Showing papers in "Molecular Nutrition & Food Research in 2008"

Flavan-3-ols: nature, occurrence and biological activity.

Abstract: Representing the most common flavonoid consumed in the American diet, the flavan-3-ols and their polymeric condensation products, the proanthocyanidins, are regarded as functional ingredients in various beverages, whole and processed foods, herbal remedies and supplements. Their presence in food affects food quality parameters such as astringency, bitterness, sourness, sweetness, salivary viscosity, aroma, and color formation. The ability of flavan-3-ols to aid food functionality has also been established in terms of microbial stability, foamability, oxidative stability, and heat stability. While some foods only contain monomeric flavan-3-ols [(-)-epicatechin predominates] and dimeric proanthocyanidins, most foods contain oligomers of degree of polymerization values ranging from 1-10 or greater than 10. Flavan-3-ols have been reported to exhibit several health beneficial effects by acting as antioxidant, anticarcinogen, cardiopreventive, antimicrobial, anti-viral, and neuro-protective agents. This review summarizes the distribution and health effects of these compounds.

Cancer chemoprevention and chemotherapy: Dietary polyphenols and signalling pathways

Abstract: Prevention of cancer through dietary intervention recently has received an increasing interest, and dietary polyphenols have become not only important potential chemopreventive, but also therapeutic, natural agents. Polyphenols have been reported to interfere at the initiation, promotion and progression of cancer. They might lead to the modulation of proteins in diverse pathways and require the integration of different signals for the final chemopreventive or therapeutic effect. Polyphenols have been demonstrated to act on multiple key elements in signal transduction pathways related to cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis and metastasis; however, these molecular mechanisms of action are not completely characterized and many features remain to be elucidated. The aim of this review is to provide insights into the molecular basis of potential chemopreventive and therapeutic activities of dietary polyphenols with emphasis in their ability to control intracellular signalling cascades considered as relevant targets in a cancer preventive approach.

Identification and quantification of methylglyoxal as the dominant antibacterial constituent of Manuka (Leptospermum scoparium) honeys from New Zealand.

Abstract: The 1,2-dicarbonyl compounds 3-deoxyglucosulose (3-DG), glyoxal (GO), and methylglyoxal (MGO) were measured as the corresponding quinoxalines after derivatization with orthophenylendiamine using RP-HPLC and UV-detection in commercially available honey samples. Whereas for most of the samples values for 3-DG, MGO, and GO were comparable to previously published data, for six samples of New Zealand Manuka (Leptospermum scoparium) honey very high amounts of MGO were found, ranging from 38 to 761 mg/kg, which is up to 100-fold higher compared to conventional honeys. MGO was unambigously identified as the corresponding quinoxaline via photodiodearry detection as well as by means of mass spectroscopy. Antibacterial activity of honey and solutions of 1,2-dicarbonyl towards Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were analyzed using an agar well diffusion assay. Minimum concentrations needed for inhibition of bacterial growth (minimum inhibitory concentration, MIC) of MGO were 1.1 mM for both types of bacteria. MIC for GO was 6.9 mM (E. coli) or 4.3 mM (S. aureus), respectively. 3-DG showed no inhibition in concentrations up to 60 mM. Whereas most of the honey samples investigated showed no inhibition in dilutions of 80% (v/v with water) or below, the samples of Manuka honey exhibited antibacterial activity when diluted to 15-30%, which corresponded to MGO concentrations of 1.1-1.8 mM. This clearly demonstrates that the pronounced antibacterial activity of New Zealand Manuka honey directly originates from MGO.

Acrolein: sources, metabolism, and biomolecular interactions relevant to human health and disease.

Abstract: Acrolein (2-propenal) is ubiquitously present in (cooked) foods and in the environment. It is formed from carbohydrates, vegetable oils and animal fats, amino acids during heating of foods, and by combustion of petroleum fuels and biodiesel. Chemical reactions responsible for release of acrolein include heat-induced dehydration of glycerol, retro-aldol cleavage of dehydrated carbohydrates, lipid peroxidation of polyunsaturated fatty acids, and Strecker degradation of methionine and threonine. Smoking of tobacco products equals or exceeds the total human exposure to acrolein from all other sources. The main endogenous sources of acrolein are myeloperoxidase-mediated degradation of threonine and amine oxidase-mediated degradation of spermine and spermidine, which may constitute a significant source of acrolein in situations of oxidative stress and inflammation. Acrolein is metabolized by conjugation with glutathione and excreted in the urine as mercapturic acid metabolites. Acrolein forms Michael adducts with ascorbic acid in vitro, but the biological relevance of this reaction is not clear. The biological effects of acrolein are a consequence of its reactivity towards biological nucleophiles such as guanine in DNA and cysteine, lysine, histidine, and arginine residues in critical regions of nuclear factors, proteases, and other proteins. Acrolein adduction disrupts the function of these biomacromolecules which may result in mutations, altered gene transcription, and modulation of apoptosis.

