Selected Functional Foods for Potential in Disease Treatment and Their Regulatory Issues

Abstract

The significant association between diet and human health broadens the consumer concept to look at food not only for its basic nutrition but also for allied health benefits. Nevertheless, a large segment of the population is still reluctant to buy functional foods due to ambiguities related to their health claims. This review highlighted the role of functional foods against various physiological threats, like cardiovascular disorders, diabetes, oxidative stress, cancer insurgence, and immune dysfunction. Recent developments in dietary supplements are also the limelight of the article. The discussion also encapsulated the role and responsibilities of regulatory agencies, such as the Food and Agriculture Organization, the Codex Alimentarius Commission, and the International Alliance of Dietary Food Supplement Association, in harmonizing the legislations regarding the risk assessment and health claims of functional foods.

Keywords:

• Functional foods
• Physiological threats
• Dietary supplements
• Regulations
• Consumer acceptability

INTRODUCTION

Diet and health linkages are no longer questionable and consumers are also conscious regarding their food choices.[1–3 3 Dietary patterns have been changed during the last two decades owing to growing awareness, and legislations have been implemented all over the globe, particularly in the United States, Japan, and the European Union.[4,5] These developments in the existing era witnessed the coinage of terms, such as functional, nutraceuticals, and pharma foods, that led the consumers to minimize the risk of diseases through diet-based strategies.[6,7] These terms intermingle with each other; nevertheless, functional foods are defined as “all those foods which provide health benefits beyond their basic nutrition.”[8]

Functional foods find their origin both in plants and in animals, but plants are more important as they synthesize complex organic molecules (phytochemicals) beneficial for human health. The plant-based functional foods include fruits and vegetables, whole grains, fortified or enhanced foods, beverages, and dietary supplements.[5,9] Some other functional foods, which are predominant in the market, include green tea, broccoli, grape juice, cabbage, tomatoes, watermelon, psyllium, oat and barley, onion, garlic, etc.[10 –12] The health promoting properties of these foods are attributed to bioactive components, such as catechins, sulforaphane, anthocyanins, polyphenols, isothiocyanates, carotenoids, fibers, essential oils, etc.[13 –15] Likewise, soy, flax seeds, and green leafy vegetables are also important as they contain phytosterols, luten and zeaxanthin, and carotenoids, respectively.[16,17]

Polyunsaturated fatty acids (PUFA)-rich fish and flax seed oils are of cardinal importance with respect to their indispensable role in healthy cardiovascular and immune systems.[9,18] Some dairy products, including yoghurt, curd, etc., also fall into the category of functional foods, as they contain beneficial microorganisms recognized as probiotics.[19] Additionally, whole grains contain dietary fiber that acts as prebiotics, which mainly is concentrated in the bran portion. Furthermore, it is also helpful in lowering blood glucose and cholesterol levels.[20]

The phytochemicals/botanicals have been in use since immemorial times in various cultures to improve human and animal health. People consuming diets rich in functional/bioactive components are at lower risk of chronic illnesses, thus, reducing the risk of mortality.[21] Introduction of ingredient assays and standards in the early 20th century has laid the foundation for modern western pharmacology. Recently conducted research interventions using these modern techniques claimed that plant-based functional foods possess antimutagenic and anticarcinogenic activities along with other health enhancing roles.[22,23] It is, therefore, important for nutritionists and health professionals to take an interest in traditional medicines as a part of a patient's drug profile.[11,24] This review article is full of developments in functional foods to combat physiological threats like cardiovascular disorders and diabetes mellitus. The discussions of their antioxidant potential, anticancer, anti-inflammatory, and immunomodulatory properties are the limelight of the article. In the last section, the regulatory affairs in different parts of the globe pertaining to functional foods and their health claims are discussed, and conclusions and recommendations are given for uniformity regarding health claims over the globe.

