Natural polyphenols: An overview

ABSTRACT

Plant-derived functional foods are gaining considerable attention due to their safety and therapeutic potentials. Research on plant-based functional foods presents several challenges ranges from hypercholesterolemia to cancer prevention. In last decade, special attention has been paid to edible plants and especially their phytochemicals. Today, there is an increasing interest in their bioactivities provided by these phytochemicals. Polyphenols are the most numerous and widely distributed group of bioactive molecules. Polyphenols have two general classes, one is flavonoids and other is phenolic acids. Among these, flavonoids are further divided into flavones, flavononse, flavonols, flavanols, isoflavones, and phenolic acids are generally classified into hydroxybenzoic and hydroxycinnamic acids. Fruit peel is one of the dense sources for flavonoids and their content may vary from species to species and due to exposure of light. Polyphenols have wide range of molecules and different set of biological activities that are mainly attributed to their structure. Investigations have revealed that polyphenols play a key role to prevent various diseases, like hypercholesterolemia, hyperglycemia, hyperlipidemia, and cancer insurgence. The current review article summarizes the literature pertaining to polyphenols and its allied health benefits.

KEYWORDS:

• Polyphenols
• Flavonoids
• Health benefits
• Functional foods
• Bioactive molecules

Introduction

Plant-based foods naturally contain polyphenols; these compounds have wide range of complex structures. The basic monomer in polyphenols is phenolic ring and generally these are classified as phenolic acids and phenolic alcohols. Depending upon the strength of phenolic ring, polyphenols can be classified in many classes, but the main classes in the polyphenols are phenolic acids, flavonoids, stiblins, phenolic alcohols, and lignans. Bioactive compounds are the phytochemicals involved in protection of human health against the chronic degenerative ailments. Polyphenols are the group of biologically active compounds in plant-based foods.^[1] These compounds are embedded in human diet and originate from plants like fruits, vegetables, cereals, and coffee. Polyphenols are also known as a preventive for the degenerative diseases. Investigations on polyphenols delayed due their particular characteristic, structural complexity. Most frequent antioxidants in our diet are polyphenols. These hinder the oxidative change in low density lipoprotein, and this is the basic mechanism in endothelial lesions taking place in atherosclerosis.^[2–4] Explorations witnessed the role of polyphenols in remedy of cardiovascular disease, osteoporosis, neurogenerative disease, cancer, and diabetes mellitus.^[2,3]

Figure 1. General structures of flavonoids.^[2]

Figure 2. General structural formulae of phenolic acids.^[2]

Figure 3. Most common derivatives of flavonoids with basic structures.^[9]

Figure 4. Chemical structures of some phenolic compounds commonly found in fruits and coffee.^[3]

Numerous fruits and vegetables contain phenolic acids as a key polyphenols like kale, onions, and broccoli.^[1] Fruits like pomegranate juice, tea extracts, and extracts of grapes had been witnessed with reduced atherosclerotic lesions. The protective role of polyphenols in health and disease are well-recognized in the food; consumed on a daily basis, and rich in antioxidants and phytochemicals.^[5] Additionally, polyphenols demonstrate the pro-oxidant property, which is against the metabolic process of cell. It may involve the block cell propagation and apoptosis as well.^[2,6] Studies also showed that many other effects of polyphenols had been observed, e.g., the reductions of enzymes like lipoxygenase and telomerase.

Classification and chemistry of polyphenols

Hydroxycinnamic and hydroxybenzoic acids are the two classes of phenolic acids. Hydroxybenzoic acids contributing to human diet are rare, and this is the reason that such compounds are not suggested to play a role in human health. Derivatives of cinnamic acid and benzoic acid have backbones of C₁-C₆ and C₃-C₆, respectively. Some phenolic acids are found in free form in vegetables and fruits, but hull, bran, and seed contains phenolic acids that in bound form.^[7,8] Bounded phenolic acids are released by acid, alkali, and enzyme hydrolysis from bran, hull, and seed. Low contents of these acids are available in plant-based foods irrespective of blackberries that contain <270 mg/kg of fresh weight, and some other red fruits as well.

