Dietary flavonoids as potential neuroprotectants

There is an increasing awareness of the role of certain nutritional components, including dietary flavonoids found in fruit, vegetables and beverages, in the maintenance of health and prevention of chronic diseases. In this regard, recent studies highlight an exciting role with respect to their potential neuroprotective actions, in particular towards deficits commonly observed with aging, such as reduced performance of cognitive, memory and learning tasks. These neurological functions, and possible mechanisms involved in controlling them, can be influenced by supplementation of single dietary flavonoids, or as part of a flavonoid-rich preparation. With this, a renewed emphasis is aimed at further understanding their modes and sites of action. Moreover a common theme among many in vitro studies examining mechanisms of neuroprotection is the failure to include biologically relevant metabolites of the flavonoids known to enter the circulation, and thus most likely to be bioavailable to cells and tissues. This oversight will ultimately influence the mechanisms of action proposed to explain the neuroprotection observed in animals and human studies. As such, emerging findings suggest a variety of potential mechanisms of action of flavonoids and their bioavailable metabolites in cytoprotection against oxidative stress, which may be independent of conventional antioxidant reducing activities. Such mechanisms might involve their interaction with cell signalling cascades, their influence on gene expression and the down regulation of pathways leading to cell death.     

Absorption and metabolism of flavonoids

The benefits of flavonoids as chemopreventive dietary or dietary supplemental agents are still only "potential." Much has been learned about possible mechanisms of action of these agents, but whether they can reach their multiple intended sites of action, particularly in humans, is largely unknown. The biological fate of the flavonoids, including their dietary glycoside forms, is highly complex, dependent on a large number of processes. This review is intended to bring some order into this complex area and deals with the fate of the naturally occurring glycosides, their enzymatic hydrolysis, as well as the resulting aglycones. The impact of membrane transporters as well as metabolic enzymes on the cellular availability of these phytochemicals is examined. A reevaluation of the concept of oral bioavailability applied to the dietary flavonoids is presented.     

Dietary flavonoids and risk of coronary heart disease

Flavonoids, a group of phenolic compounds found naturally in fruit, vegetables, nuts, flowers, seeds and bark are an integral part of the human diet. They have been reported to exhibit a wide range of biological effects, including antiischemic, antiplatelet, antineoplastic, antiinflammatory, antiallergic, antilipoperoxidant or gastroprotective actions. Furthermore, flavonoids are potent antioxidants, free radical scavengers and metal chelators, and inhibit lipid peroxidation. Oxidative modification of low-density lipoproteins (LDLs) is believed to play a crucial role in atherogenesis. Epidemiological studies have shown that the consumption of fruits and vegetables, and regular red wine consumption is related with a reduced risk of cardiovascular diseases.     

Dietary fibre and mineral metabolism

Current dietary recommendations urge, inter alia, an increased consumption of fibre-containing foods. Some experimental studies made on various animals and man indicate that the associated increases in intakes of fibre and phytic acid may prejudice mineral status respecting calcium, magnesium, iron and zinc. An examination has been made of the experimental evidence, also of the epidemiological evidence on numerous types of populations, past and present, developing and developed. It has been concluded that diets high in fibre, characteristically do not have meaningful ill effects on well-being or unequivocally enhance morbidity. In particular populations in certain regions where deleterious effects have been reported it is judged that local factors, not wholly understood, are in operation. In assessing the extent of the benefit to be derived from the dietary changes urged, results must be viewed holistically and not in isolation. It is believed that the beneficial effects respecting reduced pronenesses to various degenerative diseases are likely to far outweigh the possible adverse effects of reduced bioavailability of mineral nutrients.     

Dietary PUFA and flavonoids as deterrents for environmental pollutants

Various nutrients and plant-derived phytochemicals are associated with a reduced risk of many diet-related chronic diseases including cardiovascular disease, cancer, diabetes, arthritis and osteoporosis. A common theme that links many chronic diseases is uncontrolled inflammation. The long-chain (LC) omega-3 polyunsaturated fatty acids (PUFA) and flavonoids are known to possess anti-inflammatory actions in cell cultures, animal models and humans. Minimizing the condition of persistent inflammation has been a primary aim for drug development, but understanding how food components attenuate this process is at the nexus for improving the human condition. The prevalence of environmental toxins such as heavy metals and organics that contribute to diminished levels of antioxidants likely aggravates inflammatory states when intakes of omega-3 PUFA and flavonoids are marginal. Scientists at Purdue University have formed a collaboration to better understand the metabolism and physiology of flavonoids. This new effort is focused on determining how candidate flavonoids and their metabolites affect gene targets of inflammation in cell culture and animal models. The challenge of this research is to understand how LC omega-3 PUFA and flavonoids affect the biology of inflammation. The goal is to determine how nutrients and phytochemicals attenuate chronic inflammation associated with a number of diet-related diseases that occur throughout the life cycle. The experimental approach involves molecular, biochemical and physiological endpoints of aging, cancer, obesity and musculoskeletal diseases. Examples include investigations on the combined effects of PUFA and cyanidins on inflammatory markers in cultures of human cancer cells. The actions of catechins and PUFA on muscle loss and osteopenia are being studied in a rodent model of disuse atrophy to explain how muscle and bone communicate to prevent tissue loss associated with injury, disease and aging. The purpose of this review is to introduce the concept for studying food components that influence inflammation and how LC omega-3 PUFA and flavonoids could be used therapeutically against inflammation that is mediated by environmental pollutants.     

