Polyphenol supplement research study, health benefit
October 20 2017

Polyphenols are a large family of natural compounds widely distributed in plant foods. Daily consumption in the US ranges from 200 mg to 1 gram. Green tea polyphenols and those from wine have attracted a great deal of media attention. While dietary anti-oxidants, such as vitamins E and C, have received considerable attention, less is known about a similar anti-oxidant role for plant-derived flavonoids and phenolic acids.
   Important dietary sources in Western societies are onions (flavonols); Cacao (proanthocyanidins); tea, apples, and red wine (flavonols and catechins); citrus fruit (flavanones); berries and cherries (anthocyanidins); and soy (isoflavones).

Expert Opin Investig Drugs. 2013. Natural polyphenols in the management of major depression. Natural polyphenols, the non-essential micronutrients, found in array of plant products, are known to affect various physiological and biochemical functions in the body. Studies have shown the protective effect in different neurological and mental disorders. They modulate monoaminergic neurotransmission in the brain and thus possess antidepressant-like activity at least in animal models of depression.

They can be classified into the following categories:
Polyphenols occur in all plant foods and contribute to the beneficial health effects of vegetables and fruit. Their contribution to the antioxidant capacity of the human diet is much larger than that of vitamins. The total intake in a person's diet could amount to 1 gram a day, whereas combined intakes of beta-carotene, vitamin C, and vitamin E from food most often  is about 100 mg a day.
   Phenolic acids account for about one third of the total intake of polyphenols in our diet, and flavonoids account for the remaining two thirds.

Phenolic acids are simple molecules such as caffeic acid, vanillin, and courmaric acid. Phenolic acids form a diverse group that includes the widely distributed hydroxybenzoic and hydroxycinnamic acids. Phenolic acid compounds seem to be universally distributed in plants. They have been the subject of a great number of chemical, biological, agricultural, and medical studies. Hydroxycinnamic acid compounds (p-coumaric, caffeic acid, ferulic acid) occur most frequently as simple esters with hydroxy carboxylic acids or glucose, while the hydroxybenzoic acid compounds (p-hydroxybenzoic, gallic acid, ellagic acid) are present mainly in the form of glucosides. Ellagic acid is found in
Pomegranate. Furthermore, phenolic acids may occur in food plants as esters or glycosides conjugated with other natural compounds such as flavonoids, alcohols, hydroxyfatty acids, sterols, and glucosides. Coffee is particularly rich in bound phenolic acids, such as caffeic acid, ferulic acid, and p-coumaric acid. Phenolic acids found in blueberries include gallic acid, p-hydroxybenzoic acid, coffeic acid, p-coumaric acid and vanillic acid.   

Flavonoids -- Flavonoids are a subclass of polyphenols. Flavonoids are widely distributed in nature, albeit not uniformly. As a result, specific groups of foods are often rich sources of one or more subclasses of these polyphenols. The polyphenolic structure of flavonoids and tannins renders them quite sensitive to oxidative enzymes and cooking conditions.
       Anthocyanins and anthocyanidins are a large water-soluble pigment group found in a large number of fruits, vegetables and flowers. particularly grapes, grape seed extract
, and berries. These pigments give plants their brilliant colors ranging from pink through scarlet, purple and blue. Bilberry and other berries have a high concentration of anthocyanins. Scientists have identified more than 500 different anthocyanins including cyanidin, pelargonidin, delphinidin, malvidin, and paeonidin.
       Catechins or Flavanols -- are found found in tea.
Grape seeds have the monomeric flavan-3-ols catechin, epicatechin, gallocatechin, epigallocatechin, and epicatechin 3-O-gallate. Research shows that the cocoa bean is rich in specific antioxidants, with the basic structure of catechins and epicatechin, and especially the polymers procyanidins,
       Flavanols -- catechin and epicatechin
       Flavones -- Apigenin, Luteolin. The herb
Chamomile has a good amount of apigenin.
       Flavonols --  are
found at high concentrations in onions, apples, red wine, broccoli, tea, and Ginkgo-Biloba. The most common in the American diet are Quercetin, Kaempferol, and Myricetin. Flavonols also include fisetin, isoquercitrin and hyperoside.
       Flavanones -- Hesperidin and Naringin
       Isoflavones -- Genistein, Daidzein are found in soy and
have an influence on bone health among postmenopausal women, together with some weak hormonal effects. Isoflavones are selectively incorporated in certain tissues like the breast and ovaries. They are able to bind to the estrogen receptors alpha (ER-alpha) and beta (ER-beta). However, the binding affinity for Genistein to ER-alpha is only 4%, the affinity to ER-beta is 87% compared to 17beta-estradiol. Thus, depending on the estradiol concentration, they exhibit weak estrogenic or antiestrogenic activity. Isoflavones can influence transcription and cell proliferation. They modulate enzyme activities as well as signal transduction, and have antioxidant properties. Epidemiological studies have shown that the prevalence of hot flashes is lower in women from countries with high dietary isoflavone intake such as Japan than in Western nations with low isoflavone intake. Isoflavones are colorless.
       Lignans found in nuts and whole grain cereals.
Flaxseed has a high content of lignan.
are found in grapes (for instance grape seeds), red wine, and pine bark. Pycnogenol is a pine bark extract. Grape seed extract provides a concentrated source of polyphenols, many of which are proanthocyanidins. Proanthocyanidins share common properties with other polyphenols, in particular their reducing capacity and ability to chelate metal ions. However, their polymeric nature clearly makes them different. They have a high affinity for proteins and their absorption through the gut barrier is likely limited to the molecules of low polymerization degree and to the metabolites formed by the colonic microflora.
       Procyanidins (oligomeric catechins found at high concentrations in red wine, grapes and grape seeds, cocoa, Cranberry, apples, and some supplements such as Pycnogenol) have pronounced effects on the vascular system. Apples contain many kinds of polyphenols, and the main components are oligomeric procyanidins. Applephenon is apple polyphenol extract produced commercially from unripe apples, and has been used as food additive in order to prevent oxidation of components in foods.
       Stilbenes - Resveratrol is an exciting polyphenol which has been in the news a great deal for potential anti-cancer and anti-aging benefits. Resveratrol supplements are available for sale.
       Tannins  are found in red wine, tea, and nuts. They are large molecules.
Many flavonoids in foods also occur as large molecules (tannins). These include condensed tannins (proanthocyanidins), derived tannins and hydrolysable tannins.