Direct and indirect antioxidant properties of inducers of cytoprotective proteins.

Abstract: Cellular protection against oxidative and electrophile toxicities is provided by two types of small-molecule antioxidants: (i) direct antioxidants, which are redox active, short-lived, are sacrificed in the process of their antioxidant actions and need to be replenished or regenerated, and may evoke pro-oxidant effects; and (ii) indirect antioxidants, that may or may not be redox active. Indirect antioxidants activate the Keap1/Nrf2/ARE pathway resulting in transcriptional induction of a battery of cytoprotective proteins (also known as phase 2 enzymes) that act catalytically, are not consumed, have long half-lives, and are unlikely to evoke pro-oxidant effects. These protective systems are involved in a complex functional interplay, such that many cytoprotective proteins participate in the synthesis and/or regeneration of direct antioxidants, whereas some direct antioxidants are required for the catalytic functions of cytoprotective proteins. Importantly, many inducers of cytoprotective proteins have been isolated from edible plants, e. g., sulforaphane from broccoli and curcumin from turmeric. Both are pleiotropic agents with multiple biological activities that could collectively contribute to their protective effects in various animal studies, including models of carcinogenesis, hypertension, neuronal and retinal damage. In addition to inducing cytoprotective proteins, molecules like curcumin which contain Michael acceptor functionalities (olefins or acetylenes conjugated to electron withdrawing groups) and phenolic hydroxyl groups can scavenge directly and potently oxygen- and nitrogen-centered reactive intermediates. Such bifunctional antioxidants can play a dual protective role by: (i) scavenging hazardous oxidants directly and instantaneously, and (ii) inducing cytoprotective enzymes that in turn function to resolve the consequences of hazardous processes that are already in progress, and to ensure long-term protection against subsequent challenges.

The influence of selenium on immune responses.

Abstract: Selenium (Se) is a potent nutritional antioxidant that carries out biological effects through its incorporation into selenoproteins. Given the crucial roles that selenoproteins play in regulating reactive oxygen species (ROS) and redox status in nearly all tissues, it is not surprising that dietary Se strongly influences inflammation and immune responses. The notion that Se "boosts" the immune system has been supported by studies involving aging immunity or protection against certain pathogens. However, studies examining the effects of Se status on other types of immunity such as antiparasitic responses or allergic asthma have suggested more Se may not always be beneficial. In this review, we summarize and compare the available data regarding how the levels of Se affect different types of immunity. Overall, determining how Se intake differentially affects various types of immune responses and dissecting the mechanisms by which this occurs will lead to a better utilization of Se-supplementation for human diseases involving the immune system.

Polyunsaturated fatty acids, inflammatory processes and inflammatory bowel diseases

Abstract: With regard to inflammatory processes, the main fatty acids of interest are the n-6 PUFA arachidonic acid (AA), which is the precursor of inflammatory eicosanoids like prostaglandin E₂ and leukotriene B₄, and the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are found in oily fish and fish oils. EPA and DHA inhibit AA metabolism to inflammatory eicosanoids. They also give rise to mediators that are less inflammatory than those produced from AA or that are anti-inflammatory. In addition to modifying the lipid mediator profile, n-3 PUFAs exert effects on other aspects of inflammation like leukocyte chemotaxis and inflammatory cytokine production. Some of these effects are likely due to changes in gene expression, as a result of altered transcription factor activity. Fish oil has been shown to decrease colonic damage and inflammation, weight loss and mortality in animal models of colitis. Fish oil supplementation in patients with inflammatory bowel diseases results in n-3 PUFA incorporation into gut mucosal tissue and modification of inflammatory mediator profiles. Clinical outcomes have been variably affected by fish oil, although some trials report improved gut histology, decreased disease activity, use of corticosteroids and relapse.

Ursolic acid : An anti-and pro-inflammatory triterpenoid

Abstract: There is growing interest in the elucidation of the biological functions of triterpenoids, ubiquitously distributed throughout the plant kingdom, some of which are used as anticancer and anti-inflammatory agents in Asian countries. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, is the major component of some traditional medicine herbs and is well known to possess a wide range of biological functions, such as antioxidative, anti-inflammation, and anticancer activities, that are able to counteract endogenous and exogenous biological stimuli. In contrast to these beneficial properties, some laboratory studies have recently revealed that the effects of UA on normal cells and tissues are occasionally pro-inflammatory. Thus, UA may be designated as a double-edged sword with both positive and negative effects, and further evaluations of the effects of UA on the biological status of target cells or tissues are necessary. This review summarizes previous and current information regarding UA, and provides new insights into the underlying molecular mechanisms of its activities.

Anticancer and carcinogenic properties of curcumin: considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent.

