Functional Foods: Functional Ingredients, Sources and Classification, Health Claims, Food Intolerance, and Allergy

Abstract

The public’s hunger for healthy foods has grown considerably during the last few decades. It stimulated the development of unique food products that have positive health effects beyond basic nourishment. Functional foods are natural or processed foods that include known or unknown biologically active ingredients that provide a clinically proven and confirmed health benefit for the prevention and treatment of chronic diseases at specific, effective, and nontoxic doses. Following a thorough investigation of food labels that make health and nutrition claims, legislation to safeguard consumers from inaccurate information was introduced. As a result, more scientific investigations should include actual evidence before drawing broad judgments. It is critical to highlight that the interpretation of legislation promotes the legitimacy of functional food products. Separate pieces of legislation for both governing types are one way to ensure the right integration of functional foods. This will help customers distinguish between functional food products and those with stated health claims. This chapter examines functional foods from many sources, including their potential health benefits, health claims, food intolerance, and allergies.

1. Introduction

Consumers’ understanding of the importance of eating healthier foods rich in bioactive substances has grown dramatically.

Food is utilized to offer nutrients, as well as to satisfy hunger. Nutritious diets help to prevent nutritional problems. People’s health consciousness has grown, resulting in a global market for natural foods used as dietary supplements [1]. Because of their ingredients, all natural foods are functional; nonetheless, the idea of a functional food originated from the observation that certain manufactured foods with particular additions can improve human health. Functional foods are foods that have positive health effects that go beyond the nutritional content of the food, promoting optimal health and lowering the risk of numerous diseases. It arose from a study in which the relationships between nutrition, sensory acceptance, and fortification were explored in a food matrix enhanced with unique ingredients [2, 3]. Foods that provide health benefits beyond basic nutrition. “Knowing that certain foods can deliver unique health benefits allows us to control our health [4].” Food products are called functional foods only if they have a basic nutritional impact on the human system, either enhancing physical circumstances or decreasing illness risk [1]. “Functional foods may improve health, reduce the risk of certain diseases, and even be used to treat fever.” The fact that medical treatments for the senior population are somewhat expensive, as shown by many demographic studies, led to the recognition of the necessity for these supplies [5].

The creation of functional foods is a scientific challenge pertaining to functions that are important for maintaining health and well-being, are sensitive to dietary components’ modulation, and, if changed, may modify the risk of disease.

The demand for functional foods has increased since the discovery of whole foods or food components that can prevent cancer, osteoporosis, or cardiovascular disease, enhance immunity, detoxify the body, improve physical performance, aid in weight loss, improve cognitive function, help people cope with stress, and inhibit inflammation, antioxidants, and hormone modulation [6].

The functional food center defines functional foods as “natural or processed foods that contain known or unknown biologically active compounds which, in defined, effective nontoxic amounts, provide a clinically proven and documented health benefit for the prevention, management, or treatment of chronic disease.” [7, 8].

This term is critical to the regulatory process in relation to the FDA and EFSA’s health and nutrition claims. The potential of functional foods as an affordable and useful alternative medicine is being investigated more and more. The FDA and EFSA need to continue protecting consumers from potential risks in order to uphold their commitment to food safety in light of the growing functional food industry.

“Furthermore, health claims are restricted to claims about disease risk reduction and cannot include claims about disease diagnosis, cure, mitigation, or treatment.” The FDA must review and analyze health claims before they are used” [9]. All things considered, functional foods seem to meet the criteria the FDA provides to support a health claim; yet, the FDA has the last say. When it comes to the notion of functional food, a food item may only be designated as assisting in the prevention or reduction of disease; it cannot be used to promote the treatment or prevention of illness. This piece of legislation protects businesses and customers against misleading labeling and information. However, the functional food business has made significant progress by doing considerable research and revealing that foods containing bioactive substances have the potential to treat ailments.