Gallic acid and isoflavones are the most well-absorbed polyphenols, followed by catechins, flavanones, and quercetin glucosides. The least well-absorbed polyphenols are the proanthocyanidins, the galloylated tea catechins, and the anthocyanins. Data are still too limited for assessment of hydroxycinnamic acids and other polyphenols.

Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies.
Am J Clin Nutr. 2005.
Isoflavones (genistein and daidzein, found in soy) have significant effects on bone health among postmenopausal women, together with some weak hormonal effects. Monomeric catechins (found at especially high concentrations in tea) have effects on plasma antioxidant biomarkers and energy metabolism. Procyanidins (oligomeric catechins found at high concentrations in red wine, grapes, cocoa, cranberries, apples, and some supplements such as Pycnogenol) have pronounced effects on the vascular system, including but not limited to plasma antioxidant activity. Quercetin (the main representative of the flavonol class, found at high concentrations in onions, apples, red wine, broccoli, tea, and Ginkgo biloba) influences some carcinogenesis markers and has small effects on plasma antioxidant biomarkers in vivo, although some studies failed to find this effect. Compared with the effects of polyphenols in vitro, the effects in vivo, although significant, are more limited. The reasons for this are 1) lack of validated in vivo biomarkers, especially in the area of carcinogenesis; 2) lack of long-term studies; and 3) lack of understanding or consideration of bioavailability in the in vitro studies, which are subsequently used for the design of in vivo experiments. It is time to rethink the design of in vitro and in vivo studies, so that these issues are carefully considered. The length of human intervention studies should be increased, to more closely reflect the long-term dietary consumption of polyphenols.

J Nutr Biochem. 2013. Benefits of polyphenols on gut microbiota and implications in human health. The biological properties of dietary polyphenols are greatly dependent on their bioavailability that, in turn, is largely influenced by their degree of polymerization. The gut microbiota play a key role in modulating the production, bioavailability and, thus, the biological activities of phenolic metabolites, particularly after the intake of food containing high-molecular-weight polyphenols. In addition, evidence is emerging on the activity of dietary polyphenols on the modulation of the colonic microbial population composition or activity.

Polyphenols in the diet
Dietary polyphenols show a great diversity of structures, ranging from rather simple molecules (monomers and oligomers) to polymers. Higher-molecular-weight structures (with molecular weights of > 500) are usually designated as tannins, which refers to their ability to interact with proteins. Among them, condensed tannins (proanthocyanidins) are particularly important because of their wide distribution in plants and their contributions to major food qualities. There are a number of foods that have high polyphenol content, including my favorite, cacao.

Polyphenols in wine
Red wine has anthocyanosides, catechins, proanthocyanidins, stilbenes and other phenolics.