Abstract: A growing body of research suggests that curcumin, the major active constituent of the dietary spice turmeric, has potential for the prevention and therapy of cancer. Preclinical data have shown that curcumin can both inhibit the formation of tumors in animal models of carcinogenesis and act on a variety of molecular targets involved in cancer development. In vitro studies have demonstrated that curcumin is an efficient inducer of apoptosis and some degree of selectivity for cancer cells has been observed. Clinical trials have revealed that curcumin is well tolerated and may produce antitumor effects in people with precancerous lesions or who are at a high risk for developing cancer. This seems to indicate that curcumin is a pharmacologically safe agent that may be used in cancer chemoprevention and therapy. Both in vitro and in vivo studies have shown, however, that curcumin may produce toxic and carcinogenic effects under specific conditions. Curcumin may also alter the effectiveness of radiotherapy and chemotherapy. This review article analyzes the in vitro and in vivo cancer-related activities of curcumin and discusses that they are linked to its known antioxidant and pro-oxidant properties. Several considerations that may help develop curcumin as an anticancer agent are also discussed.

Effect of curcumin supplementation on blood glucose, plasma insulin, and glucose homeostasis related enzyme activities in diabetic db/db mice

Abstract: We investigated the effect of curcumin on insulin resistance and glucose homeostasis in male C57BL/KsJ-db/db mice and their age-matched lean non-diabetic db/+ mice. Both db/+ and db/db mice were fed with or without curcumin (0.02%, wt/wt) for 6 wks. Curcumin significantly lowered blood glucose and HbA 1c levels, and it suppressed body weight loss in db/db mice. Curcumin improved homeostasis model assessment of insulin resistance and glucose tolerance, and elevated the plasma insulin level in db/db mice. Hepatic glucokinase activity was significantly higher in the curcumin-supplemented db/db group than in the db/db group, whereas glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities were significantly lower. In db/db mice, curcumin significantly lowered the hepatic activities of fatty acid synthase, beta-oxidation, 3-hydroxy-3-methylglutaryl coenzyme reductase, and acyl-CoA: cholesterol acyltransferase. Curcumin significantly lowered plasma free fatty acid, cholesterol, and triglyceride concentrations and increased the hepatic glycogen and skeletal muscle lipoprotein lipase in db/db mice. Curcumin normalized erythrocyte and hepatic antioxidant enzyme activities (superoxide dismutase, catalase, gluthathione peroxidase) in db/db mice that resulted in a significant reduction in lipid peroxidation. However, curcumin showed no effect on the blood glucose, plasma insulin, and glucose regulating enzyme activities in db/+ mice. These results suggest that curcumin seemed to be a potential glucose-lowering agent and antioxidant in type 2 diabetic db/db mice, but had no affect in non-diabetic db/+ mice.

Impact of apoE genotype on oxidative stress, inflammation and disease risk.

Abstract: The aetiology of apoE4 genotype-Alzheimer's disease (AD) association are complex. The current study emphasizes the impact of apoE genotype and potential beneficial effects of vitamin E (VE) in relation to oxidative stress. Agonist induced neuronal cell death was examined 1) in the presence of conditioned media containing equal amounts of apoE3 or apoE4 obtained from stably transfected macrophages, and 2) after pretreatment with alpha- and gamma-tocopherol, and -tocotrienol. ApoE3 and apoE4 transgenic mice were fed a diet poor or rich in VE to study the interplay of both apoE genotype and VE status, on membrane lipid peroxidation, antioxidative enzyme activity and glutathione levels in the brain. Cytotoxicity of hydrogen peroxide and glutamate was higher in neuronal cells cultured with apoE4 than apoE3 conditioned media. VE pre-treatment of neurons counteracted the cytotoxicity of a peroxide challenge but not of nitric oxide. No significant effects of apoE genotype or VE supplementation were observed on lipid peroxidation or antioxidative status in the brain of apoE3 and apoE4 mice. VE protects against oxidative insults in vitro, however, no differences in brain oxidative status were observed in mice. Unlike in cultured cells, apoE4 may not contribute to higher neuronal oxidative stress in the brain of young targeted replacement mice.

Bioavailability issues in studying the health effects of plant polyphenolic compounds.

Abstract: Polyphenolic compounds are common in the diet and have been suggested to have a number of beneficial health effects including prevention of cancer, cardiovascular disease, diabetes, and others. For some dietary polyphenols, certain benficial effects are suggested by epidemiological studies, some are supported by studies in animal models, and still others are extrapolated from studies in vitro. Because of the relatively poor bioavailability of many of these compounds, the molecular basis of these beneficial effects is not clear. In the present review, we discuss the potential health benefits of dietary polyphenols from the point of view of bioavailability. Tea catechins, curcumin, and proanthocyanidins are used as examples to illustrate some of the problems that need to be resolved. Further research on both the biological activity and bioavailability of dietary polyphenols is needed to properly assess their usefulness for the prevention and treatment of disease.

