to their hydrolysis product, EA, which induced apoptosis via mitochondrial pathway in colon cancer Caco-2 cells but not in normal colon cells.
Abstract: Polyphenol-rich dietary foodstuffs have attracted attention due to their cancer chemopreventive and chemotherapeutic properties. Ellagitannins (ETs) belong to the so-called hydrolysable tannins found in strawberries, raspberries, walnuts, pomegranate, oak-aged red wine, etc. Both ETs and their hydrolysis product, ellagic acid (EA), have been reported to induce apoptosis in tumour cells. Ellagitannins are not absorbed in vivo but reach the colon and release EA that is metabolised by the human microflora. Our aim was to investigate the effect of a dietary ET [pomegranate punicalagin (PUNI)] and EA on human colon cancer Caco-2 and colon normal CCD-112CoN cells. Both PUNI and EA provoked the same effects on Caco-2 cells: down-regulation of cyclins A and B1 and upregulation of cyclin E, cell-cycle arrest in S phase, induction of apoptosis via intrinsic pathway (FAS-independent, caspase 8-independent) through bcl-XL down-regulation with mitochondrial release of cytochrome c into the cytosol, activation of initiator caspase 9 and effector caspase 3. Neither EA nor PUNI induced apoptosis in normal colon CCD-112CoN cells (no chromatin condensation and no activation of caspases 3 and 9 were detected). In the case of Caco-2 cells, no specific effect can be attributed to PUNI since it was hydrolysed in the medium to yield EA, which entered into the cells and was metabolised to produce dimethyl-EA derivatives. Our study suggests that the anticarcinogenic effect of dietary ETs could be mainly due to their hydrolysis product, EA, which induced apoptosis via mitochondrial pathway in colon cancer Caco-2 cells but not in normal colon cells.
409 citations
TL;DR: This review highlights some recent advances in the understanding of metabolic and molecular mechanisms concerning the effect of dietary PUFAs (fish oil) and focuses on the prevention and/or improvement of dyslipidemia, insulin resistance, impaired glucose homeostasis, diabetes and obesity in experimental animal models, with some extension to humans.
Abstract: For many years, clinical and animal studies on polyunsaturated n-3 fatty acids (PUFAs), especially those from marine oil, eicosapentaenoic acid (20:5,n-3) and docosahexaenoic acid (22:6,n-3), have reported the impact of their beneficial effects on both health and diseases. Among other things, they regulate lipid levels, cardiovascular and immune functions as well as insulin action. Polyunsaturated fatty acids are vital components of the phospholipids of membrane cells and serve as important mediators of the nuclear events governing the specific gene expression involved in lipid and glucose metabolism and adipogenesis. Besides, dietary n-3 PUFAs seem to play an important protecting role against the adverse symptoms of the Plurimetabolic syndrome. This review highlights some recent advances in the understanding of metabolic and molecular mechanisms concerning the effect of dietary PUFAs (fish oil) and focuses on the prevention and/or improvement of dyslipidemia, insulin resistance, impaired glucose homeostasis, diabetes and obesity in experimental animal models, with some extension to humans.
361 citations
TL;DR: Catechins are dietary polyphenolic compounds associated with a wide variety of beneficial health effects in vitro, in vivo and clinically as discussed by the authors, which have been attributed to the catechins' antioxidant and free radical scavenging effects.
Abstract: Catechins are dietary polyphenolic compounds associated with a wide variety of beneficial health effects in vitro, in vivo and clinically. These therapeutic properties have long been attributed to the catechins' antioxidant and free radical scavenging effects. Emerging evidence has shown that catechins and their metabolites have many additional mechanisms of action by affecting numerous sites, potentiating endogenous antioxidants and eliciting dual actions during oxidative stress, ischemia and inflammation. Catechins have proven to modulate apoptosis at various points in the sequence, including altering expression of anti- and proapoptotic genes. Their anti-inflammatory effects are activated through a variety of different mechanisms, including modulation of nitric oxide synthase isoforms. Catechins' actions of attenuating oxidative stress and the inflammatory response may, in part, account for their confirmed neuroprotective capabilities following cerebral ischemia. The versatility of the mechanisms of action of catechins increases their therapeutic potential as interventions for numerous clinical disorders. However, more epidemiological and clinical studies need to be undertaken for their efficacy to be fully elucidated.
272 citations
TL;DR: Current knowledge on the effects of these compounds contained in VOO on vascular dysfunction and the mechanisms by which they modulate endothelial activity are summarized.
Abstract: The endothelium is involved in many of the processes related to the development of atherosclerosis, which is considered an inflammatory disease. Actually, traditional risk factors for atherosclerosis predispose to endothelial dysfunction, which is manifested as an increase in the expression of specific cytokines and adhesion molecules. There are firm evidence supporting the beneficial effects of olive oil, the most genuine component of the Mediterranean diet. Although the effects of olive oil and other oleic acid-rich dietary oils on atherosclerosis and plasma lipids are well known, the roles of minor components have been less investigated. Minor components constitute only 1-2% of virgin olive oil (VOO) and are composed of hydrocarbons, polyphenols, tocopherols, sterols, triterpenoids and other components usually found in traces. Despite their low concentration, non-fatty acid constituents may be of importance because studies comparing monounsaturated dietary oils have reported different effects on cardiovascular disease. Most of these compounds have demonstrated antioxidant, anti-inflammatory and hypolipidemic properties. In this review, we summarize current knowledge on the effects of these compounds contained in VOO on vascular dysfunction and the mechanisms by which they modulate endothelial activity. Such mechanisms involve the release of nitric oxide, eicosanoids (prostaglandins and leukotrienes) and adhesion molecules, in most cases by activation of nuclear factor kappaB by reactive oxygen species.
267 citations
TL;DR: There is increasing evidence that dysregulation of energy homeostasis is associated with colorectal carcinogenesis. as discussed by the authors provides an overview of the epidemiology of body size and colorctal neoplasia and outlines current knowledge of putative mechanisms advanced to explain this relation.