Several studies have shown that a group of polyphenol antioxidant compounds found in grapes, green tea, soybeans and wine may lower the risk of a range of cancers, but exactly how these powerful compounds work has remained unclear.

Now, researchers report that plant-derived polyphenols can slow the growth of cancer cells in mice and curb the spread of cells by triggering a series or reactions that causes the cells to self-destruct, a process known as apoptosis.

Pycnogenol is a patented product obtained from the bark of French maritime pine. The primary ingredients are phenolic compounds such as catechin, epicatechin, and taxifoin, as well as flavonoids including procyanidins and proanthocyanidins.

Potential benefits
Polyphenols are the most abundant antioxidants in the human diet and are widespread constituents of fruits and beverages, such as tea, coffee, and wine. Epidemiological, clinical, and animal studies support their role in the prevention of various chronic diseases. For a long time, their direct antioxidant effect has been reported as the mechanism responsible for the observed health properties. However, recent findings revealed that they could interact with cellular signaling cascades regulating the activity of transcription factors and consequently affecting the expression of genes. They have been shown to affect the expression of microRNAs (miRNA). miRNAs are small, noncoding RNAs implicated in the regulation of gene expression that control both physiological and pathological processes such as development and cancer.

Most have anti-inflammatory properties.

Extracts from onion and various flavonoids induce the cellular antioxidant system. Onion extract and quercetin were able to increase the intracellular concentration of glutathione by approximately 50%. Polyphenols may be helpful in diabetic retinopathy.
Heart -- A high intake of polyphenols is likely to have beneficial effects on the cardiovascular system. Vasodilation and nitric oxide production--Diets rich in either red wine, quercetin or catechin induce endothelium-dependent vasorelaxation in rat aorta in a resting state through the enhancement of (*)NO production, without modifying O(2)(.-) generation, thus the bioavailability of (*)NO was increased. The increase in the (*)NO-cyclic GMP pathway explains the beneficial effect of flavonoids at vascular level.

Comprehensive study on vitamin C equivalent antioxidant capacity (VCEAC) of various polyphenols in scavenging a free radical and its structural relationship.
Crit Rev Food Sci Nutr. 2004.
Department of Food Science and Technology, Cornell University, Geneva, New York
Antioxidant capacity for a wide range of natural or synthetic polyphenols was comprehensively evaluated by vitamin C equivalent antioxidant capacity assay. The polyphenols tested are grouped into the following categories: vitamins (beta-carotene, alpha-tocopherol, vitamin A, and vitamin C), phenolic acids (benzoic acid, phenylacetic acid, cinnamic acid, and their derivatives), flavonoids (anthocyanidin, flavanol, chalcone, flavanone, flavone, flavonol, isoflavone, and their derivatives), synthetic food additives (BHA, BHT, TBHQ, and PG), and other miscellaneous polyphenols (ellagic acid, sesamol, eugenol, thymol.). A positive linear relationship between VCEAC and the number of free OH groups around the flavonoid framework was found, whereas, for phenolic acids, the linear relationship was not as good as with the flavonoid aglycones. Groups of chemicals having comparable structures generally showed similar trends. Polyphenols commonly showed a higher VCEAC compared to monophenolics. Compounds like gallic acid with 3 vicinal hydroxy substitutions on the aromatic ring in phenolic acids or like epigallocatechin with 3 vicinal hydroxy substitutions on the B ring in flavonoids showed the highest antioxidant capcity among the groups. In the flavonoids, 2 characteristic chemical structures were very important, the catechol moiety in the B ring and the 3-OH functional group in a chroman ring. Glycosylated flavonoids showed less potent antioxidant capacity than their aglycone alone. Synthetic antioxidant food additives (BHA, TBHQ, and BHT) conventionally used in the food industry were less effective antioxidants than ascorbic acid. Other naturally occurring polyphenols tested followed the expected general trends of phenolic acids and flavonoids.

Cancer prevention, anti-tumor -- most have anti-carcinogenicity properties
Inhibition of carcinogenesis by polyphenols: evidence from laboratory investigations.
Am J Clin Nutr. 2005.
Many plant polyphenolic compounds have been shown to have cancer-preventing activities in laboratory studies. For example, tea and tea preparations have been shown to inhibit tumorigenesis in a variety of animal models of carcinogenesis, involving organ sites such as the skin, lungs, oral cavity, esophagus, stomach, liver, pancreas, small intestine, colon, and prostate. In some of these models, inhibitory activity was demonstrated when tea was administered during the initiation, promotion, or progression stage of carcinogenesis. The cancer-preventing activities of these and other polyphenols, such as curcumin, genistein, and quercetin, are reviewed.