Biotransformation of brominated flame retardants into potentially endocrine-disrupting metabolites, with special attention to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47).

Abstract: In this study, the endocrine-disrupting (ED) potency of metabolites from brominated flame retardants (BFRs) was determined. Metabolites were obtained by incubating single-parent compound BFRs with phenobarbital-induced rat liver microsomes. Incubation extracts were tested in seven in vitro bioassays for their potency to compete with thyroxine for binding to transthyretin (TTR), to inhibit estradiol-sulfotransferase (E2SULT), to interact with thyroid hormone-mediated cell proliferation, and to (in-)activate the androgen, progesterone, estrogen, or aryl hydrocarbon receptor. For most BFRs, TTR-binding potencies, and to a lesser extent E2SULT-inhibiting potencies, significantly increased after biotransformation. Microsomal incubation had less pronounced effects on other ED modes of action, due to low biotransformation efficiency and background activities determined in control incubations without BFRs. Moreover, cell-based bioassays suffered from cytotoxicity from metabolites of lower-brominated polybrominated diphenyl ethers. For the environmentally relevant 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), six hydroxylated metabolites were identified. Individual metabolites had TTR-binding and E2SULT-inhibiting potencies 160-1600 and 2.2-220 times higher than BDE-47 itself, whereas their combined potencies in a realistic mixture were well predicted via concentration addition. In combination with other environmentally relevant hydroxylated organohalogens acting on TTR-binding and E2SULT inhibition, internal exposure to BFR metabolites may significantly contribute to the overall risk of endocrine disruption.

Analysis of proanthocyanidins

Abstract: Plant phenolics are aromatic secondary metabolites that are ubiquitously spread throughout the plant kingdom. They comprise more than 8000 substances with highly diverse structures and molecular masses ranging from a100 Da for simple phenolic compounds to A30000 Da for highly polymerized structures. Plant phenols can be subdivided in the following classes: phenolic acids, flavanones, flavones and flavonols, anthocyanidins, flavan-3-ols and proanthocyanidins (PAC). For flavonoids, more than 5000 different kinds have been described [1]. The colorless PAC are also known as oligoflavanoids; they comprise condensed polyphenols or condensed tannins. Apart from lignin, they represent the most abundant class of natural phenolic compounds. The PAC obtained their name from the characteristic oxidative depolymerization reaction in acidic medium, which yields colored anthocyanidins. PAC consist of monomeric flavan-3-ol units, which are mainly linked through C4 fi C8 or sometimes C4 fi C6 bonds. These linkages are both called B-type linkages. When an additional ether linkage is formed (mainly) between C2 and C7, compounds are called A-type PAC (Fig. 1); this subclass lacks two hydrogens compared to the B-type. In addition to the 2b fi O7 linkage, A-types with a 2b fi O5 linkage are also found, e.g., in cocoa [2]. There are a variety of different classes of PAC depending on the substitution pattern of the monomeric flavan-3-ol units; the most common monomeric units are represented in Fig. 2 [3]. The PAC that exclusively consist of (epi)catechin units are designated procyanidins, the most abundant type of PAC in plants. The less common PAC containing (epi)afzelechin or (epi)gallocatechin subunits are termed propelargonidin or prodelphinidin, respectively. 5-Deoxy subunits [(epi)robinetinidol or (epi)fisetinidol] are also known. Pecan nut (Carya illionensis) pith tannin is predominatly a prodelphinidin tannin (prodelphinidins: procyanidin = 6:1), pine (Pinus radiate) bark tannin an entirely procyanidin of high mean degree of polymerization (DPm), quebracho (Schinopsis balansae var. chaqueno) wood tannin a predominantly profisetinidin/prorobinetinidin tannin, and apple (Malus silvestris) tannin, for the most part, a procyanidin of low molecular mass. In red wines colored PAC with anthocyan units in polymeric alliance have also been identified [4]. The flavan-3-ol subunits may carry acyl or glycosyl substituents. The most common substituent bound as an ester is gallic acid to form 3-O-gallates. Several glycosylated PAC oligomers have been identified, with the sugar linked to the C3 or the C5 position as the most widely distributed glycosylation. Procyanidins have a high structural diversity that is based on the four possible monomer units, (2R, 3S)-catechin, (2S, 3R)-ent-catechin, (2R, 3R)-epicatechin and (2S, 3S)-entepicatechin, with the diastereomeric monomers (2R, 3S)catechin and (2R, 3R)-epicatechin being predominant (Fig. 2). Regarding the stereochemistry of their C2-C3 bond, they exhibit cis (2R, 3R; epicatechin) or trans (2R, 3S; catechin) configuration. Monomers with 2S-configuration are marked by the prefix ent(enantio). The bond and its direction are displayed in brackets and configuration of the 1381