Abstract: There is increasing evidence that dysregulation of energy homeostasis is associated with colorectal carcinogenesis. Epidemiological data have consistently demonstrated a positive relation between increased body size and colorectal malignancy, whereas mechanistic studies have sought to uncover obesity-related carcinogenic pathways. The phenomenon of "insulin resistance" or the impaired ability to normalize plasma glucose levels has formed the core of these pathways, but other mechanisms have also been advanced. Obesity-induced insulin resistance leads to elevated levels of plasma insulin, glucose and fatty acids. Exposure of the colonocyte to heightened concentrations of insulin may induce a mitogenic effect within these cells, whereas exposure to glucose and fatty acids may induce metabolic perturbations, alterations in cell signaling pathways and oxidative stress. The importance of chronic inflammation in the pathogenesis of obesity has recently been highlighted and may represent an additional mechanism linking increased adiposity to colorectal carcinogenesis. This review provides an overview of the epidemiology of body size and colorectal neoplasia and outlines current knowledge of putative mechanisms advanced to explain this relation. Family based studies have shown that the propensity to become obese is heritable, but this is only manifest in conditions of excess energy intake over expenditure. Inheritance of a genetic profile that predisposes to increased body size may also be predictive of colorectal cancer. Genomewide scans, linkage studies and candidate gene investigations have highlighted more than 400 chromosomal regions that may harbor variants that predispose to increased body size. The genetics underlying the pathogenesis of obesity are likely to be complex, but variants in a range of different genes have already been associated with increased body size and insulin resistance. These include genes encoding elements of insulin signaling, adipocyte metabolism and differentiation, and regulation of energy expenditure. A number of investigators have begun to study genetic variants within these pathways in relation to colorectal neoplasia, but at present data remain limited to a handful of studies. These pathways will be discussed with particular reference to genetic polymorphisms that have been associated with obesity and insulin resistance.
245 citations
TL;DR: In this paper, the authors examined the evidence on the possible mechanisms for which soy protein has beneficial effects in diabetes, obesity and some forms of chronic renal disease, and concluded that soy protein intake may reduce the clinical and biochemical abnormalities in diseases mediated by lipid disorders.
Abstract: Soybeans have a high-quality protein that has been consumed for approximately 5000 years in Oriental countries. The awareness that soy products are healthy has increased their consumption in Western countries. Substantial data from epidemiological surveys and nutritional interventions in humans and animals indicate that soy protein reduces serum total and low-density lipoprotein (LDL) cholesterol and triglycerides as well as hepatic cholesterol and triglycerides. This review examines the evidence on the possible mechanisms for which soy protein has beneficial effects in diabetes, obesity and some forms of chronic renal disease. Consumption of soy protein due to low methionine content reduces serum homocysteine concentration, decreasing the risk of acquiring a cardiovascular disease. On the other hand, soy protein reduces the insulin/glucagon ratio, which in turn down-regulates the expression of the hepatic transcription factor sterol regulatory element binding protein (SREBP)-1. The reduction of this factor decreases the expression of several lipogenic enzymes, decreasing in this way serum and hepatic triglycerides as well as LDL cholesterol and very LDL triglycerides in diabetes and obesity, reducing lipotoxicity in the liver. Soy protein intake also reduces hepatic lipotoxicity by maintaining the number of functional adipocytes, preventing the transfer of fatty acids to extra adipose tissues. Furthermore, soy protein isoflavones stimulate the transcription factor SREBP-2, increasing serum cholesterol clearance. The reduction of serum cholesterol and triglyceride concentrations by soy protein intake produces beneficial effects in the kidney preventing the inflammatory response, increasing the renal flow by releasing endothelial nitric oxide (NO) synthase from the caveolae, facilitating the synthesis of NO. Thus, soy protein consumption may reduce the clinical and biochemical abnormalities in diseases mediated by lipid disorders.
206 citations
TL;DR: A healthy food pattern, which includes a combination of antioxidant compounds and flavonoid-rich foods, appears effective to decrease LDL particle oxidizability, which may give some insight of the cardiovascular benefits associated with the Mediterranean diet.
Abstract: Oxidized low-density lipoproteins (ox-LDLs) appear to play a significant role in atherogenesis. In fact, circulating ox-LDL concentrations have been recognized as a risk factor for cardiovascular disease (CVD). A higher intake of some nutrients and specific food compounds such as monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs) and flavonoids have also been associated with a lower risk of CVD. These dietary factors could be associated to a lower risk of CVD through a reduction of the atherogenicity of LDL particles through limited oxidation. Therefore, the purpose of this article is to review human clinical studies that evaluated effects of dietary antioxidant vitamins, fatty acids (MUFA, PUFA) and specific flavonoid-rich foods on LDL particle oxidation and describe potential mechanisms by which dietary factors may prevent oxidation of LDL particles. Antioxidant vitamin supplements such as alpha-tocopherol and ascorbic acid as well as beta-carotene and fish-oil supplements have not been clearly demonstrated to prevent oxidation of LDL particles. Moreover, inconsistent documented effects of flavonoid-rich food such as olive oil, tea, red wine and soy on LDL particle oxidizability may be explained by difference in variety and quantity of flavonoid compounds used among studies. However, a healthy food pattern such as the Mediterranean diet, which includes a combination of antioxidant compounds and flavonoid-rich foods, appears effective to decrease LDL particle oxidizability, which may give some insight of the cardiovascular benefits associated with the Mediterranean diet.
173 citations
TL;DR: The presence of different numbers of -OH moieties on the B-ring of the flavonols may contribute to their antioxidant activity as well as their toxicity and may play an important role in their potency for biological action such as angiogenesis and immune-endothelial cell adhesion, which, respectively, are important processes in the development of cancer and atherosclerosis.