Flavonoids are built of two benzene rings that may be connected with three carbon chain from the nearby pyran ring. Further, six classes of flavonoids differ from others, primarily on the bases of oxidation state of central carbon, these classes include flavanones, flavanols, flavonols, isofalvons, flavons, and anthocyanidins. Additionally, more than 4000 flavonoids have been identified from plant sources. Flavonols, a double bond had been seen with between C₃ and C₂, and a hydroxyl group is attached at C₃. Most of the flavonoids in different sources of food are flavonols. Onions are the main supply for these compounds; broccoli and leeks also contain such polyphenols.

The general backbone structure of flavonoids is C₆-C₃-C₆, and it contains two units of phenolic nature (C₆). Flavonoles, flavones, flavanones, and anthocyanadins are the sub-classes of flavonoids on the bases of hydroxylation configuration. Most flavonoids have structure in which C₂ of C ring is attached with B ring, but C₃ and C₄ attachments are also found. Chalcones are considered as the part of flavonoid family even they have no C ring, and apples and hops are the source for chalcones. Glycones are these fundamental structures, and plants contain such structures as glycosides.

Ring C is attached from its C₃ edge with B ring in isoflavones. Legumes are also abundant source of such compounds. Isoflavones demonstrate superior effect on health, where the soybean is the major supply for food. Two major isoflavones found in soy are; daidzein and genistein along with glycetein.^[9–11] Red clovers are also source for such compounds. 7-O-glucosides and 6”-O-malonyl-7-O-glucosides are the most abundant forms of isoflavone-aglycones. The prime neo-flavonoid embedded in plant-based foods is dalbergin.^[12]

Fruit coverings are dense in flavonols, because their production is activated by the light. The flavonol contents vary in fruits on the same plant, and even on the same piece of fruit, this is due to the light exposure to their different edges.^[2] Flavanols are found in mono, as well as poly molecules. These flavonoids are not found in glycosylated form in the human diet, regardless of other classes of flavonoids, e.g., flavons, flavonons. Catechins and epicatechins are core ambassador of this class.^[2,10] Flavones are relatively less frequent flavonoids; a double bond is present in between C₃ and C₂. Flavones are found abundantly in the fruit peel or skin. Mandarin essential oil contains 6.5 g/L of flavones.

Flavonones contain an oxygen molecule at C₄, and these flavonones are characterized by saturated three carbon ring. Citrus fruits are recognized as the main source of flavanones, but aromatic plants also contain such compounds. Oranges contain hesperidin and lemons contain eriodictyol. Hesperidin content in citrus fluids is 470–761 mg/L.^[13] Flavonones are found in rigid part of fruits and coverings; their content in whole foods is five times more than juices. Isoflavones, the array of these compounds is likely to estrogens, the presence of –OH in between C₄ and C₇ is similar to estradiol. These compounds are entitled as phytoestrogens due to their esterogen receptor binding property.

The main commodity to get isoflavones is soy and its products, particularly glycitein and geinstein are present, found in aglycones form or sometimes conjugated with glucose monomer. Fresh soy contains up to 1530 and 130 mg/L in soy milk.^[9] These are temperature responsive and converted to glycosides on exposure to heat, like soy milk.^[2,14] Anthocyanins are hydrophilic colorants, vegetables and fruits exhibit red or blue color because of these pigments. Anthocyanins are found primarily in anthocyanidins form and a moiety of sugar at C₃ or at 5, 7-position of A-ring, fruit covering is the major source for anthocyanins.