Compartmental models for human iodine metabolism

Compartmental models for the various aspects of human iodine metabolism are reviewed, emphasizing the role of Mones Berman in the development of this field. The review first presents published submodels for the peripheral distribution of inorganic iodine, for the thyroidal iodide trapping function, and for the peripheral distribution and metabolism of the thyroid hormones. Approaches to improving understanding of the physiology of the thyroid gland itself through compartmental modeling techniques are then discussed in more detail. The three submodels described above are incorporated into overall models of thyroid iodine metabolism after being simplified to various degrees. Previously published models for thyroid-gland radioiodine metabolism, as well as current work in progress, are illustrated by attempting to fit the models to data from a single (previously unpublished) detailed prolonged ¹²⁵I feeding experiment in a normal human subject. Published thyroid gland models reviewed include: (1) the usual presentation, where the thyroid is a single homogeneous iodine compartment; (2) the model of DeGroot and colleagues, where thyroidal iodine is presented as MIT, DIT, T3, and T4, each with an active and linked storage compartment; (3) the thyroid model developed by Berman and colleagues, with less chemical subcategorization but incorporating a delay compartment, in which a fraction of the iodinated material in the thyroid is partially or completely inaccessible to secretion during the delay; and the later updating of Berman's model to include a thyroidal iodide recirculation pool. The experimental data presented fits most of these models for the first 1–2 weeks, but the fit could not be extended to longer data collection times. To overcome this shortcoming, a new thyroid gland model is introduced. It is based on the latest Berman model but describes thyroglobulin metabolism as incorporating multiple delay compartments of various time periods. The overall fit of the long term data is better with this model construct than with any of the published models. It appears that a complex thyroidal substructure, such as that of the multidelay model under development, will be required to account for overall thyroid iodine metabolism as isotopic equilibrium in man is approached.     

Pharmacokinetics and metabolism of dietary flavonoids in humans

Flavonoids are components of fruit and vegetables that may be beneficial in the prevention of disease such as cancer and cardiovascular diseases. Their beneficial effects will be dependent upon their uptake and disposition in tissues and cells. The metabolism and pharmacokinetics of flavonoids has been an area of active research in the last decade. To date, approximately 100 studies have reported the pharmacokinetics of individual flavonoids in healthy volunteers. The data indicate considerable differences among the different types of dietary flavonoids so that the most abundant flavonoids in the diet do not necessarily produce the highest concentration of flavonoids or their metabolites in vivo. Small intestinal absorption ranges from 0 to 60% of the dose and elimination half-lives (T_1/2) range from 2 to 28 h. Absorbed flavonoids undergo extensive first-pass Phase II metabolism in the small intestine epithelial cells and in the liver. Metabolites conjugated with methyl, glucuronate and sulfate groups are the predominant forms present in plasma. This review summarizes the key differences in absorption, metabolism and pharmacokinetics between the major flavonoids present in the diet. For each flavonoid, the specific metabolites that have been identified so far in vivo are indicated. These data should be considered in the design and interpretation of studies investigating the mechanisms and potential health effects of flavonoids.     

Perturbations of iodine metabolism by lithium

A kinetic study of the effects of lithium on iodine metabolism in hyperthyroidism is reviewed. The analysis, carried out in collaboration with Mones Berman, disclosed several unexpected findings. In addition to the inhibition of thyroid iodine release predicted by animal studies, an apparent decrease in extrathyroidal iodine disappearance was observed. This was confirmed by a direct study of the metabolic clearance of labeled thyroxine in hyperthyroid subjects. In euthyroid subjects, lithium did not alter thyroxine disappearance. Also unexpectedly, the lithium-induced perturbations did not promptly return to the control state after the serum lithium level had become undetectable. This suggested a delayed release of lithium from extravascular pools, a phenomenon later described in bone. These findings demonstrated the power of kinetic modeling when used as an analytical tool.     