Abstract: The antioxidant activity of flavonoids has been suggested to contribute to several health benefits associated with the consumption of fruits and vegetables. Four flavonols - myricetin (M), quercetin (Q), kaempferol (K) and galangin (G), all with different numbers of hydroxyl moieties (-OH) - were examined for their antioxidant activity and cytotoxicity on human umbilical vein endothelial cells (HUVECs) and for their potential antiangiogenic and cell adhesion effects. The relative antioxidant capacity of these flavonols in cell culture medium (cell-free system) and their intracellular antioxidant activity were M = Q > K = G, which correlated respectively with the presence of 3, 2, 1 and 0 moieties of -OH on their B-ring. The higher the numbers of -OH moieties on the B-ring the less toxic the flavonol was to HUVEC, and the LD50 was determined as: M (100 microM) > Q (50 microM) > K (20 microM) > G (10 microM). These flavonols at approximately 0.5 LD50 doses suppressed the vascular endothelial growth factor (VEGF)-stimulated HUVEC tubular structure formation by: M (47%) > Q (37%) > K (15%) > G (14%), which was not linearly associated with their numbers of -OH moieties. However, the magnitude of flavonols' suppression of activated U937 monocytic cells adhesion to HUVEC was associated with the number of -OH moieties on the B-ring. This was prominent when U937 cells were pretreated with these flavonols. In contrast, the numbers of -OH moiety had no apparent influence on the adhesion or expression of adhesion molecules when activated HUVECs were pretreated with these flavonols. The presence of different numbers of -OH moieties on the B-ring of the flavonols may contribute to their antioxidant activity as well as their toxicity and may play an important role in their potency for biological action such as angiogenesis and immune-endothelial cell adhesion, which, respectively, are important processes in the development of cancer and atherosclerosis.
156 citations
TL;DR: Rutin and circulating metabolites of rutin can inhibit early glycation product formation, including both fluorescent and nonfluorescent AGEs induced by glucose glycation of collagen I in vitro, which likely contribute to the beneficial health effects associated with r Rutin consumption.
Abstract: Several lines of evidence suggest that rutin, flavonoid in fruits and vegetables, or one of its metabolites may effectively modulate advanced glycation end product (AGE) formation. Following ingestion, rutin forms metabolites that include 3,4-dihydroxyphenylacetic acid (3,4-DHPAA), 3,4-dihydroxytoluene (3,4-DHT), m-hydroxyphenylacetic acid (m-HPAA), 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA) and 3,5,7,3',5'-pentahydroxyflavonol (quercetin). We studied the effects of rutin and its metabolites on the formation of AGE biomarkers such as pentosidine, collagen-linked fluorescence, N(epsilon)-carboxymethyllysine (CML) adducts, glucose autoxidation and collagen glycation, using an in vitro model where collagen I was incubated with glucose. Rutin metabolites containing vicinyl dihydroxyl groups, i.e., 3,4-DHT, 3,4-DHPAA and quercetin, inhibited the formation of pentosidine and fluorescent adducts, glucose autoxidation and glycation of collagen I in a dose-dependent manner, whereas non-vicinyl dihydroxyl group-containing metabolites, i.e., HVA and m-HPAA, were much less effective. All five metabolites of rutin effectively inhibited CML formation. In contrast, during the initial stages of glycation and fluorescent AGE product accumulation, only vicinyl hydroxyl group-containing rutin metabolites were effective. These studies demonstrate that rutin and circulating metabolites of rutin can inhibit early glycation product formation, including both fluorescent and nonfluorescent AGEs induced by glucose glycation of collagen I in vitro. These effects likely contribute to the beneficial health effects associated with rutin consumption.
TL;DR: The cancer-preventive effects of citrus fruits demonstrated in epidemiological studies may be due in part to stimulation of DNA repair by NR, which by stimulating BER processes may prevent mutagenic changes in prostate cancer cells.
Abstract: As part of a systematic study of the effects of phytochemicals beyond antioxidation on cancer prevention, we investigated whether naringenin (NR), a citrus flavonoid, stimulates DNA repair following oxidative damage in LNCaP human prostate cancer cells. The 8-hydroxydeoxyguanosine (8-OH-dG) to deoxyguanosine (dG) ratio was measured after cells were treated with 200 micromol/L of ferrous sulfate in serum-free medium followed by NR exposure for 24 h in growth medium. The results demonstrated that exposure to 10-80 micromol/L of NR led to a significant decrease in the ratio of 8-OH-dG to 10(6) dG. Because cells were treated with NR after ferrous sulfate was removed, we conclude that we demonstrated an effect on DNA repair beyond antioxidation. In support of this conclusion, we determined the induction of mRNA expression over time after oxidative stress followed by NR administration of three major enzymes in the DNA base excision repair (BER) pathway: 8-oxoguanine-DNA glycosylase 1 (hOGG1), apurinic/apyrimidinic endonuclease and DNA polymerase beta (DNA poly beta). hOGG1 and DNA poly beta mRNA expression in cells after 24-h exposure to NR was increased significantly compared with control cells without NR. The intracellular concentration of NR after exposure to 80 micromol/L was 3 pmol/mg protein, which is physiologically achievable in tissues. In conclusion, the cancer-preventive effects of citrus fruits demonstrated in epidemiological studies may be due in part to stimulation of DNA repair by NR, which by stimulating BER processes may prevent mutagenic changes in prostate cancer cells.
TL;DR: Results suggest that decreased expression of Bcl-2 by t9t11-CLA might increase the sensitivity of cells to lipid peroxidation and to programmed cell death, apoptosis.