Bioavailability

Polyphenols depend, primarily, upon their bioavailability to express their biological properties. Their limit and speed of absorption in intestines is decided by their chemical structure. Green tea contains catechins with high bioavailability, and citrus fruits are a rich source of flavanones.^[15] When the concentrations of phenolic compounds are measured from plasma and urine, the antioxidant potential of plasma, after ingestion of a polyphenol rich food, provides the evidence needed for quantifying the absorption of such compounds in the intestines.^[16] The plasma content gradually decreases when a number of flavonoids are absorbed into the intestines. Plasma albumin has a high affinity, this is the reason that quercetin has a relatively higher elimination half-life. Flavones, isoflavones, flavonols, and anthocyanins are frequently glycosylated.^[17] The glucose and rhamnose are chemically linked and sometimes xylose, glucronic acid, and glactose are as well.

Polyphenols generally contain one sugar but may have two or three, and substitutions of a wide range for sugars. The malonic acid group can also be substituted by sugars. Chemical, physical, and biological attributes of polyphenols are decided by glycosylation and this is the reason for the difference in hydrophilic property of quercetin and quercetin-3-O-rhamnoglucoside. Gastrointestinal mucosa and colon micro flora are the sites where the activity of glycosidase can occur, and sparingly, its activity can be endogenous, occurring in food itself. β-glucosidases are sometimes secreted by human cells, and particularly the tissue-specific model of expression is usually regulated while the development is being done. When xylose or glucose is attached with polyphenols, these are the latent substrates for individual cells.

Microflora-rhamnosidases are the only source to cut the polyphenol attached with rhamnose because it cannot be cloven by human β-glucosidases. Epicatichins are mostly acylated with acids like gallic acid. The partition coefficient is not significantly changed by galloyl substitution of flavanols, and bioavailability is not affected like that of glycosylation. Irrespective of hydrolysis, flavanols are absorbed while passing through the biological membranes.^[18] Sugars, lipids, and organic acids are generally esterified with caffeic acid. When quinic acid is esterified with caffeic acid, they form chlorogenic acid which is found in significant amounts in coffee. Chlorogenic acid cannot be cloven by esterases present in human tissues and caffeic acid cannot release from chlorogenic acid. The only site where chlorogenic acid can be metabolized is within the colon microflora.

Furthermost, polyphenols pass through the small intestine without being absorbed, thus manipulating the intestinal microbiota that colonize there. Two-dimensional reactions take places due to these passing polyphenols.^[20] First, polyphenols are biologically transformed into their relatively more bioavailable metabolites. And second, polyphenols modify the configuration of the gut microbial community most likely by the inhibition of pathogenic bacteria and the stimulation of beneficial bacteria. In the latter, these may act as a prebiotic metabolite and enrich the beneficial bacteria. Therefore, the interactions of dietary polyphenols and gut microbiota may result in impact on human host health.^[21]

Polyphenols and cardiovascular disease

A key factor for mortality in developed countries are strokes and coronary heart disease.^[19] The initiation, propagation, and development of cardiovascular disease are driven by environmental and genetic factors. The features involved in prevalence of cardiovascular disease are physical activity, smoking, saturated fat intake, etc.^[20,21] It is hard to find the single factor in this complex group that is responsible for such diseases. A wide range of epidemiological studies and human trials have demonstrated that a diet dense in polyphenols, like tea, vegetables, fruits, and cocoa, has a higher chance of cardiac safety.^[22,23] An inverse correlation had been found in coronary disease and consumption of flavanols, flavonols, and flavones.^[24] Deaths rate related to cardiovascular disease were reduced with ingestion of flavanones and anthocyanins.^[23] There was an 11% reduction in the risk of cardiovascular disease demonstrated by having 3 cups tea per day.^[25]

A dispute still remains on which polyphenols are more efficient in reference to cardiovascular disease. Flavonoids found in cocoa and soy present favorable outcomes on cardiovascular disease,^[26] and others are not as efficient.^[27,28] The antioxidant potential of polyphenols is related to the cardio-protective properties of such compounds; because reduced blood pressure,^[29,30] with improved function of endothelial tissues,^[31,32] and the aggregation of platelets is inhibited^[33] by the reduction in oxidation of low density lipoprotein^[34] and by lowering the response of inflammation.^[35] A diet rich in flavanol containing cocoa reduces the incidence of cardiovascular disease, hypertension,^[36] and lowers the blood pressure.^[30,37] Reports revealed that increasing the frequency of drinking of black tea lowers the risk of high blood pressure.^[38] The short span of tea consumption did not demonstrate a significant impact on the reduction of blood pressure.^[39,40] Purple grapes, tea, and cocoa exert beneficial effects on cardiac health.^[41,42]