On the importance of selenium and iodine metabolism for thyroid hormone biosynthesis and human health

Abstract: The trace elements iodine and selenium (Se) are essential for thyroid gland functioning and thyroid hormone biosynthesis and metabolism. While iodine is needed as the eponymous constituent of the two major thyroid hormones triiodo-L-thyronine (T3), and tetraiodo-L-thyronine (T4), Se is essential for the biosynthesis and function of a small number of selenocysteine (Sec)-containing selenoproteins implicated in thyroid hormone metabolism and gland function. The Se-dependent iodothyronine deiodinases control thyroid hormone turnover, while both intracellular and secreted Se-dependent glutathione peroxidases are implicated in gland protection. Recently, a number of clinical supplementation trials have indicated positive effects of increasing the Se status of the participants in a variety of pathologies. These findings enforce the notion that many people might profit from improving their Se status, both as a means to reduce the individual health risk as well as to balance a Se deficiency which often develops during the course of illness. Even though the underlying mechanisms are still largely uncharacterised, the effects of Se appear to be exerted via multiple different mechanisms that impact most pronounced on the endocrine and the immune systems.

Molecular mechanisms of natural products in chemoprevention: induction of cytoprotective enzymes by Nrf2.

Abstract: Cancer chemoprevention involves the use of natural or synthetic compounds to reduce the risk of developing cancer. One of the potential strategies for preventing cancer in the human population is to use food-based natural products to induce cytoprotective enzymes, such as NAD(P)H:quinone oxidoreductase 1, glutathione S-transferase, superoxide dismutase, and heme oxygenase-1. The regulatory regions of these inducible genes contain the antioxidant response element (ARE), which is activated upon binding of the nuclear factor E2-related protein 2 (Nrf2) transcription factor protein. Nrf2 has been shown to be essential in the upregulation of these genes in response to oxidative stress and treatment with certain dietary phytochemicals. This review presents the current body of knowledge regarding the molecular mechanisms of Nrf2 regulation, and highlights the need for future investigations into how these mechanisms apply to natural product inducers of cytoprotective enzymes.

Multi-targeted therapy by curcumin: how spicy is it?

Abstract: Although traditional medicines have been used for thousands of years, for most such medicines neither the active component nor their molecular targets have been very well identified. Curcumin, a yellow component of turmeric or curry powder, however, is an exception. Although inhibitors of cyclooxygenase-2, HER2, tumor necrosis factor, EGFR, Bcr-abl, proteosome, and vascular endothelial cell growth factor have been approved for human use by the United States Food and Drug Administration (FDA), curcumin as a single agent can down-regulate all these targets. Curcumin can also activate apoptosis, down-regulate cell survival gene products, and up-regulate p53, p21, and p27. Although curcumin is poorly absorbed after ingestion, multiple studies have suggested that even low levels of physiologically achievable concentrations of curcumin may be sufficient for its chemopreventive and chemotherapeutic activity. Thus, curcumin regulates multiple targets (multitargeted therapy), which is needed for treatment of most diseases, and it is inexpensive and has been found to be safe in human clinical trials. The present article reviews the key molecular mechanisms of curcumin action and compares this to some of the single-targeted therapies currently available for human cancer.

Phenolic compounds: Evidence for inhibitory effects against obesity and their underlying molecular signaling mechanisms

Abstract: Phenolic compounds are widely present in the plant kingdom. Many epidemiological studies have indicated that consumption of some plant-derived foodstuffs with high phenolic content is associated with the prevention of some diseases and that these compounds may have similar properties to antioxidants, antimutagenic agents, antithrombotic agents, anti-inflammatory agents, anti-HIV-1, and anticancer agents. However, obesity is an important topic in the world of public health and preventive medicine. Relationships between body mass index, waist circumference, or waist-to-hip ratio and the risk of development of some diseases (such as heart disease, dyslipidemia, hypertension, non-alcoholic fatty liver disease, diabetes, kidney failure, cancer, stroke, osteoarthritis, and sleep apnea) have been observed. Evidence that phenolic compounds have beneficial effects in fighting obesity is increasingly being reported in the scientific literature. These in vitro and in vivo effects of phenolic compounds on the induction of pre-adipocytic and adipocytic apoptosis and inhibition of adipocytic lipid accumulation are considered in detail here. This review presents evidence of their inhibitory effects on obesity and their underlying molecular signaling mechanisms.

Quantification of free and protein-bound trans-resveratrol metabolites and identification of trans-resveratrol-C/O-conjugated diglucuronides - two novel resveratrol metabolites in human plasma.