Abstract: This study compared the growth inhibitory effects of pure conjugated linoleic acid (CLA) isomers [cis(c)9,c11-CLA, c9,trans(t)11-CLA, t9,t11-CLA, and t10,c12-CLA] on human colon cancer cell lines (Caco-2, HT-29 and DLD-1). When Caco-2 cells were incubated up to 72 h with 200 microM, each isomer, even in the presence of 10% fetal bovine serum (FBS), cell proliferation was inhibited by all CLA isomers in a time-dependent manner. The strongest inhibitory effect was shown by t9,t11-CLA, followed by t10,c12-CLA, c9,c11-CLA and c9,t11-CLA, respectively. The strongest effect of t9,t11-CLA was also observed in other colon cancer cell lines (HT-29 and DLD-1). The order of the inhibitory effect of CLA isomer was confirmed in the presence of 1% FBS. CLA isomers supplemented in the culture medium were readily incorporated into the cellular lipids of Caco-2 and changed their fatty acid composition. The CLA contents in cellular lipids were 26.2+/-2.7% for t9,t11-CLA, 35.9+/-0.3% for c9,t11-CLA and 46.3+/-0.8% for t10,c12-CLA, respectively. DNA fragmentation was clearly recognized in Caco-2 cells treated with t9,t11-CLA. This apoptotic effect of t9,t11-CLA was dose- and time-dependent. DNA fragmentation was also induced by 9c,11t-CLA and t10,c12-CLA. However, fragmentation levels with both isomers were much lower than that with t9,t11-CLA. t9t11-CLA treatment of Caco-2 cells decreased Bcl-2 levels in association with apoptosis, whereas Bax levels remained unchanged. These results suggest that decreased expression of Bcl-2 by t9t11-CLA might increase the sensitivity of cells to lipid peroxidation and to programmed cell death, apoptosis.
TL;DR: The results indicate that phenolic acids from beer are absorbed from the gastrointestinal tract and are present in blood after being largely metabolized to the form of glucuronide and sulfate conjugates.
Abstract: In spite of the wide literature describing the biological effects of phenolic compounds, scarce data are available on their absorption from diet. In the present work, we studied the absorption in humans of phenolic acids from beer, a common beverage rich in different phenolic acids with related chemical structures. Beer was analyzed for free and total (free+bound) phenolic acids. Ferulic, caffeic and sinapic acids were present in beer mainly as bound forms, while 4-hydroxyphenylacetic acid and p-coumaric acid were present mainly as free forms. Vanillic acid was present equally in the free and bound forms. Plasma samples were collected before and 30 and 60 min after beer administration and analyzed for free and conjugated phenolic acid content. A significant two- to fourfold increase in plasma levels of phenolic acids was detected with peak concentrations at 30 min after beer ingestion. 4-Hydroxyphenylacetic acid was present in plasma mainly as nonconjugated forms while p-coumaric acid was present equally as nonconjugated and conjugated forms. Ferulic, vanillic and caffeic acids were present in plasma predominantly as conjugated forms, with a slight prevalence of sulfates with respect to glucuronates. Our results indicate that phenolic acids from beer are absorbed from the gastrointestinal tract and are present in blood after being largely metabolized to the form of glucuronide and sulfate conjugates. The extent of conjugation is related to the chemical structure of phenolic acids: the monohydroxy derivatives showing the lowest conjugation degree and the dihydroxy derivatives showing the highest one.
TL;DR: The results showed that supranutritional selenate doses influenced two important mechanisms involved in insulin-resistant diabetes, namely, PTPs and PPARgamma, which, in turn, can be assumed as being responsible for the changes in intermediary metabolism.
Abstract: In recent years, a number of investigations on the antidiabetic effects of supranutritional selenate doses have been carried out. Selenate (selenium oxidation state +VI) was shown to possess regulatory effects on glycolysis, gluconeogenesis and fatty acid metabolism, metabolic pathways which are disturbed in diabetic disorders. An enhanced phosphorylation of single components of the insulin signalling pathway could be shown to be one molecular mechanism responsible for the insulinomimetic properties of selenate. In type II diabetic animals, a reduction of insulin resistance could be shown as an outcome of selenate treatment. The present study with db/db mice was performed to investigate the antidiabetic mechanisms of selenate in type II diabetic animals. Twenty-one young adult female db/db mice were randomly assigned to three experimental groups (selenium deficient=0Se, selenite-treated group=SeIV and selenate-treated group=SeVI) with seven animals each. Mice of all groups were fed a selenium-deficient diet for 8 weeks. The animals of the groups SeIV and SeVI were supplemented with increasing amounts of sodium selenite or sodium selenate up to 35% of the LD50 in week 8 in addition to the diet by tube feeding. Selenate treatment reduced insulin resistance significantly and reduced the activity of liver cytosolic protein tyrosine phosphatases (PTPs) as negative regulators of insulin signalling by about 50%. In an in vitro inhibition test selenate (oxidation state +VI) per se did not inhibit PTP activity. In this test, however, selenium compounds of the oxidation state +IV were found to be the actual inhibitors of PTP activity. Selenate administration in vivo further led to characteristic changes in the selenium-dependent redox system, which could be mimicked in an in vitro assay and provided further evidence for the intermediary formation of SeIV metabolites. The expression of peroxisome proliferator-activated receptor gamma (PPARgamma), another important factor in the context of insulin resistance and lipid metabolism, was significantly increased by selenate application. In particular, liver gluconeogenesis and lipid metabolism were influenced strongly by selenate treatment. In conclusion, our results showed that supranutritional selenate doses influenced two important mechanisms involved in insulin-resistant diabetes, namely, PTPs and PPARgamma, which, in turn, can be assumed as being responsible for the changes in intermediary metabolism, e.g., gluconeogenesis and lipid metabolism. The initiation of these mechanisms thereby seems to be coupled to the intermediary formation of the selenium oxidation state +IV (selenite state) from selenate.
TL;DR: It is shown that dietary DHA lowers the ratio of 18:2n-6 (linoleic acid)/n-3 in bone compartments and that this ratio in tissue correlates with reduced Pyd but higher bone alkaline phosphatase activity and BMC values that favor bone conservation in OVX rats.