However, when it comes to health claims, claims of illness treatment, or risk reduction, the EC has far laxer regulations. The commission accepts a range of health claims as long as they are supported by scientific evidence and are clear enough for consumers to understand. “A health claim is any statement that makes a connection between food and health.” The task of evaluating the scientific foundation for health claims falls to the European Food Safety Authority (EFSA) [10]. Despite being substantially similar to the FDA’s version of the guideline, the EC makes no reference of a claim being able to promote the treatment, mitigation, diagnosis, or cure of a disease.

The study of functional components in food is not restricted to phytochemicals; the discovery of new effects of classic nutritional nutrients is also ongoing [11]. Furthermore, various functional foods have recently been introduced to the market in order to provide nutrition, safety, and convenience to customers. As a result, functional meals with the functions of regulating the human body, preventing diseases, and boosting rehabilitation have gotten a lot of attention, and understanding the usefulness of functional food ingredients has become a hot zone in functional food research and development. Therefore, this chapter discusses functional foods from various sources, as well as their possible health advantages, health claims, food intolerance, and allergy.

2. Functional foods health claims

Health claims discuss the relationship between lowering the risk of an illness or other health-related condition and functional foods (nutraceuticals) or their bioactive ingredient(s). This indicates that substances (whether they be foods or dietary components) and diseases or conditions connected to health are the two main components of health claims.

2.1 Food and Drug Administration claims

This section examines the four categories of health claims that the Food and Drug Administration (FDA) recognizes and that is typical practice for food safety. These claims on food labels provide customers with health information based on a standardized 2000-calorie diet [12]. “Depending on the claim and what information is required to prevent the claim from being misleading, a variety of information is required.” “Almost all claims require nutrition labeling” [9].

The earliest type of food label is the nutritional content claim. “Nutrient content claim: A nutrient content claim is a claim on a food product that directly or indirectly characterizes the level of a nutrient in the food (e.g., “low fat,” “high in oat bran,” or “contains 100 calories’)” [9]. Generally speaking, these kinds of statements emphasize the clearly visible nutritional content of a particular food or food-related product. However, not all statements on nutrient content are obvious and have to fall within a specific range. These types of claims include relevant facts that assist consumers in understanding the nutritional value of a certain food product.

Another kind of claim on a food label is an approved health claim. “Health claim” refers to “any claim made on the label or in the labeling of a food, including a dietary supplement, that expressly or by implication, including “third party” references, written statements (e.g., a brand name including a term such as “heart”), symbols (e.g., a heart symbol), or vignettes, characterizes the relationship of any substance to a disease or health-related condition” [9]. It is not appropriate to use health claims as a means of preventing illness. More importantly, there is no need for a food label to state clearly in English that there is a connection between the product and illness. “Implied health claims include those statements, symbols, vignettes, or other forms of communication that suggest, within the context in which they are presented, that a relationship exists between the presence or level of a substance in the food and a disease or health-related condition” [9].

Authorized health claims are subjected to a rigorous evaluation procedure because they must adhere to a significant scientific agreement (SSA). Furthermore, such statements are crucial for assuring consumer safety. Despite their similarities, qualified health claims (QHC) do not adhere to the same strict guidelines as conventional health claims. QHCs are still based on all publicly available evidence, but the scientific support does not have to be as robust as it does for SSA [9]. “Based on the totality of publicly available scientific evidence, health claims require significant scientific agreement.” Therefore, unlike health claims, QHCs must be accompanied by a disclaimer or otherwise qualified [9]. “Past court decisions resulting in QHCs on dietary supplements focused on whether a manufacturer could make statements about diet/disease relationships even when the science supporting the claim did not meet the SSA standard, provided that the claim about the relationship was stated or “qualified” in such a way as not to mislead consumers.”

It is interesting to note that, as long as a disclaimer is provided, qualified health claims permit manufacturers to make claims in the absence of scientific evidence. An example of an approved health claim is “three grams of soluble fiber from muesli daily in a diet low in saturated fat and cholesterol may reduce the risk of heart disease” [9]. An approved health claim is defined as meeting the criteria for both a substance and a disease or health-related condition. Qualified health claims are also different from dietary counseling statements in that they are usually structure/function claims (S/F claims) for any product that provides nutritional advice.