FUNCTIONAL FOODS FOR CARDIOVASCULAR CARE

Cardiovascular disparities are the leading cause of morbidity and mortality throughout the world. High cholesterol, homocysteine, hypertension, and inflammation are the major risk factors for cardiovascular complexities. The consumption of a healthy diet and physical exercise can control these problems, thus, minimizing the chances of causality.[25] Management of plasma cholesterol levels continues to be a cardinal issue in cardiovascular disease (CVD) prevention as hypercholesterolemia plays a key role in pathogenesis of atherosclerosis and related heart diseases.[26,27] Different drugs are in use for its treatment but concerning the length of therapy, natural products may be a suitable substitute.[28]

The functional foods, including garlic, onion, black cumin, ginseng, guava leaves, propolis, grape extracts, etc., are effective in reducing the extent of cardiovascular disorders.[29] There are several mechanisms of actions, however; the fatty acids profile of the functional foods is among the most promising solutions. In this context, the ratio of Ώ-3 and Ώ-6 fatty acids is important. Flax, fish, and soybean contain appreciable quantities of omega-3 fatty acids that hold the potential to reduce LDL cholesterol significantly. Moreover, dietary flaxseed is a valuable strategy to help endothelial-dependent vasorelaxation malfunctioning.[30] In two animal models (F344 rats with normal lipid levels and obese SHR/N-cp rats with elevated levels of cholesterol and triglyceride), flaxseed meal at 20% significantly decreased plasma cholesterol and triglyceride concentrations.[31] Additionally, flaxseed is the richest source of the lignan secoisolariciresinol diglucoside (SDG) that has a beneficial impact on cardiovascular disorders. SDG at 500 mg/day for approximately 8 weeks is needed to observe positive effects on cardiovascular risk factors (improving lipid profile, lowering blood pressure, and mitigating oxidative stress-induced inflammatory processes) in human patients.[32]

The foods rich in dietary fiber contents are also effective in reducing the extent of atherosclerosis.[33 –35] Dietary reference intakes recommend consumption of 14 g of dietary fiber per 1000 kcal, or 25 g for adult women and 38 g for adult men, based on epidemiologic studies showing protection against cardiovascular threat.[36] The people in the USA with reported intake of 25–30 g of dietary fiber are at a lesser risk of coronary heart disease (CHD).[37] The intake of a dietary fiber-rich barley diet significantly decreased plasma total cholesterol, triglycerides, and free fatty acid levels (Tables 1 and 2).[38]

Owing to rich phytochemistry with special reference to polyphenols, natural products might be a suitable preventive measure in coronary care and regulating blood cholesterol.[26,27] Based on evidence presented in some research interventions, amaranth oil could be of significant benefit for patients with CVD.[39] Consumption of berries, a rich source of polyphenols, improved the lipid metabolism and functionality of the cardiovascular system. Moreover, it is effective in lowering blood pressure and platelet aggregation. Flavonoids present in chocolate exhibit antioxidant potential that helps in reduced oxidative modification of LDL.[40,41]

Consumption of soy protein is also linked to a decreased risk of cardiovascular diseases owing to its isoflavones content.[42] Ginsenosides from ginseng trigger vascular relaxation by releasing nitric oxide, enhancing enzymes activities, and stimulation of calcium–potassium channels; these pathways are important modules to control hypertension. Similarly, intake of green and black tea improved blood circulation by endothelial-dependent dilation of the brachial artery in CHD patients.[43] The quercetin, an important component of garlic and onion, at 10 mg/kg for a period of 5 weeks improved the antioxidant status, thus, decreasing the chances of LDL oxidation and subsequent atherosclerosis. Some other components of garlic, e.g., Allicin/ajoene, inhibit nitric oxide synthase activity resulting in reducing atherosclerotic lesions.[29]

Homocysteine, a metabolite from methionine, is an independent cardiovascular disease risk factor, which causes thrombosis and oxidative-stress damage. The deleterious effects associated with its higher levels can be overcome using foods rich in vitamin E and C. Moreover, whole grain intake is also inversely associated with homocysteine level.[27,44]

Efforts have been in progress for the last few years to develop specialized products to prevent and reduce the risk of cardiovascular disorders. Accordingly, specially designed functional oils rich in PUFA may reduce the level of LDL cholesterol, thus, protecting against atherosclerosis and allied consequences.[45] In 2003, St-Onge et al.[46] developed/prepared a functional oil using medium-chain fatty acids, flaxseed oil, and phytosterols. They further observed that consumption of synthetic functional oil could decrease total cholesterol (12.5%) and LDL cholesterol (13.9%), thus, improving the lipid profile in human subjects.[47] Later, Cho et al.[48] developed a new synthetic functional oil containing mono and diacylglycerol from corn oil. They suggested that the synthetic functional oil possesses blood cholesterol-lowering effects. The inhibitory effects are due to reduced activities of atherogenic enzymes, i.e., liver acyl-CoA:cholesterol acyltransferase and serum lipoprotein-associated phospholipase A2. Recently, Jacobs Jr. et al.[3] introduced a new concept of food synergy that emphasized the interactive effect of dietary components. Some other concepts like optimum nutrition are also important in designing functional foods with some therapeutic potential. Conclusively, consumption of functional foods as a part of a daily diet can reduce the risk of cardiovascular ailments. However, health claims for the functional foods available in the market must follow the regulations of the respective country. There is a need for uniform regulation over the globe in order to bring meticulousness. Indeed, clinical advice from a nutritionist can help consumers to select suitable functional food.