Dietary subacute zinc deficiency and potassium metabolism

In a controlled animal experiment the effects of dietary subacute Zn deficiency on growth, Zn concentration, and tissue 42-K distribution were studied. Growth retardation caused lower body weight because both skeletal and heart muscle showed a reduction in cell mass. Zn concentrations were reduced in most tissues, however, they remained unaltered in heart muscle. 42-K activity increased in skeletal muscle and pancreas. We hypothesize the latter reflects the organs rate of metabolism, inducing the exocrine pancreas to increase Zn absorption; in skeletal muscle it may induce also alterations in cell potentiation, causing restless behavior. As suggested by the calculated specific K activity (Bq/mol), the K uptake was highest in liver and bone, high in pancreas and skeletal muscle and low in heart muscle. The latter suggests K retention in heart muscle. Specific activity in plasma and jejunum remained unaltered: K status and absorption seem unaffected. Zn deficiency causes different 42-K activities in the various tissues, that respond by alterations in K metabolism without the induction of K deficiency.     

Dietary exposure and risk assessment to trace elements and iodine in seaweeds

IntroductionSeaweeds are a rich source of elements such as iodine, and are also able to accumulate contaminants such as trace elements.MethodsThe aim of this study was to assess the dietary exposure as well as the risk from iodine and trace elements in edible seaweeds for the French population using current consumption data. The contribution of seaweeds to overall dietary exposure to trace elements and iodine was evaluated, and for those substances with minimal contribution to overall dietary exposure, simulations were performed to propose increased maximal limits in seaweeds.ResultsCadmium, inorganic arsenic and mercury in seaweeds were very low contributors to total dietary exposure to these contaminants (0.7 % 1.1 % and 0.1 % on average, respectively). Dietary exposure to lead via seaweed may contribute up to 3.1 % of total dietary exposure. Dietary consumption of iodine via seaweed may contribute up to 33 % of total exposure to iodine, which makes seaweeds the strongest contributor to iodine in diet.DiscussionNew maximal values in seaweeds are proposed for the very low contributors to total dietary exposure: 1 mg/kg dw for cadmium, 10 mg/kg dw for inorganic arsenic and 0.3 mg/kg dw for mercury.     

The intracellular metabolism of iodine in carcinogenesis

Research from this laboratory and others have concluded that significant glandular atypia, and often neoplasia, occurs in the breast tissues of rodents and humans under conditions of iodine deprivation. These cellular changes caused by iodine deficiency are intensified, by aging, steroid hormones, and pituitary hormones. There has been controversy concerning the effect of iodine deficiency on stimulation and maintenance of cancer of the breast in rodents when the cancer is induced chemically or by transplantation. However, neither within this induced neoplastic framework nor with the dysplastic changes seen by deficiency alone have laboratory studies of thepathway of intracellular iodine been previously possible. The new research data addresses the question of whether organification occurs and whether iodine significantly affects the intracellular structures. An hypothesis will be presented that places the inorganic element, iodine, into association with receptor protein complexes that may be responsible for intracellular sex hormone activity. The relationship of this mechanism to carcinogenesis in breast tissue will be considered.     

Forskolin stimulates adenylate cyclase and iodine metabolism in thyroid

Forskolin is a potent activator of the cyclic AMP-generating system in many tissues. In dog thyroid slices, the enhancement of cyclic AMP level was rapid, sustained in the presence of forskolin, but easily reversible after its withdrawal. Contrary to TSH, forskolin induced little apparent desensitization. Forskolin potentiated the effects of TSH, PGE1 and cholera toxin. However, the forskolin-induced cyclic AMP accumulation was still sensitive to inhibitors of dog thyroid adenylate cyclase such as iodide, norepinephrine and adenosine. As fluoride, but contrary to TSH and PGE1, forskolin stimulated adenylate cyclase in a medium where Mg2+ was replaced by Mn2+. This suggests that in thyroid, as in other tissues, forskolin acts beyond the receptor level but, as it potentiates hormone action and does not impair modulation by inhibitors, it may interact with the nucleotide-binding regulatory proteins. Forskolin mimicked the effect of TSH on iodide organification and secretion.     

Dietary fiber, lipid metabolism, and atherosclerosis

Despite the physiochemical complexity of dietary fibers (plant cell walls) and their individual components, there is substantial epidemiologic, clinical, and experimental evidence that these dietary components may have a role in modifying certain risk factors in coronary heart disease. Particulate fibers, such as wheat bran, do not appear to significantly alter plasma lipids or lipoprotein distributions in humans, or the atherogenicity of diets in experimental animals. Dietary fibers found in fruits, legumes, and vegetables, in contrast, show more definitive responses. Among the fiber isolates, the gelling and mucilaginous fibers, such as pectins and guar gum, predictably decrease circulating lipids in humans and animals and increase excretion of fecal metabolites of cholesterol, the bile acids. These fibers and fiber components can be shown to influence luminal solubility of lipids and the extent of lymphatic absorption of both cholesterol and triglyceride. In addition, these same fibers are effective in reducing postprandial levels of glucose, insulin, and other hormones. These direct effects on lipid absorption, and secondary effects of glucose and insulin on hepatic and peripheral lipoprotein metabolism, can account for many of the hypolipidemic responses to specific dietary fibers or their components, and may be of long-term consequence in coronary heart disease.