A mechanism of action for the cardiac health benefits of polyphenols includes the ability to amend the activity of an enzyme, nitric oxide synthase and its level, and the bioavailability of nitric oxide for endothelium.^[43,44] Investigations revealed that endothelium-dependent relaxation has been seen by consumption of polyphenols.^[45,46] Coffee, cocoa, black tea, and purple grape juice are all associated with the chronic or acute inhibition of platelet aggregation and activation.^[47] Vascular injury, related to age, may be prevented by flavanols and flavonols.^[48]

Polyphenols and cancer

Cancer is related to a group of diseases associated with an alteration in the control of cell growth and metabolism.^[49] In fact, control of the imbalanced cell proliferation is a primary feature of the cancerous cells, any molecule which is able to inhibit the proliferation of cancerous cells could be used as chemo preventive agent.^[50] There are many different types of cancer, for example, breast (predominantly in women), lung, colorectal, and prostate, they account for over half of all the newly diagnosed cases. There is a broad consensus that a high level daily intake of fruits and vegetables will help to prevent the occurrence and progression of cancer. In last 20 years, the case-control studies have shown that the regular consumption of fruits and vegetables have an inverse relationship with the progression of several types of cancer, including prostate and colorectal cancer.^[51,52]

More recently, data from large group studies have also confirmed these epidemiological associations.^[53,54] Yet, there is a contradiction between some studies that reported no-reduction in bladder, pancreas, and stomach cancers, and the incidence of cancer due to consumption of fruits and vegetables,^[55,56] but now a recent epidemiological study has proven that no, or very little, relationship is present between fruit and vegetable consumption and overall cancer risk.^[57,58] However, there is a possibility in many fruits and vegetables with some polyphenols and other bioactive compounds with potential and protective effects against the development of cancer, particularly in the gastrointestinal tract where they will be in stronger concentrations. In fact, many studies have shown that different fruits and vegetables rich in polyphenols and bioactive compounds are particularly effective in protecting against the development of colon cancer.^[59]

There is strong enough evidence that polyphenols and bioactive compounds found in tea, red wine, cocoa, fruits, fruit juices, and olive oil influence the carcinogenesis and tumor development at the cellular level.^[57] For example, they can interact with nutrients, reactive metabolites, activated carcinogens, and mutagens.^[60] It also can modulate the activity of key proteins involved in the control of cell cycle progression^[61] and influence the expression of many genes associated with cancer.^[62] Green tea flavanols reported in animal models have great effects and anti-cancer properties^[63] on human cell lines^[64] and in human intervention studies.^[65] Furthermore, green tea consumption has been proposed to greatly reduce the cancer risk of the bile duct,^[66] bladder,^[67] breast,^[68] and colon.^[50]

Many anticancer properties combined with green tea are believed to be mediated by the flavanol, epigallocatechin gallate (EGCG), which has been shown to induce apoptosis and inhibit cancer cell growth by changing the expression of proteins signaling, cell cycle regulatory proteins and activity involved in cell growth, transformation, and metastasis.^[69] In addition to flavonoids, phenolic alcohols, lignans, and secoiridoides are present in high concentrations of olive oil. It is also believed to induce anticancer effects^[70] and has been reported in models of the large cells intestinal cancer in animals^[71,72] and humans.^[70] These effects may be intervened by the attitude of phenolic compounds in olive oil, inhibition of the initiation, promotion, and metastasis in cells of human colon adenocarcinoma^[73,74] and down regulation of expression of cyclooxygenase-2 (COX-2, an enzyme) protein and Bcl-2 plays a crucial role in colorectal carcinogenesis.^[75]