DIABETES MELLITUS AND FUNCTIONAL FOODS

Diabetes mellitus and its complications are one of the leading causes of death over the globe. According to an estimate, at the end of the year 2030, approximately 376 million people will be diabetic worldwide.[49] No doubt, drugs used for the treatment of diabetes mellitus are effective, but the side effects associated with their use often call for an alternative from natural products. Even in some cases, their effectiveness decreases with the passage of time.[50] Under these circumstances, diet selection is imperative for the management of diabetes and its allied complications. There are number of natural products available that are helpful in controlling the progression of diabetes mellitus. Hundreds of plants are being used as herbal remedies and many of them have been reported in the literature, including Rutaceae, Leguminosae, and Cucurbitaceae families.[51] The examples also include green tea, mulberry, fenugreek, black cumin, garlic, spinach, turmeric, sweet potato, guar gum, oat, whole grains, soybean, flax seeds, etc. Some of the anti-diabetic agents are also extracted from plants, especially from the peel of potato, bougainvillea, etc.[52 –54] More recently, Qi et al.[55] updated the list of families of medicinal plants useful against diabetes mellitus, including Leguminosae, Cucurbitaceae, Araliaceae, Liliaceae, Chenopodiaceae, Solanaceae, Compositae, Campanulaceae, Cornaceae, Rhamnaceae, Scrophulariaceae, Euphorbiaceae, Ginkgoceae, Gramineae, Myrtaceae, Sterculiaceae, Annonaceae, Labiatae, and Crassulaceae. The anti-diabetic potential of these plants are often attributed to the functional ingredients in them (e.g., dietary fiber in barley and oat).[12,56] Additionally, the inhibition of enzymes associated with carbohydrate metabolism is also an effective strategy to modulate glucose and insulin response in human subjects.[57]

The foods having a high fiber content, such as oat, guar gum, pyslium husk, etc., are effective in weight management,[35] thus, reducing the extent of diabetes mellitus. In this regard, Weickert et al.[58] reported that increased insoluble dietary fiber intake for 3 days significantly improved whole-body insulin sensitivity, thus, reducing the risk of diabetes. More recently, Li et al.[38] suggested that intake of unrefined cereal foods, especially barley, can be used as a diet therapy for reducing the risk of diabetes mellitus. The benefits associated with the consumption of dietary fiber are associated with their ability to enhance glucose tolerance and control lipid metabolism. Additionally, high dietary fiber diets hold a low glycemic index (GI), thus, being effective in controlling the menace of hyperglycemia.[38,56] The whole yellow-pea flour (WYPF) can be used to produce low-glycemic functional foods possessing sensory attributes that are comparable to identical food products containing whole wheat flour.[59] The addition of β-glucan predictably reduces the glycemic index. In a 50-g carbohydrate portion, each gram of β-glucan reduces the GI by 4 units, making it a useful functional food component for reducing hyperglycemia.[60] Oat bran flour contains significantly higher amounts of β-glucan, therefore having a low glycemic response and, thus, can be helpful in reducing postprandial diabetes.[61]

Black cumin also holds insulinotropic properties and has the ability to maintain β-cell integrity, playing an important role in diabetes management.[62] Similarly, garlic and onion hold antioxidant potential that is helpful in reducing the extent of this menace.[63] The bioactive molecules present in such functional foods (e.g., α-lipoic acid, tocopherols, and selenium) are helpful to control diabetes and its complications.[64,65] SDG from flax seeds and its metabolites may protect against metabolic syndrome by reducing glucose concentrations in human subjects.[32]