Abstract: Hypoestrogenic states escalate bone loss in animals and humans. This study evaluated the effects of the amount and ratio of dietary n-6 and n-3 polyunsaturated fatty acids (PUFAs) on bone mineral in 3-month-old sexually mature ovariectomized (OVX) Sprague-Dawley rats. For 12 weeks, the rats were fed either a high-PUFA (HP) or a low-PUFA (LP) diet with a ratio of n-6/n-3 PUFAs of 5:1 (HP5 and LP5) or 10:1 (HP10 and LP10). All diets (modified AIN-93G) provided 110.4 g/kg of fat from safflower oil and/or high-oleate safflower oil blended with n-3 PUFAs (DHASCO oil) as a source of docosahexaenoic acid (DHA). Fatty acid analyses confirmed that the dietary ratio of 5:1 significantly elevated the amount of DHA in the periosteum, marrow and cortical and trabecular bones of the femur. Dual-energy X-ray absorptiometry measurements for femur and tibia bone mineral content (BMC) and bone mineral density showed that the DHA-rich diets (HP5 and LP5) resulted in a significantly lower bone loss among the OVX rats at 12 weeks. Rats fed the LP diets displayed the lowest overall serum concentrations of the bone resorption biomarkers pyridinoline (Pyd) and deoxypyridinoline, whereas the bone formation marker osteocalcin was lowest in the HP groups. Regardless of the dietary PUFA content, DHA in the 5:1 diets (HP5 and LP5) preserved rat femur BMC in the absence of estrogen. This study indicates that the dietary ratio of n-6/n-3 PUFAs (LP5 and HP5) and bone tissue concentration of total long-chain n-3 PUFAs (DHA) minimize femur bone loss as evidenced by a higher BMC in OVX rats. These findings show that dietary DHA lowers the ratio of 18:2n-6 (linoleic acid)/n-3 in bone compartments and that this ratio in tissue correlates with reduced Pyd but higher bone alkaline phosphatase activity and BMC values that favor bone conservation in OVX rats.
TL;DR: In this paper, the role of nutrition in carnitine metabolism was discussed, followed by a discussion of carnitines and acetyl-l-carnitine in mitochondrial dysfunction, in aging, and in age-related disorders.
Abstract: Aging is associated with a reduced ability to cope with physiological challenges. Although the mechanisms underlying age-related alterations in stress tolerance are not well defined, many studies support the validity of the oxidative stress hypothesis, which suggests that lowered functional capacity in aged organisms is the result of an increased generation of reactive oxygen and nitrogen species. Increased production of oxidants in vivo can cause damage to intracellular macromolecules, which can translate into oxidative injury, impaired function and cell death in vulnerable tissues such as the brain. To survive different types of injuries, brain cells have evolved networks of responses, which detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Among these, heat shock proteins form a highly conserved system responsible for the preservation and repair of the correct protein conformation. The heat shock response contributes to establishing a cytoprotective state in a wide variety of human diseases, including inflammation, cancer, aging and neurodegenerative disorders. Given the broad cytoprotective properties of the heat shock response, there is now a strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. Acetylcarnitine is proposed as a therapeutic agent for several neurodegenerative disorders, and there is now evidence that it may play a critical role as modulator of cellular stress response in health and disease states. In the present review, we first discuss the role of nutrition in carnitine metabolism, followed by a discussion of carnitine and acetyl-l-carnitine in mitochondrial dysfunction, in aging, and in age-related disorders. We then review the evidence for the role of acetylcarnitine in modulating redox-dependent mechanisms leading to up-regulation of vitagenes in brain, and we also discuss new approaches for investigating the mechanisms of lifetime survival and longevity.
TL;DR: The present results indicate that ISL inhibits prostate cancer cell growth by the induction of apoptosis, which is mediated through mitochondrial events, which are associated with an evident disruption of the mitochondrial membrane potential and the release of cytochrome c and Smac/Diablo, and the activation of caspase-9.
Abstract: Isoliquiritigenin (ISL), a simple chalcone derivative, 4,2′,4′-trihydroxychalcone, found in licorice, shallot and bean sprouts, has been reported to have chemoprotective effects. To examine the effects of ISL on the growth of prostate cancer cells, we cultured MAT-LyLu (MLL) rat and DU145 human prostate cancer cells with various concentrations (0–20 μmol/L) of ISL. Treatment of the cells with increasing concentrations of ISL led to dose-dependent decreases in the viable cell numbers in both DU145 and MLL cells (P<.05). Hoechst 33258 dye staining of condensed nuclei and annexin V binding to surface phosphatidylserine revealed increased numbers of apoptotic cells after ISL treatment. Western blot analysis revealed that ISL increased the levels of membrane-bound Fas ligand (FasL), Fas, cleaved casapse-8, truncated Bid (tBid), Bax and Bad in DU145 cells (P<.05). Isoliquiritigenin increased the percentage of cells with depolarized mitochondrial membranes, in a concentration-dependent manner (P<.05). Isoliquiritigenin induced the release of cytochrome c and Smac/Diablo from the mitochondria into the cytoplasm (P<.05). Isoliquiritigenin dose-dependently increased the levels of cleaved caspsase-9, caspase-7, caspase-3 and poly(ADP-ribose) polymerase (P<.05). The present results indicate that ISL inhibits prostate cancer cell growth by the induction of apoptosis, which is mediated through mitochondrial events, which are associated with an evident disruption of the mitochondrial membrane potential, and the release of cytochrome c and Smac/Diablo, and the activation of caspase-9.
TL;DR: EGCG inhibits the intestinal absorption of lipids, which is in part associated with its inhibition of phosphatidylcholine hydrolysis, and data suggest that EGCG may inhibit the absorption of other highly lipophilic organic compounds.