These polyphenols have potential to exert anticancer effects through a large variety of mechanisms, including withdrawal^[61,70] of cancer cell signaling carcinogenic agents^[69,76] and cell cycle progression,^[77,78] promotion, apoptosis, and modulation of enzymatic activities.^[79] For example, the improvement of glutathione peroxidase, catalase, nicotinamide adenine dinucleotide phosphate (NADPH), quinone oxidoreductase, glutathione-S-transferase, and/or activity of the P450 enzyme, polyphenol can help detoxifying carcinogens^[80] and may also modulate the activity of signaling pathways^[81,82] that are involved in proliferation of cancer cells.^[83,84] Mitogen-activated protein kinases (MAPK) signaling pathway is considered as an attractive pathway for anticancer therapies in accordance with its central role in regulating cell growth and survival of a wide range of^[85] human cancers, and it plays an important role in the transcriptional and post-transcriptional activation of COX-2.^[86]

Anti-diabetic activity of polyphenols

A complex disorder accompanied by the resistance development of insulin, malfunctioning of β-cells, reduced signaling of insulin, irregular fat and glucose metabolism, and upgraded oxidative stress is medically well-recognized as diabetes type 2. All of the previous disorders lead toward diseased situations that involve neuropathy, nephropathy, macro and micro vascular impediments, retinopathy, and increase death rate and life quality.^[87] Diet is the key factor that can be modified to suppress the incidence of degenerative diseases like diabetes mellitus. Low risk of diabetes and its factors had been seen in epidemiological studies related to diet rich in high total antioxidant capacity, phytochemicals with high content and high phenolic content. Pathology studies have witnessed that many pharmacological interventions are involved in management of diabetes and diet preventions to improve the glycemic index.^[88] Diabetes may be remedied and treated with polyphenols due to their biological properties.

Glycemic control can be enhanced by following four mechanisms, first, the prevention of glucose induced toxicity and oxidative stress to protect pancreatic β-cells. Second, the inhibition of absorption and digestion of starch, and third, the reduction of glucose release from the liver and finally the enhancement of glucose endorsement in muscles and other peripheral tissues.^[89] Malfunctioning and decrease in number of β-cells are the indictors of diabetes before its occurrence. Polyphenols intake and maintenance of insulin secretion from β-cells in a culture has been seen in many investigations. A high intake of phenolic contents has also been seen with the protection from oxidative damage induced by increased glucose in rats^[90] and insulin secretion also can be modulated in humans.^[91] Major contents of polyphenols are reserved in the intestinal path and, without absorption, are forwarded to the colon. Sucrose and starch react with these contents of the polyphenols. The extracts rich in polyphenbols reduce the activity of enzymes, like α-amylase and α-glucosidase, involved in the release of glucose in gastrointestinal tract from the starch.^[92] Inhibition may differ on the bases of phenolic composition, for example, tannins inhibit the amylase and a range of polyphenols may be involved in the inhibition of glucosidase.^[93] The intestinal absorption of glucose can be influenced by the interaction with sodium dependent glucose transporter and transporter of glucose in the human intestinal tract. Insulin stimulated uptake of glucose and basal uptake can be increased by the polyphenols. Phenolic compounds may involve in the insulin sensing pathways indirectly reducing the glucose synthesis in liver.^[94]

Conclusion

During the last few decades, the interests of the consumers have burgeoned in the natural products due to the raised awareness. Among various bioactive molecules, polyphenols are recognized as a food article is an outstanding source of variety of compounds with extraordinary diverse composition. Quite a significant amount of experimentation on its biological activity and promising application of these compounds has been executed. Polyphenols are the secondary metabolites of plant origin and are widely distributed. These compounds attained the prominent position due to their wide distribution in plant-based foods and significant evidence of negative correlation of their consumption with cancers, diabetes, and cardiovascular diseases.