Diabetes mellitus is often accompanied by cardiovascular disorders and immune dysfunction with decreased activities of liver enzymes, such as glutathione peroxidase (GSHPx), catalase, glucose-6-phosphate dehydrogenase (G6PDH), and glutathione S-transferase (GST) activity,[66] resulting in progression of oxidative stress that may damage liver pancreatic β-cells.[67] Myocardial necrosis and cardiac hypertrophy are the cardiovascular disorders associated with diabetes mellitus.[68,69] Functional foods are not only important for diabetes but also for overcoming its complications.[70,71] The plants, which are helpful in this regard, are garlic, black cumin, green tea, fenugreek, Bauhinia forficate, Cissus sicyoides L., etc., owing to their antioxidant constituents.[72,73] Likewise, dietary intake of fiber-rich sources, such as barley, may possess the ability to decrease cholesterol, triglycerides, and free fatty acid (FFA) levels.[38] Additionally, olive oil containing polyphenols, such as oleuropein and hydroxytyrosol, reverses the chronic inflammation and oxidative stress in diet-induced obesity and diabetes.[74] Tapsell et al.[75] suggested that structuring “whole of diet” should contain 30 g of walnuts/day, which will be able to deliver substantial amounts of polyunsaturated fatty acid that can improve the lipid profile of patients with type 2 diabetes. The improvement in lipid profile can render body protection against cardiovascular disparities. Recently, Ahmed and Urooj[76] highlighted the role of Ficus racemosa bark as an adjunct in the management of complications associated with diabetes mellitus due to its strong hypoglycemic effects. In another study, grape seed extract was reported to reduce the oxidative stress under diabetic conditions. Thus, the enhanced antioxidant defense capabilities against reactive oxygen species are helpful in protecting the liver cells from damage.[77]

Diet-based therapies are now becoming popular for the treatment of diabetic patients. However, the mechanism of action of functional foods and diet-drug interaction require attention of the research for meticulousness. In total, diversity in consumption of functional foods may prosper their inclusion in a daily human diet to prevent the onset of diabetes mellitus.

FUNCTIONAL FOODS AS ANTIOXIDANTS

Excessive production of reactive oxygen species (ROS) can potentially lead to damage of almost all types of biological molecules. The unchecked production of free radicals creates a condition referred to as oxidative stress,[78] resulting in DNA damage, production of mutated genes, and induction of cell death. These pathological events are involved in cardiovascular, neurodegenerative, and carcinogenic processes. Improved antioxidant defense may provide protection against these maladies, rendering the intake of antioxidant vitamins and trace elements imperative.[79]

Various functional foods or their components possess the ability to scavenge free radicals that result in amelioration of oxidative stress.[80] α-Lipoic acid is one of the important dietary supplements used both in the prevention and treatment of various oxidative stress-related maladies. Similarly, anthocyanin supplementation plays a vital role in the prevention of chronic inflammatory diseases. Mechanisms of action include inhibition of NF-kappaB trans-activation and deceased plasma concentrations of pro-inflammatory chemokines, cytokines, and inflammatory mediators.[81]

Some functional foods and their extracts are also effective against oxidative stress, e.g., Ginkgo biloba leaves. It is among the most widely sold herbal dietary supplements in the United States due to its purported health effects. It is also effective in platelets aggregation and holds anti-inflammatory, anti-tumor, and anti-aging activities.[82] Garlic and its various preparations possess antioxidant potential that can be utilized in mitigating the adverse consequences of oxidative stress and allied disparities. There are several evidences for the antioxidant and free radical scavenging activity of functional ingredients of garlic.[29] Likewise, consumption of black cumin (Nigella sativa) exhibits in vitro antioxidant activity, which may be used to express its health promoting properties.[68] Cocoa powder is also rich in polyphenols, such as catechins and procyanidins, and has been used in various models to inhibit LDL oxidation and atherogenesis.[83] Supplementation of tomato products containing lycopene has been shown to lower biomarkers of oxidative stress and carcinogenesis.[84] Green tea and its functional ingredients, catechins especially (-)-epigallocatechin-3-gallate (EGCG), lower the extent of oxidative damage and improves the antioxidant status of the body. They are also effective in reducing collagen-induced arthritis and oxidative stress-induced neurodegenerative diseases.[85] There are many other examples of functional foods available in the market that can be employed as a safeguard against oxidative stress, e.g., essential oil and extracts of many plants, adducts of Millard reactions, antioxidant vitamins, and polyphenols.

Herbs and spices are a good source of antioxidants thereby employed to combat metabolic and age-related degenerative disorders. They have proven wholesomeness but still need further attention of the researchers. Immediate studies should focus on validating the antioxidant capacity of herbs and spices, as well as testing their effects through in vitro and in vivo studies,[86] and results of such investigations would be used as a tool by the nutritionists and stakeholders.