Abstract: This study was conducted to examine whether the inhibition of intestinal lipid absorption by green tea is associated with the inhibitory effect of its catechins on pancreatic phospholipase A(2) (PLA(2)). PLA(2) activity was assayed by using 1,2-dioleoylphosphatidylcholine (DOPC), porcine pancreatic PLA(2) and catechins at varying concentrations (0.075-1.80 micromol/L). The amount of 1-oleoyl-2-hydroxyphosphatidylcholine liberated was determined by HPLC. The percentage of inhibition of PLA(2) by catechins at 0.6 micromol increased in the order of (-)-epicatechin (23.3%), (+)-catechin (CAT; 24.8%), (-)-epigallocatechin (25.7%), (-)-epicatechin gallate (39.7%) and (-)-epigallocatechin gallate (EGCG; 64.9%). In an in vivo study, ovariectomized rats with lymph cannula were infused intraduodenally for 8 h with a triolein emulsion containing [dioleoyl-1-(14)C]-phosphatidylcholine, DOPC, alpha-tocopherol (alphaTOH) and retinol (ROH) without (CAT0) or with CAT or EGCG. The lymphatic total (14)C-radioactivity was significantly lowered by EGCG (45.5+/-4.9% dose) compared with CAT (56.2+/-5.2% dose) and CAT0 (64.7+/-2.0% dose). The (14)C-radioactivity remaining in the small intestinal lumen and cecum was higher in EGCG (24.1% dose) than in CAT (9.5% dose) and CAT0 rats (9.0% dose). Significantly less (14)C radioactivity was incorporated into lymph triacylglycerol and cholesteryl ester in EGCG rats. The absorption of alphaTOH, used as a marker of extremely hydrophobic lipids, was significantly lower in EGCG (7.8+/-1.7 micromol) than in CAT (14.4+/-2.8 micromol) and CAT0 rats (16.8+/-2.1 micromol). The absorption of ROH was unaffected, whereas oleic acid output was lower in EGCG rats. The results show that EGCG inhibits the intestinal absorption of lipids, which is in part associated with its inhibition of phosphatidylcholine hydrolysis. Data suggest that EGCG may inhibit the absorption of other highly lipophilic organic compounds.
TL;DR: Five studies have identified five novel biotinylation sites in human histones; histone H2A is unique among histones in that its biot vinylation sites include amino acid residues from the C-terminus.
Abstract: In eukaryotic cell nuclei, DNA associates with the core histones H2A, H2B, H3 and H4 to form nucleosomal core particles. DNA binding to histones is regulated by posttranslational modifications of N-terminal tails (e.g., acetylation and methylation of histones). These modifications play important roles in the epigenetic control of chromatin structure. Recently, evidence that biotinidase and holocarboxylase synthetase (HCS) catalyze the covalent binding of biotin to histones has been provided. The primary aim of this study was to identify biotinylation sites in histone H2A and its variant H2AX. Secondary aims were to determine whether acetylation and methylation of histone H2A affect subsequent biotinylation and whether biotinidase and HCS localize to the nucleus in human cells. Biotinylation sites were identified using synthetic peptides as substrates for biotinidase. These studies provided evidence that K9 and K13 in the N-terminus of human histones H2A and H2AX are targets for biotinylation and that K125, K127 and K129 in the C-terminus of histone H2A are targets for biotinylation. Biotinylation of lysine residues was decreased by acetylation of adjacent lysines but was increased by dimethylation of adjacent arginines. The existence of biotinylated histone H2A in vivo was confirmed by using modification-specific antibodies. Antibodies to biotinidase and HCS localized primarily to the nuclear compartment, consistent with a role for these enzymes in regulating chromatin structure. Collectively, these studies have identified five novel biotinylation sites in human histones; histone H2A is unique among histones in that its biotinylation sites include amino acid residues from the C-terminus.
TL;DR: Direct evidence is provided for the role of CAPE as a potent antimetastatic agent, which can markedly inhibit the metastatic and invasive capacity of malignant cells.
Abstract: Caffeic acid phenethyl ester (CAPE) derived from honeybee propolis has been used as a folk medicine. Recent study also revealed that CAPE has several biological activities including antioxidation, anti-inflammation and inhibition of tumor growth. The present study investigated the effect of CAPE on tumor invasion and metastasis by determining the regulation of matrix metalloproteinases (MMPs). Matrix metalloproteinases, which are zinc-dependent proteolytic enzymes, play a pivotal role in tumor metastasis by cleavage of extracellular matrix (ECM) as well as nonmatrix substrates. On this line, we examined the influence of CAPE on the gene expression of MMPs (MMP-2, MMP-9, MT1-MMP), tissue inhibitor of metalloproteinase-2 (TIMP-2) and in vitro invasiveness of human fibrosarcoma cells. Dose-dependent decreases in MMP and TIMP-2 mRNA levels were observed in CAPE-treated HT1080 human fibrosarcoma cells as detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Gelatin zymography analysis also exhibited a significant down-regulation of MMP-2 and MMP-9 expression in HT1080 cells treated with CAPE compared to controls. In addition, CAPE inhibited the activated MMP-2 activity as well as invasion, motility, cell migration and colony formation of tumor cells. These data therefore provide direct evidence for the role of CAPE as a potent antimetastatic agent, which can markedly inhibit the metastatic and invasive capacity of malignant cells.
TL;DR: The results suggest that Bax and Bid regulated apoptosis induction by γ-T3, indicating that caspase-8 and casp enzyme were involved in apoptotic cell death induction in Hep3B cells.
Abstract: We evaluated the antitumor activity of tocotrienol (T3) on human hepatoma Hep3B cells. At first, we examined the effect of T3 on the proliferation of human hepatoma Hep3B cells and found that γ-T3 inhibited cell proliferation at lower concentrations and shorter treatment times than α-T3. Then, we examined the effect of γ-T3 apoptosis induction and found that γ-T3 induced poly (ADP-ribose) polymerase (PARP) cleavage and stimulated a rise in caspase-3 activity. In addition, γ-T3 stimulated a rise in caspase-8 and caspase-9 activities. We also found that γ-T3-induced apoptotic cell death was accompanied by up-regulation of Bax and a rise in the fragments of Bid and caspase-8. These data indicate that γ-T3 induced apoptosis in Hep3B cells and that caspase-8 and caspase-9 were involved in apoptosis induction. Moreover, these results suggest that Bax and Bid regulated apoptosis induction by γ-T3.
TL;DR: In spite of increasing antioxidant defences in response to the oxidative stress induced by the exhaustive exercise, lymphocyte oxidative damage was produced after the stage as demonstrated by the increased carbonyl index even in very well trained athletes.