Diabetes and high blood sugar
A diet rich in plant polyphenols lowers blood sugar.

Heart disease and heart health
Cardiovascular diseases, type 2 diabetes, and their associated risk factors including metabolic syndrome and obesity, are the leading causes of death worldwide. Plant foods are rich sources of different groups of bioactive compounds, polyphenols, caffeine and plant sterols, which might not be essential throughout life but promote health and well-being by reducing the risk of age-related chronic diseases.

A blend of polyphenols explains the stimulatory effect of red wine on human endothelial NO synthase.
Nitric Oxide. 2005.
Red wine is a rich source of polyphenols which upregulate eNOS, a protective enzyme in the cardiovascular system. The increase in eNOS in response to red wine involves several polyphenolic compounds with a major contribution from trans-resveratrol and lesser contributions from cinnamic and hydroxycinnamic acids, cyanidin, and some phenolic acids.

Immune system
Most have anti-microbial activity.

Osteoporosis, bone strength
Antioxidants (Basel). 2014. Dietary Polyphenols, Berries, and Age-Related Bone Loss: A Review Based on Human, Animal, and Cell Studies. Natural antioxidant supplementation has been researched to aid in reducing bone loss caused by oxidative stress. Naturally occurring polyphenols, such as anthocyanins rich in berries, are known to have anti-oxidative properties. Several studies have been reviewed to determine the impact polyphenol intake-particularly that of berries-has on bone health. Studies reveal a positive association of high berry intake and higher bone mass, implicating berries as possible inexpensive alternatives in reducing the risk of age related bone loss.

Weight loss, thermogenesis
Adv Nutr. 2017. Dietary Polyphenols, Brown Adipose Tissue Activation, and Energy Expenditure: A Narrative Review. This review critically discusses the evidence supporting the concept that the antiobesity effects ascribed to polyphenols might be dependent on their capacity to promote energy dissipation by activating brown adipose tissue. Most in vivo studies with rodents strongly support the role of some polyphenol classes, particularly flavan-3-ols and resveratrol, in promoting energy expenditure. Some human data currently are available and most are consistent with studies in rodents.

At this time I believe enough research has been accumulated to begin taking advantage of these fascinating compounds in clinical use. A number of medical conditions could be prevented or improved with the use of polyphenols. These include circulatory disorders such as hypertension and coronary artery disease, lung disorders such as asthma, cancers of various types, inflammatory conditions, certain liver conditions, diabetes, mood disorders, eye disorders such as cataracts, weak eyesight due to aging, and macular degeneration. We should consider polyphenols as compounds necessary for the various organs and tissues, and part of the countless substances necessary for proper functioning of this amazing organism we call the human body.

Can you comment on an article I read recently about the French Paradox: "Scientists call it the "French paradox" — a society that, despite consuming food high in cholesterol and saturated fats, has long had low death rates from heart disease. Research has suggested it is the red wine consumed with all that fatty food that may be beneficial — and not only for cardiovascular health but in warding off certain tumors and even Alzheimer's disease. Now, Alzheimer's researchers at UCLA, in collaboration with Mt. Sinai School of Medicine in New York , have discovered how red wine may reduce the incidence of the disease. Reporting in the Nov. 21 issue of the Journal of Biological Chemistry, David Teplow, a UCLA professor of neurology, and colleagues show how naturally occurring compounds in red wine called polyphenols block the formation of proteins that build the toxic plaques thought to destroy brain cells, and further, how they reduce the toxicity of existing plaques, thus reducing cognitive deterioration. Past research has suggested that such polyphenols may inhibit or prevent the buildup of toxic fibers composed primarily of two proteins — Aß40 and Aß42 — that deposit in the brain and form the plaques which have long been associated with Alzheimer's. Until now, however, no one understood the mechanics of how polyphenols worked."
    It is possible that the consumption of red wine reduces the risk for certain diseases, but one should also compare the average weight of a French person versus the average weight of an American. Is the higher rate of caloric consumption and obesity in the USA the primary reason for the higher incidence of a number of chronic diseases?

I know there are several different types of polyphenols, but when one is considering a supplement, is there one type that is better than another? Is it dangerous to take different kinds of simultaneously? For example, is ingesting bilberry, grapeseed, and apple all at the same time just redundant, or does each type of polyphenol provide a specific benefit? Also, in regard to those in apple, I have read various articles about the benefits, but apple supplements seem to be scarce in comparison with the other ones. Is there a reason? And what would be a healthy dose?
   Apple consumption is common in the US so there is little reason to supplement with a capsule. They all have different health properties and as long as intake is not excessively excessive, many of them can be combined.