Abstract: The polyphenol trans-resveratrol (t-RES) is present as t-RES-3-O-beta-D-glycoside, termed piceid, in several plant-derived foods. Although data on the metabolism and on in vivo effects of t-RES have been reported, quantitative data on the metabolites formed after dietary intake of t-RES or piceid are still lacking. In this study, 85.5 mg of piceid per 70 kg of body weight (bw) were administered to healthy volunteers in a bolus dose. t-RES metabolites formed in plasma and urine were identified and quantified by LC-MS/MS, NMR, and HPLC-DAD analysis using chemically synthesized t-RES conjugate standards. In addition, the amount of t-RES metabolites bound noncovalently to plasma proteins was determined for the first time in humans. The metabolites identified and quantified were t-RES-3-sulfate, t-RES-3,4'-disulfate, t-RES-3,5-disulfate, t-RES-3-glucuronide and t-RES-4'-glucuronide, with t-RES-sulfates being the dominant conjugates in plasma and urine. Besides these metabolites, two novel t-RES-C/O-conjugated diglucuronides have been identified and quantified in plasma and urine. Moreover, it could be shown that up to 50% of the plasma t-RES-3-sulfate, t-RES-disulfates, and the novel t-RES-C/O-diglucuronides were bound to proteins. Total recovery of the dietary administered piceid in urine ranged between 13.6 and 35.7%.

6-Shogaol suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages

Abstract: Ginger, the rhizome of Zingiber officinale, is a traditional medicine with carminative effect, antinausea, anti-inflammatory, and anticarcinogenic properties. In this study, we investigated the inhibitory effects of 6-shogaol and a related compound, 6-gingerol, on the induction of nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) in murine RAW 264.7 cells activated with LPS. Western blotting and reverse transcription-PCR analyses demonstrated that 6-shogaol significantly blocked protein and mRNA expression of inducible NOS (iNOS) and COX-2 in LPS-induced macrophages. The in vivo anti-inflammatory activity was evaluated by a topical 12-O-tetradecanoylphorbol 13-acetate (TPA) application to mouse skin. When applied topically onto the shaven backs of mice prior to TPA, 6-shogaol markedly inhibited the expression of iNOS and COX-2 proteins. Treatment with 6-shogaol resulted in the reduction of LPS-induced nuclear translocation of nuclear factor-kappaB (NF kappaB) subunit and the dependent transcriptional activity of NF kappaB by blocking phosphorylation of inhibitor kappaB (I kappaB)alpha and p65 and subsequent degradation of I kappaB alpha. Transient transfection experiments using NF kappaB reporter constructs indicated that 6-shogaol inhibits the transcriptional activity of NF kappaB in LPS-stimulated mouse macrophages. We found that 6-shogaol also inhibited LPS-induced activation of PI3K/Akt and extracellular signal-regulated kinase 1/2, but not p38 mitogen-activated protein kinase (MAPK). Taken together, these results show that 6-shogaol downregulates inflammatory iNOS and COX-2 gene expression in macrophages by inhibiting the activation of NF kappaB by interfering with the activation PI3K/Akt/I kappaB kinases IKK and MAPK.

6-Shogaol induces apoptosis in human colorectal carcinoma cells via ROS production, caspase activation, and GADD 153 expression.

Abstract: Ginger, the rhizome of Zingiber officinale, is a traditional medicine with anti-inflammatory and anticarcinogenic properties. This study examined the growth inhibitory effects of the structurally related compounds 6-gingerol and 6-shogaol on human cancer cells. 6-Shogaol [1-(4-hydroxy-3-methoxyphenyl)-4-decen-3-one] inhibits the growth of human cancer cells and induces apoptosis in COLO 205 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of 6-shogaol-induced apoptosis, preceding cytochrome c release, caspase activation, and DNA fragmentation. Up-regulation of Bax, Fas, and FasL, as well as down-regulation of Bcl-2 and Bcl-XL were observed in 6-shogaol-treated COLO 205 cells. N-acetylcysteine (NAC), but not by other antioxidants, suppress 6-shogaol-induced apoptosis. The growth arrest and DNA damage (GADD)-inducible transcription factor 153 (GADD153) mRNA and protein is markedly induced in a time- and concentration-dependent manner in response to 6-shogaol.

Medication-induced mitochondrial damage and disease

Abstract: Since the first mitochondrial dysfunction was described in the 1960s, the medicine has advanced in its understanding the role mitochondria play in health and disease. Damage to mitochondria is now understood to play a role in the pathogenesis of a wide range of seemingly unrelated disorders such as schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis. Medications have now emerged as a major cause of mitochondrial damage, which may explain many adverse effects. All classes of psychotropic drugs have been documented to damage mitochondria, as have stain medications, analgesics such as acetaminophen, and many others. While targeted nutrient therapies using antioxidants or their precursors (e. g., N-acetylcysteine) hold promise for improving mitochondrial function, there are large gaps in our knowledge. The most rational approach is to understand the mechanisms underlying mitochondrial damage for specific medications and attempt to counteract their deleterious effects with nutritional therapies. This article reviews our basic understanding of how mitochondria function and how medications damage mitochondria to create their occasionally fatal adverse effects.