Abstract: It has been reported that exercise induces oxidative stress and causes adaptations in antioxidant defences. The aim of this study was to determine the adaptations of lymphocytes to the oxidative stress induced by an exhaustive exercise. Nine voluntary male subjects participated in the study. The exercise was a cycling mountain stage (171.8 km), and the cyclists took a mean of 283 min to complete it. Blood samples were taken the morning of the cycling stage day, after overnight fasting, and 3 h after finishing the stage. We determined the blood glutathione redox status (GSSG/GSH), lymphocyte antioxidant enzyme activities and superoxide dismutase (SOD) levels; the plasma and lymphocyte vitamin E levels; the serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities and urate levels; the plasma carotene and malonaldehyde (MDA) levels; and the lymphocyte carbonyl index. The cycling stage induced significant increases in blood-oxidized (glutathione/GSSG), plasma MDA and serum urate levels. The exercise also produced increases in CK and LDH serum activities. The mountain cycling stage induced significant increases in lymphocyte vitamin E levels, glutathione peroxidase and glutathione reductase activities as well as increased SOD activity and protein levels. The protein carbonyl levels increased significantly in lymphocytes after the stage. In conclusion, in spite of increasing antioxidant defences in response to the oxidative stress induced by the exhaustive exercise, lymphocyte oxidative damage was produced after the stage as demonstrated by the increased carbonyl index even in very well trained athletes.
TL;DR: Caloric restriction has been shown to attenuate the age-associated adaptations in TNF-α signaling in skeletal muscle, which may be a possible mechanism by which CR prevents apoptosis and the loss of muscle fibers with age.
Abstract: Past the age of 50 years, aging individuals lose muscle mass at an approximate rate of 1–2% per year. This age-related muscle atrophy, termed sarcopenia, can have significant effects on individual health and quality of life and can also impact the socioeconomic status. Sarcopenia is due to both a decrease in the number of fibers and the atrophy of the remaining fibers. The mechanisms causing loss of fibers have not been clearly defined, but may likely involve apoptosis. Elevated levels of circulating tumor necrosis factor α (TNF-α) and adaptations in TNF-α signaling in aged skeletal muscle may be contributing factors for the activation of apoptosis. These adaptations may be fiber-type specific, which could explain the selective loss of type II fibers, vs. type I fibers, in the aging process. Caloric restriction, a proven antiaging intervention, is known to attenuate the loss of muscle mass and function with age. Furthermore, caloric restriction has been shown to attenuate the age-associated adaptations in TNF-α signaling in skeletal muscle, which may be a possible mechanism by which CR prevents apoptosis and the loss of muscle fibers with age. The potential role of TNF-α in the progression of sarcopenia will be discussed, as well as the effects of life-long caloric restriction on TNF-α signaling.
TL;DR: In vitro resveratrol, like well-known antioxidant DFO, has inhibitory effects on ONOO- -mediated oxidation of proteins and lipids in human plasma.
Abstract: The protective effects of resveratrol (3, 4′, 5-trihydroxystilbene; present naturally in different plants) against the oxidative/nitrative damage of human plasma proteins induced by peroxynitrite (ONOO − ) were studied and compared with those of deferoxamine (DFO; a natural siderophore isolated from Streptomyces pilosus ), which is a typical and well-known antioxidant. We also studied the effect of ONOO − on plasma lipid peroxidation and the role of tested antioxidants in this process. ONOO − at the used concentrations (0.01–1 mM) showed toxicity to human plasma components. Exposure of plasma to ONOO − (0.1 mM) resulted in an increase of the level of carbonyl groups and nitrotyrosine residues in plasma proteins (approximately 4-fold and 76-fold, respectively) and in a distinct augmentation of lipid peroxidation (approximately 2-fold). In the presence of 0.1-mM resveratrol, a distinct decrease of carbonyl group formation and tyrosine nitration in plasma proteins caused by 0.1-mM ONOO − was observed (by approximately 70% and 65%, respectively). Addition of 0.1-mM DFO to plasma also distinctly reduced the level of carbonyl groups and nitrotyrosines caused by 0.1-mM ONOO − (by approximately 50% and 60%, respectively). Moreover, these antioxidants also inhibited plasma lipid peroxidation induced by ONOO − (0.1 mM). The obtained results indicate that in vitro resveratrol, like well-known antioxidant DFO, has inhibitory effects on ONOO − -mediated oxidation of proteins and lipids in human plasma.
TL;DR: Urinary daidzein recovery was similar for all three foods ingested with total urinary output of 33-34% of ingested dose, and peak genistein concentrations were attained in serum earlier following consumption of a liquid matrix rather than a solid matrix, although there was a lower total urinary recovery of geniste in following ingestion of juice than that of the two other foods.
Abstract: If soy isoflavones are to be effective in preventing or treating a range of diseases, they must be bioavailable, and thus understanding factors which may alter their bioavailability needs to be elucidated. However, to date there is little information on whether the pharmacokinetic profile following ingestion of a defined dose is influenced by the food matrix in which the isoflavone is given or by the processing method used. Three different foods (cookies, chocolate bars and juice) were prepared, and their isoflavone contents were determined. We compared the urinary and serum concentrations of daidzein, genistein and equol following the consumption of three different foods, each of which contained 50 mg of isoflavones. After the technological processing of the different test foods, differences in aglycone levels were observed. The plasma levels of the isoflavone precursor daidzein were not altered by food matrix. Urinary daidzein recovery was similar for all three foods ingested with total urinary output of 33-34% of ingested dose. Peak genistein concentrations were attained in serum earlier following consumption of a liquid matrix rather than a solid matrix, although there was a lower total urinary recovery of genistein following ingestion of juice than that of the two other foods.
TL;DR: In rats rendered hyperlipidemic by maintaining them on a high-fat diet (30%) for 8 weeks, inclusion of spice principles or capsaicin or garlic in the diet produced significant hypotriglyceridemic effect, and activities of ouabain-sensitive Na(+),K(+)-ATPase as well as acetylcholinesterase of erythrocyte membranes in high-Fat fed rats remained unaltered.