ANTICANCER POTENTIAL OF FUNCTIONAL FOODS

It has been realized that diet-based therapies are one of the effective and sustainable ways to overcome various chronic syndromes. The role of dietary components in maintaining body homeostasis is indispensable for regulation and proper functionality of various systems.[87] Similarly, a healthy lifestyle and dietary habits can protect humans from deleterious effects of cancer insurgence.[88] Diet-based chemoprevention modules require knowledge of nutrients’ dense sources, target communities, and, indeed, selection of a suitable vehicle.[89,90]

The growth of a body is dependent upon the balance between production and death of specialized cells and imbalance resulting in abnormal cell production characterized by tumor formation. The increased production of free radicals is also associated with oxidative DNA damage that ultimately increases the risk of cancer. The antioxidant supplementation or consumption of antioxidant-rich food sources is beneficial in this perspective.[91,92] Many functional foods could suppress DNA oxidation and prevent cancerous growth of the cells. Tocopherols, carotenoids, lycopene, anthocyanins, and flavonoids may possibly prevent cancer insurgence.[93] Catechin, epicatechin, quercetin, and resveratrol hold the ability to inhibit growth of human breast cancer cells. The same compounds potently inhibit human prostate cancer cells. Likewise, retinoids and carotenoids also have inhibitory activities on breast cancer cells proliferation.[94,95] Garlic and it bioactive molecules are effective in chemopreventive strategies to combat colon, prostate, skin, breast, and brain tumors.[96] Similarly, green tea and its bioactive molecules can play a significant role in a nutritional support program as a chemopreventive agent. Recently, Butt and Sultan[85] explicated green tea as nature's defense against malignancies. They highlighted its potential role against colon, prostate, breast, lung, and skin cancer cell lines. Likewise, black cumin, fenugreek, astragalus, Echinacea, asparagus, and licorice are some other examples of plant species with anticancer properties.[15] The bioactive molecules, such as diosgenin, phytosterol, α-henderin, coumarin, organosulfur compounds, anthocyanins, etc., are attributed to their anticancer activities.[97,98] Additionally, some studies highlighted the importance of probiotics and prebiotics in cancer protection.[99]

Table 1 Some examples of functional foods and their bioactive molecules for cardiovascular protection

Sr. #	Plants	Bioactive molecules	Potential roles
1	Garlic	Sulfur containing compounds	• Antioxidants
			• Lowers LDL oxidation
			• Reduce platelet aggregation
2	Green tea	Catechin	• Weight reduction
			• Lowers LDL oxidation
3	Black cumin	Fatty acid profile	• Reduce the cholesterol
		Thymoquinone	• Prevents LDL oxidation
4	Flax	Omega-3 fatty acids	• Reduce the LDL cholesterol
			• Cure endothelial-dependent vasorelaxation malfunctioning
5	Soybean	Isoflavanoids	• Reduce the cholesterol
		Omega-3 fatty acids	• Prevents LDL oxidation
6	Grape extracts	Polyphenols	• Lower thrombosis
			• LDL modification
7	Guava leaves	Fibers	• Reduced cholesterol
8	Whole grains	Dietary fiber	• Cholesterol absorption and adsorption
9	Germ oil	Polyunsaturated fatty acids	• Reduce LDL cholesterol
			• Improves HDL cholesterol
Source: Butt et al.[29]

Table 2 Some examples of functional foods and their bioactive molecules for the management of diabetes mellitus

Sr. #	Potential mechanism
1	Weight management and obesity	Oat, garlic, onion, green and black tea, psyllium husk, guar gum, wheat bran, fenugreek, etc.
2	Insulinotropic	Black cumin
3	Insulin like activity	Black cumin, fenugreek, sweet potato
4	Antioxidant activities (diabetes complications)	Fenugreek, Bauhinia forficate, Cissus sicyoides
5	Enzymes modulation	α-Lipoic acid, tocopherols, and selenium containing plants and their extracts, fenugreek
Source: Butt et al.[29]