Bifidobacterium carbohydrases-their role in breakdown and synthesis of (potential) prebiotics.

Abstract: There is an increasing interest to positively influence the human intestinal microbiota through the diet by the use of prebiotics and/or probiotics. It is anticipated that this will balance the microbial composition in the gastrointestinal tract in favor of health promoting genera such as Bifidobacterium and Lactobacillus. Carbohydrates like non-digestible oligosaccharides are potential prebiotics. To understand how these bacteria can grow on these carbon sources, knowledge of the carbohydrate-modifying enzymes is needed. Little is known about the carbohydrate-modifying enzymes of bifidobacteria. The genome sequence of Bifidobacterium adolescentis and Bifidobacterium longum biotype longum has been completed and it was observed that for B. longum biotype longum more than 8% of the annotated genes were involved in carbohydrate metabolism. In addition more sequence data of individual carbohydrases from other Bifidobacterium spp. became available. Besides the degradation of (potential) prebiotics by bifidobacterial glycoside hydrolases, we will focus in this review on the possibilities to produce new classes of non-digestible oligosaccharides by showing the presence and (transglycosylation) activity of the most important carbohydrate modifying enzymes in bifidobacteria. Approaches to use and improve carbohydrate-modifying enzymes in prebiotic design will be discussed.

Brominated flame retardants in US food.

Abstract: We and others recently began studying brominated flame retardant levels in various matrices in the US including human milk and other food. This paper reviews the food studies. In our studies, ten to thirteen polybrominated diphenyl ether (PBDE) congeners were measured, usually including BDE 209. All US women's milk samples were contaminated with PBDEs from 6 to 419 ng/g, lipid, orders of magnitude higher than levels reported in European studies, and are the highest reported worldwide. We compared our market basket studies of meat, fish and dairy products with other US food studies of meat and fish. US studies showed somewhat higher levels of PBDEs than reported elsewhere. Fish were most highly contaminated (median 616 pg/g), then meat (median190 pg/g) and dairy products (median 32.2 pg/g). However, unlike some European countries where fish predominates, dietary intake of PBDEs in the US is mostly from meat, then fish and then dairy products. Broiling can decrease the amount of PBDEs per serving. We also measured levels of hexabromocyclododecane (HBCD), another brominated flame retardant, in human milk. The levels are lower than PBDEs, 0.16-1.2 ng/g, similar to European levels, unlike PBDEs where US levels are much higher than European levels.

Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea.

Abstract: Cytochrome P450 2D6 (CYP2D6), an important CYP isoform with regard to drug-drug interactions, accounts for the metabolism of approximately 30% of all medications. To date, few studies have assessed the effects of botanical supplementation on human CYP2D6 activity in vivo. Six botanical extracts were evaluated in three separate studies (two extracts per study), each incorporating 16 healthy volunteers (eight females). Subjects were randomized to receive a standardized botanical extract for 14 days on separate occasions. A 30-day washout period was interposed between each supplementation phase. In study 1, subjects received milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa). In study 2, kava kava (Piper methysticum) and goldenseal (Hydrastis canadensis) extracts were administered, and in study 3 subjects received St. John's wort (Hypericum perforatum) and Echinacea (Echinacea purpurea). The CYP2D6 substrate, debrisoquine (5 mg), was administered before and at the end of supplementation. Pre- and post-supplementation phenotypic trait measurements were determined for CYP2D6 using 8-h debrisoquine urinary recovery ratios (DURR). Comparisons of pre- and post-supplementation DURR revealed significant inhibition (approximately 50%) of CYP2D6 activity for goldenseal, but not for the other extracts. Accordingly, adverse herb-drug interactions may result with concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 substrates.

Selenium attenuates pro-inflammatory gene expression in macrophages

Abstract: Selenium (Se) is an important element required for the optimal functioning of the immune system. Particularly in macrophages, which play a pivotal role in immune regulation, Se acts as a major antioxidant in the form of selenoproteins to mitigate the cytotoxic effects of reactive oxygen species. Here we describe the role of Se as an anti-inflammatory agent and its effect on the macrophage signal transduction pathways elicited by bacterial endotoxin, LPS. Our studies demonstrate that supplementation of Se to macrophages (Se-deficient) leads to a significant decrease in the LPS-induced expression of two important pro-inflammatory genes, cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) via the inhibition of MAP kinase pathways. Furthermore, Se-deficiency in mice exacerbated the LPS-mediated infiltration of macrophages into the lungs suggesting that Se status is a crucial host factor that regulates inflammation. In summary, our results indicate that Se plays an important role as an anti-inflammatory agent by tightly regulating the expression of pro-inflammatory genes in immune cells.