Interestingly, qualified health claims allow manufacturers to make claims without empirical data as long as a disclaimer is included. “Three grams of soluble fiber from muesli daily in a diet low in saturated fat and cholesterol may reduce the risk of heart disease,” is an example of an authorized health claim, “which by definition must contain the elements of a substance and a disease or health-related condition” [9]. Furthermore, qualified health claims differ significantly from dietary counseling statements in that any product that gives nutritional guidance is typically a structure/function claim (S/F claim). “A dietary recommendation statement, such as ‘carrots are beneficial for your healthʼ or ‘calcium is healthy for youʼ refers to a specific food or food component without mentioning any disease or health condition.” Once more, neither one nor both of the ingredients are present [9].

In the United States, the European Union, Japan, Russia, and other developed and some emerging countries [12], food labeling, product composition, food processing, packaging, marketing, registration, and licensing details are carefully regulated. Many international and national academic, scientific, and regulatory organizations are working to create a scientific foundation for functional food health claims because it can be challenging to discern between foods and traditional medicines. This will shield consumers from deceptive and false claims while also pushing producers of these foods to innovate in their product development, marketing, and promotion. As of right now, there is no uniform international law governing health claims [12]. The terms “preventing, treating, or curing a human disease” cannot be used on any food product due to labeling regulations in the majority of nations [12]. Convincing customers that foods advised as functional foods can help lower the risk of sickness and increase well-being is the main objective of health claims.

The Japanese government has currently approved two types of functional foods: those with approved health claims and those with potential health benefits but no health claims [12].

Any food can be deemed functional if it has a good effect on the physiological, metabolic, and behavioral processes listed below: Health claims pertaining to a substance’s or nutrient’s role in the body’s growth, development, and functions; psychological and behavioral functions; gastrointestinal physiology and function; defense against reactive oxidative species; metabolism of substrates; weight control; slimming; or reduction in the amount of energy available from food.

The common thread here is that such claims do not clearly state that there is a causal relationship between a food product’s ability to treat an illness. “Structure/function (S/F) claims describe the effect that a substance has on the structure or function of the body and do not make reference to disease” [9]. S/F claims, in their most basic form, do not require any scientific evidence proving that the product will have an effect on a condition. The most crucial aspect of S/F claims is that they are not deceptive. “First, the law states that you can make these claims if you have evidence that the claims are true and not misleading.” You must have this documentation before making any claims. “Second, you must tell the FDA that you are using the claim within 30 days of selling your product for the first time. Third, the claim must include the mandatory disclaimer statement required by law” [9].

2.2 Functional food and FDA claims

The question that has to be addressed based on the information supplied concerning the FDA’s health and nutrient claims is: How does this relate to functional food? To put it simply, to answer this question, you must first understand the attributes of the Functional Meal Centre (FFC), which defines the characteristics of a functional meal. “Natural or processed foods that contain known or unknown biologically active compounds, which, in defined and effective nontoxic amounts, provide a clinically proven and documented health benefit for the prevention, management, or treatment of chronic disease” [7, 8]. A cursory analysis of this criterion reveals that no claim could legitimately accept a functional meal as part of a disease management strategy. According to a single explanation, “the Federal Food, Drug, and Cosmetic Act (FFDCA; 1), as amended, does not provide a statutory definition of functional foods; thus, the Food and Drug Administration (FDA) has no authority to establish a formal regulatory category for such foods” [13].

However, this does not exclude functional foods from making reasonable claims. “Because there are no specific regulatory categories for functional foods, they are regulated through existing food and drug regulations” [13]. Because functional food does not exist under FDA regulation, they remove the essence of functional food and generalize it as a food or supplement (Table 1).