Table 3 Ten examples of functional foods and their anticancer perspectives

Sr. #	Plants	Bioactive molecules	Cancer type	Potential roles
1	Green tea	• Epigallocatechin-3-gallate	Colon cancer	• Induces apoptosis
		• Epicatechin	Skin cancer	• Promotes cell growth arrest by altering the expression of cell cycle regulatory proteins
		• Epicatechin-3-gallate	Lung cancer	• Activating killer caspases
		• Epigallocatechin	Prostate cancer	• Suppressing nuclear factor kappa-B activation
			Breast cancer	• Regulates and promotes IL-23 dependent DNA
				• Modulate signal transduction pathways
2	Turmeric	Curcumin	Colorectal cancer	• Inhibits transcription via AP-1
				• Suppresses cell proliferation
				• Inhibits metastasis
				• Apoptosis
				• G(1)/S arrest of the cell-cycle
				• Boosting antioxidant defenses
3	Grapes/Berries	Resveratrol/ Piceatannol	Skin cancer	• Inhibit DNA strand breakage
			Lung cancer	• Inhibitors of topoisomerase I
			Colorectal cancer	• Antimetastatic effects
			Breast cancer	• Cell cycle arrest
				• Down-regulation of PI3Kinase to induce apoptosis
4	Tomatoes	Lycopene	Prostate cancer	• Reduced oxidative stress through modulation of antioxidant defense system
			Skin cancer	• Increased nuclear NF-E2-related factor-2
			Colon cancer	• Inhibit DNA damage
				• Down regulation of cyclin D1, Bcl-2, and Bcl-xL expression
5	Pomegranate	Polyphenols	Breast cancer	• Arrest cell cycle in G0/G1 and G(2)/M phase
		Ellagic acid	Colon cancer	• Apoptosis
		Ellagitannins	Lung cancer	• Antiproliferative
			Skin cancer	• Antiaromatase activity
				• Inhibited NF-kappaB and cell viability
				• Modulating Bax:Bcl-2 proteins
6	Soybean	Soy isoflavones, genistein, daidzein, glyceollins	Breast cancer	• Nuclear factor-kappa B (NF-kappaB) pathway
			Gastric cancer	• Decreased risk for gastric and lung cancer
			Ovarian cancer	• Arrest cell cycle arrest in G2/M phase
			Lung cancer	• Induction of apoptosis and repair of DNA damage
				• Induces expression of p21, p53, and caspase-3 proteins
				• Inhibition of VEGF expression
7	Fish oil	Omega-3 tatty acids	Colon cancer	• Caspase 8 activation
			Breast cancer	• Induction of apoptosis
				• Reduced risk for breast cancer
				• Enhanced lipid peroxidation
				• Modulation of mitochondrial calcium homeostasis
				• Enhanced production of reactive oxygen species
				• Activation of p53
8	Flax seed	Omega-3 fatty acids, lignans	Prostate cancer	• Decreased mRNA expressions of Bcl2, cyclin D1, pS2, ERalpha
			Breast cancer	• Apoptosis
				• Decreased VEGF secretion
				• Enhancement in antioxidant defense enzymes activities
				• Reduced tumor growth and metastasis
9	Garlic	Alicin, DAS, DADS, Ajoene, etc.	• Gastrointestinal tract cancer	• Increase the level of many detoxification enzymes
			• Prostate cancer	• ROS generation and regulating Bax/Bak proteins
			• Mammary carcinoma	• Apoptosis in prostate cancer
			• Hepatocellular carcinoma	• Regulation of p21/ras protein expression
			• Lung cancer	• Antiproliferative inhibited progression at G2/M
			• Skin and esophagus cancer	• Caspases activities
				• Inhibition of gene expression
10	Ginger	Gingerols, Shoagols, Zerumbone	Colorectal cancer	• Reduces oxidative stress
			Breast cancer	• Inhibits proliferation
			Lung cancer	• Induces mitochondria-regulated apoptosis
(Source: Gullet et al.[100])

Some functional foods are listed in Table 3 along with their bioactive molecules and mode of actions. However, it is consensus among the researchers that induction of apoptosis and inhibition of cancerous cell proliferation are two broader anticancer mechanisms of functional foods. There are some hypotheses presented that boosting the immune responses and modulation of signal transduction pathways can lead to anticancer effects of functional foods.[29,100] Craig and Mangels[101] enumerated the potential benefits of vegetarian diets in relation to various physiological threats and highlighted that consumption of fruits and vegetables are associated with reduced risk of cancer. In the existing era, it has been reported that functional foods may interact with the immune response to reduce the risk of cancer.[102]

Genomic approaches are becoming increasingly important in characterizing potential mechanisms of cancer prevention, optimizing the rational selection of dietary bioactive food components, or application of nutrigenomics for identifying humans with differing nutrient requirements for cancer protection. Dietary flavonoids and other polyphenols have the potential to act effectively in food supplements for the treatment of cancer and other related symptoms.