Curcumin and the cellular stress response in free radical-related diseases

Abstract: Free radicals play a main pathogenic role in several human diseases such as neurodegenerative disorders, diabetes, and cancer. Although there has been progress in treatment of these diseases, the development of important side effects may complicate the therapeutic course. Curcumin, a well known spice commonly used in India to make foods colored and flavored, is also used in traditional medicine to treat mild or moderate human diseases. In the recent years, a growing body of literature has unraveled the antioxidant, anticarcinogenic, and antinfectious activity of curcumin based on the ability of this compound to regulate a number of cellular signal transduction pathways. These promising data obtained in vitro are now being translated to the clinic and more than ten clinical trials are currently ongoing worldwide. This review outlines the biological activities of curcumin and discusses its potential use in the prevention and treatment of human diseases.

Tocotrienol-rich fraction of palm oil exhibits anti-inflammatory property by suppressing the expression of inflammatory mediators in human monocytic cells

Abstract: Tocotrienol-rich fraction (TRF) of palm oil has been shown to possess potent antioxidant, anticancer, and cholesterol lowering activities. In this study, our aim was to examine the effects of TRF on LPS-induced inflammatory response through measuring the production of inflammatory mediators, namely nitric oxide (NO), prostaglandin E(2) (PGE(2)), inducible nitric oxide synthase (iNOS), cytokines (TNF-alpha, IL-4, and IL-8), cyclooxygenase-1 and -2 (COX-1 and COX-2), and nuclear factor-kappaB (NF-kappaB) in human monocytic (THP-1) cells. At concentrations 0.5-5.0 microg/mL, TRF dose-dependently protected against LPS-induced cell death. At same concentrations, TRF also showed potent anti-inflammatory activity as demonstrated by a dose-dependent inhibition of LPS (1 microg/mL)-induced release of NO and PGE(2), and a significant decrease in the transcription of proinflammatory cytokines. TRF at 1.0 microg/mL significantly blocked the LPS induction of iNOS and COX-2 expression, but not COX-1. This anti-inflammatory activity was further supported by the inhibition of NF-kappaB expression. These results conclude that TRF possesses potent anti-inflammatory activity, and its mechanism of action could be through the inhibition of iNOS and COX-2 production, as well as NF-kappaB expression.

Dietary exposure to brominated flame retardants correlates with male blood levels in a selected group of Norwegians with a wide range of seafood consumption

Abstract: This study investigates dietary exposure and serum levels of polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD) in a group of Norwegians (n = 184) with a wide range of seafood consumption (4-455 g/day). Mean dietary exposure to Sum 5 PBDEs (1.5 ng/kg body weight/day) is among the highest reported. Since concentrations in foods were similar to those found elsewhere in Europe, this may be explained by high seafood consumption among Norwegians. Oily fish was the main dietary contributor both to Sum PBDEs and to the considerably lower HBCD intake (0.3 ng/kg body weight/day). Milk products appeared to contribute most to the BDE-209 intake (1.4 ng/kg body weight/day). BDE-209 and HBCD exposures are based on few food samples and need to be confirmed. Serum levels (mean Sum 7 PBDEs = 5.2 ng/g lipid) and congener patterns (BDE-47 > BDE-153 > BDE-99) were comparable with other European reports. Correlations between individual congeners were higher for the calculated dietary exposure than for serum levels. Further, significant but weak correlations were found between dietary exposure and serum levels for Sum PBDEs, BDE-47, and BDE-28 in males. This indicates that other sources in addition to diet need to be addressed.

Anti-obesity effects of conjugated linoleic acid, docosahexaenoic acid, and eicosapentaenoic acid.

Abstract: Obesity has become a prevailing epidemic throughout the globe. Effective therapies for obesity become attracting. Food components with beneficial effects on "weight loss" have caught increasing attentions. Conjugated linoleic acid (CLA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) belong to different families of polyunsaturated fatty acids (PUFA). However, they have similar effects on alleviating obesity and/or preventing from obesity. They influence the balance between energy intake and expenditure; and reduce body weight and/or fat deposition in animal models, but show little effect in healthy human subjects. They inhibit key enzymes responsible for lipid synthesis, such as fatty acid synthase and stearoyl-CoA desaturase-1, enhance lipid oxidation and thermogenesis, and prevent free fatty acids from entering adipocytes for lipogenesis. PUFA also exert suppressive effects on several key factors involved in adipocyte differentiation and fat storage. Despite their similar effects and shared mechanisms, they display differences in the regulation of lipid metabolism. Moreover, DHA and EPA exhibit "anti-obesity" effect as well as improving insulin sensitivity, while CLA induces insulin resistance and fatty liver in most cases. A deeper and more detailed investigation into the complex network of anti-obesity regulatory pathways by different PUFA will improve our understanding of the mechanisms of body weight control and reduce the prevalence of obesity.