Abstract: In rats rendered hyperlipidemic by maintaining them on a high-fat diet (30%) for 8 weeks, inclusion of spice principles [curcumin (0.2%) or capsaicin (0.015%)] or garlic (2.0%) in the diet produced significant hypotriglyceridemic effect. Plasma cholesterol remained unaffected in high-fat treatment. Hepatic triglyceride content was significantly higher in high-fat fed rats, and this increase was effectively countered by inclusion of the hypolipidemic spice agents - curcumin, capsaicin or garlic in the diet. The lipid profile of erythrocyte membranes of hyperlipidemic rats was similar to basal controls. An examination of the osmotic fragility of erythrocytes in various groups indicated that the red blood cells of hyperlipidemic rats display a slight resistance to osmotic lysis. Inclusion of spice principles [curcumin (0.2%) or capsaicin (0.015%)] or garlic (2.0%) in the diet, which produced the hypotriglyceridemic effect, appeared to beneficially correct this altered osmotic fragility of erythrocytes. Activities of ouabain-sensitive Na+,K+-ATPase as well as acetylcholinesterase of erythrocyte membranes in high-fat fed rats remained unaltered. Activity of Ca2+,Mg2+-ATPase in erythrocyte membrane was significantly decreased in high-fat fed animals, whereas dietary spice principles and garlic countered this reduction in enzyme activity. In the absence of any change in the cholesterol/phospholipid molar ratio in the erythrocyte membrane, a decreased activity of membrane-bound Ca2+,Mg2+-ATPase could have probably contributed to the accumulation of intracellular calcium leading to the diminished deformability of the erythrocytes in high-fat fed rats.
TL;DR: Results suggest that also genistin, due to its antioxidant and anticarcinogenic properties, contributes to the overall biological activity of soy and could have promising applications in the field of dermatology.
Abstract: In recent years, genistein has received considerable attention because epidemiologic studies showed that consumption of soybean-containing diets was associated with a lower incidence of certain human cancers in Asian populations. In vitro studies further showed that such chemopreventive and antineoplastic effects were associated with the antioxidant activity of genistein and inhibitor activities on cell proliferation and angiogenesis. Genistein was shown to arrest the growth of malignant melanoma in vitro and to inhibit ultraviolet (UV) light-induced oxidative DNA damage. Recently, it has been demonstrated that genistin, as other flavonoid glycosides, is partly absorbed without previous cleavage and does not have to be hydrolyzed to be biologically active. Therefore, not only isoflavone aglycons, but also glycosides can be of physiological relevance. In the present study, we evaluated in cell-free systems the effect of genistin and daidzin on pBR322 DNA cleavage induced by hydroxyl radicals, generated from UV photolysis of hydrogen peroxide, and their superoxide anion scavenging capacity. In addition, we investigated the growth inhibitory activity of these isoflavones against human melanoma cell line (M14). Under our experimental conditions, genistin and daidzin showed a protective effect on DNA damage and exhibited a superoxide dismutase-like effect, but only genistin was able to reduce significantly the vitality of M14 cells, confirming the importance of the 5,7-dihydroxy structure in the A ring. These results suggest that also genistin, due to its antioxidant and anticarcinogenic properties, contributes to the overall biological activity of soy and could have promising applications in the field of dermatology.
TL;DR: Drinking gazpacho significantly increases plasma concentrations of vitamin C and significantly decreases 8-epi-PGF2alpha, PGE2 and MCP-1 concentrations in healthy humans.
Abstract: Consumption of fruits and vegetables is associated with a reduced risk of death from all causes including heart disease and stroke. In this work, the bioavailability of vitamin C from a Mediterranean vegetable soup (gazpacho) constituted mainly of tomato, pepper and cucumber, and its influence on plasma vitamin C, 8-epi-prostaglandin F(2alpha) (8-epi-PGF2alpha), prostaglandin E2 (PGE2), monocyte chemotactic protein-1 (MCP-1), and the cytokines/tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 concentrations in a healthy human population were assessed. Six men and six women consumed 500 ml of commercial gazpacho per day for 14 days, corresponding to an intake of 78 mg of ascorbic acid per day. There were no differences (P = .22) in baseline plasma vitamin C concentrations between the men and women. The maximum increase (P < .05) in plasma vitamin C occurred 4 h postdose in both men and women. Vitamin C concentrations were significantly higher (P < .03) on Days 7 and 14 of the intervention. Baseline concentrations of uric acid and 8-epi-PGF2alpha were significantly higher (P < or = .032) in men than in women. Baseline concentrations of 8-epi-PGF2alpha decreased significantly (P < or = .05) by Day 14 of the intervention. A significant inverse correlation was observed between vitamin C and 8-epi-PGF2alpha (r = -.415, P = .049). Baseline concentrations of PGF2 and MCP-1 were significantly higher (P< or = .025) in men than in women but decreased significantly (P< or = .05) by Day 14 of the intervention. No effect on TNF-alpha, IL-1beta and IL-6 was observed at Day 14 of the intervention. Drinking gazpacho (500 ml/day) significantly increases plasma concentrations of vitamin C and significantly decreases 8-epi-PGF2alpha, PGE2 and MCP-1 concentrations in healthy humans.
TL;DR: Findings indicate that blueberry flavonoids may use multiple mechanisms in down-regulating MMP activity in these cells, which is crucial to regulate extracellular matrix (ECM) proteolysis which is important in metastasis.
Abstract: Regulation of the matrix metalloproteinases (MMPs) is crucial to regulate extracellular matrix (ECM) proteolysis which is important in metastasis. This study investigated the mechanism(s) by which three flavonoid-enriched fractions from lowbush blueberry ( Vaccinium angustifolium ) down-regulate MMP activity in DU145 human prostate cancer cells. Metalloproteinase activity was evaluated from cells exposed to "crude," anthocyanin-enriched (AN) and proanthocyanidin-enriched (PAC) fractions. Differential down-regulation of MMPs was observed. The activity of the endogenous tissue inhibitors of metalloproteinases (TIMPs) from these cells was also evaluated. Increases in TIMP-1 and TIMP-2 activity were observed in response to these fractions. The possible involvement of protein kinase C (PKC) and mitogen-activated protein (MAP) kinase pathways in the flavonoid-mediated decreases in MMP activity was observed. These findings indicate that blueberry flavonoids may use multiple mechanisms in down-regulating MMP activity in these cells.