FUNCTIONAL FOODS AND IMMUNE DYSFUNCTION

Recent research findings illustrated that functional foods and their bioactive molecules including omega-3 fatty acids, dietary fibers, vitamins, antioxidants, plant sterols, and flavonoids have a beneficial effect on human health.[103] Diets rich in phytochemicals possess immunomodulatory and anti-inflammatory properties.[80,92] The functional ingredients include macronutrients, such as amino acids (glutamine or arginine), lipids (omega-3 polyunsaturated fatty acids, DHA, or EPA), and novel non-digestible carbohydrates. The micronutrients, such as vitamins C and E, are employed as antioxidants, while zinc and selenium are minerals effective to boost up the immune system. Some of the most potent immunomodulators are phytochemicals, such as the polyphenols, EGCG, curcumin, and isothiocyanates.[104]

Table 4 Some promising genera and strains of probiotics

Sr. #	Plants	Bioactive molecules	Potential roles
1	Bifidobacterium	B. bifidum	• Protects the intestinal mucosa
		B. breve	• Helps with the immune response
		B. infantis 35624	• Prevents E. coli and salmonella infections
			• Anti-inflammatory properties
			• Stimulates the immune system
			• Helps digestion
			• Can be used to make yogurt and is one of the most dominant species of beneficial bacteria in the human intestinal system
2	Lactobacillus	L. acidophilus	• Protects the intestinal mucosa
		L. bulgarius	• Prevents inflammatory bowel disease
		L. casei	• Prevents E. coli and salmonella infections
		L. crispatus	• Lactose intolerance
		L. rhamnosus strain	• Helps the body manufacture antioxidants
		L. amylovorus	• Crohn's disease
		L. delbrueckii	• Supports the immune system
		L. gallinarum	• Helps encourage the growth of other good bacteria in the digestive system, e.g., L. rhamnosus helps stabilize beneficial bacteria in the intestinal system
		L. johnsonii
		L. plantarum
		L. salivarius
		L. sporogenes
3	Lactococcus	L. lactis	• Helps prevent diarrhea
4	Saccharomyces	S. cerevisiae	• Prevents diarrhea
		S. boulardii
5	Streptococcus	S. thermophilus	• Prevents infection
			• Makes milk products more digestible for the lactose intolerant
Source: Saulnier et al.[110] and Gibson.[111]

The probiotics and prebiotics are pivotal in extending the immune defense system.[105] The microorganisms used for fermentative production of food grade products are more or less probiotics. Specialized cultures were developed to enhance immunity and are being sold in the markets as dietary staples. Humans lack the ability to digest certain dietary components, e.g., dietary fiber, and these components act as a substrate for microbial growth in the gastrointestinal tract (GIT) denoted as prebiotics. Additionally, they are important in releasing antioxidants in GIT, e.g., ferrulic acid.[106]

The microbes residing in the digestive tract enhance the metabolic potential; dietary modifications can be helpful in maintaining the health and metabolic activity that consequently influence nutrient availability.[107] Probiotics modulate immunity in humans,[108] while the effects of prebiotics are not as consistent as revealed from many research investigations.[26] In this context, supplementation of Bacillus polyfermenticus improved the immune function by enhancing IgG production by modulating the immune cells.[109] In Table 4, a list of genera falling under the category of probiotics and their potential health benefits are described.[110,111]

The effects of prebiotic-like polysaccharides have recently received much attention and were reported to induce immune modulation.[112] Some of the prebiotics, like fructo-oligosaccharides, provide protection against pathogens probably through promoting the growth of gastrointestinal bacteria like Bifidobacteria and Lactobacilli.[113] Afterwards, Sun and Liu[114] suggested that water-soluble polysaccharide could be a potential immunostimulating agent and act as functional food against both pathogens and cancer lines. These results suggest that probiotics and prebiotics act synergistically.[115,116] The unraveling role of functional foods and bioactive molecules in enhancing immunity has opened a new gateway to control gastrointestinal disorders. Future studies should be conducted in order to generate statistical data to determine the ability of immune and epithelial cells to identify different bioactive plant species for the improvement of body resistance.

REGULATORY AFFAIRS

During the 20th century, efforts were directed to develop nutritional standards, such as recommended daily allowance. However, the development that food components are linked with each other and, in many cases, availability of one nutrient is dependent on another, was made in the last few years.[117] During the last two decades, various products were introduced in the markets claiming attractive benefits by their use. However, most such claims are exaggerations of the actual facts and are often misleading to earn a high profit. In order to reduce such malpractices, Japan was the first country who formulated a regulatory framework in order to ensure safety of the products for the end user. The Japanese government formulated the term FOSHU (food for specific health use) in the mid 1980s; nevertheless, owing to technology developments, a new FOSHU regulatory system, FHC (foods with health claims) and FNFC (foods with nutrient function claims) were introduced. These foods were collectively termed as “health foods.” In the year 2005, further amendments were made by the authorities (Ministry of Health and Welfare) and health foods were characterized into standardized FOSHU, qualified FOSHU, and FOSHU with disease risk reduction claims.[118]

The Asian communities were familiar with the concept of functionality of food products centuries ago and the knowledge transferred generation wise; still, herbal medicines are fetching a good premium in the market. The concept of functional food was somewhat newer for the European and American regions. Thus, legislations were made in order to protect the citizens from hazardous effects of specially designed foods. The International Life Science Institute (ILSI) of Europe summarized the use of functional foods with approved recommendations, accordingly the European Union made legislation in 1999 that functional foods should be tested for risk assessment. The enforced laws focused on a risk analysis framework comprising of three important components (i.e., risk assessment, risk management, and risk communication).[119] Currently, laws are still prevailing in some countries of the European Union that prohibit the mention of health claims on the packaging.[120]

The legislations made by the USDA categorized the health claims into five categories; functional foods should be sold according to their respective group as described in the Dietary Supplement Health and Education Act of 1994. The benefits are analyzed through various modules; the Federal Drug Authority (FDA) has the signing power for their approval.[45] Similarly, the Codex Alimentarius in 1999 posted a draft mainly aimed at defining health claims into different categories, i.e., A and B. The health claim A related with the structure of the product, while B deals with associated health benefit. A similar legislation was adopted later by some European Union countries, such as Sweden.[121]

Recently, some Asian countries started legislation, e.g., Korea with the Korean Health/Functional Food Act 2004, that specified that the Korean Food and Drug Administration (KFDA) is the authority for approving specific products as healthy functional food (HFF). Furthermore, KFDA is solely responsible for evaluating health claim registration.[122]

Likewise, the Indian government in 2004 approved its first Food Safety and Standard Act (2004) to empower the Food Safety and Standard Authority to monitor the food business. It deals mainly with food safety and security, nonetheless, still lacking in the specific legislation regarding functional and nutraceuticals.[123] On the contrary, some regulations persist in China regarding the concern following Japan. One of the loopholes for healthy humankind is the persistence of protein and micronutrient deficiencies among the Afro-Asian and Latin American cultures. In order to improve the nutritional profile of such target communities, there is a dire need to develop functional foods with added micronutrients.

In a nutshell, existing variations in the regulations worldwide are creating problems for the stakeholders and health professionals for choosing the right food for the vulnerable segment. Some of the foods are still controversial, as they are considered functional in one region but need to be recommended as healthy food in other parts of the world. Such discrepancies are problematic for consumers too, which is why they are a bit reluctant to buy such items. The international organizations, including the Food and Agriculture Organization (FAO), World Health Organization (WHO), Codex Alimentarius, Joint Expert Committee on Food Additives (JECFA), and the US Flavor and Extract Manufacturers Expert Panel (FEXPAN), can play a significant role in bringing uniform regulations over the globe. Similarly, some agencies, like the Ministry of Health and Welfare (MHW) Japan and KFDA Korea, can take a lead for the introduction of such foods and their standards in the developing economies. The International Alliance of Dietary Food Supplement Association (IADSA) should step forward for developing such regulations, keeping in mind the health of consumers and interest of stakeholders.

Furthermore, the concept of optimum nutrition and food synergy with special reference to enhance the consumption of plants rich in bioactive molecules must be addressed in order to promote diligence. However, toxicological aspects and drug-diet interactions should be considered before formulating uniform policy over the globe that will result in greater acceptability of the consumers towards functional foods.

CONCLUSIONS

Growth of functional foods is expanding due to consumer awareness that naturalness of diet could be helpful in providing protection against physiological threats. However, an array of products strengthened with unidentified health claims are one of the reasons confusing the buyers regarding their real effectiveness. Implementation of a uniform global policy regarding functional foods and their use is possibly supportive to prevent various physiological threats. Nevertheless, products should be examined for risk assessment in different geological zones in order to enhance meticulousness for safe use. It is advisable that various international agencies, such as Codex Alimentarius, FDA, USDA, and IADSA, should emphasize on the legislation for the use of approved functional foods to prevent various maladies.