Organization	Definition
International Food Information Council	Foods or dietary elements that could offer health benefits above and beyond those of basic nourishment and could help lower or minimize the risk of certain illnesses and other medical issues
European Commission	A diet that improves one or more target bodily processes in a way that is relevant to either a lower risk of disease or an enhanced state of health and well-being, in addition to having adequate nutritional effects. It is a customary eating schedule. It is not a pill, capsule, or nutritional supplement of any kind
Academy of Nutrition and Dietetics	Foods that are characterized as whole foods or foods that have been fortified, enriched, or improved and that, when regularly consumed in appropriate amounts as part of a balanced diet, may have a positive impact on health
International Life Sciences Institute	Foods that, because they include nutrients that are physiologically active, offer health advantages beyond basic nourishment
Institute of Food Technologists	“Foods and food components that provide health benefits above and beyond basic nutrition (for the intended population)” [14]
Health Canada	Beyond its fundamental nutritional role, functional foods have been demonstrated to offer physiological advantages and/or lower the risk of chronic disease. They can be traditional foods or they can resemble them, and they are ingested as part of a regular diet
Functional Food Center	Natural or processed foods that, at specified, effective, nontoxic proportions, offer a clinically demonstrated and confirmed health benefit for the prevention, management, or treatment of chronic disease. These foods may contain known or undiscovered biologically active substances
Japanese Ministry of Health, Labor, and Welfare	Foods with health-related functions that have been formally approved to claim physiological effects on the human body are referred to as FOSHU [food for specified health uses]. Consuming FOSHU is advised for people who wish to control health issues, such as blood pressure or cholesterol

Table 1.

Table modified from [14].

It is critical to recognize that each claim reduces the possibility of misleading information and protects consumers from the interpretation of causal links. As a result, the FDA’s regulation impedes the genuine definition of functional food. However, if the definition calls for flexibility in the ability to make such claims, functional foods can make any one of the four nutrition claims. “To define functional food using the health benefit concept, one should focus not on the presence of health claims, but rather on the level of proofs required by the government to use a health claim” [15]. Above all, a functional food claim cannot be considered to offer health benefits unless it satisfies FDA regulations.

But most people think that “it has proven health benefits that reduce the risk of specific chronic diseases or beneficially affect target functions beyond its basic nutritional functions” [15] is a general description of functional foods. In any event, claims serve as a resource for customers to learn about the attributes of beneficial and healthy products, as well as to assist in their discovery. “Food claims on product packages are primarily used to communicate to consumers the potential health benefits of functional foods.” [16]. Furthermore, it has been shown that general health claims, such as S/F claims, are far more likely to be purchased than items with risk reduction claims. “In general, health claims are preferred over disease risk reduction claims” [16]. This is primarily due to the scarcity of studies supporting those statements.

According to a review study on qualified health claims, studies on health claims are generally focused on risk reduction rather than persons who have already been diagnosed. Because health claims are intended to reduce the risk of disease in people who do not already have the disease or health-related condition that is the subject of the claim, the FDA will consider evidence from studies that include people who have been diagnosed with the disease that is the subject of the health claim, but only if extrapolation of the study’s findings to people who do not have the disease is scientifically appropriate [17]. The phytochemical lycopene contained in tomatoes and its link to cancer were the focus of this investigation. The active component, lycopene, was claimed to have cancer-prevention properties in the study. Unfortunately, the FDA found insufficient evidence to approve the less stringently controlled qualified health claim. “The FDA concluded that there was very limited credible evidence for qualified health claims for tomatoes and/or tomato sauce and a reduced risk of prostate, gastric, ovarian, and pancreatic cancers, provided the qualified health claims were appropriately worded so as not to mislead consumers” [17].

2.3 European Commission and European Food Safety Authority Claims

The European Commission (EC) is the governing body of the European Union that contains the food safety department. The European Food Safety Authority (EFSA), the European version of the FDA, is part of the EC. Food labeling divides claims into two categories: nutrition claims and health claims. A “nutrition claim” is defined as any statement, implication, or suggestion that a food has specific advantageous nutritional attributes [18]. The role of a nutrient in the physiological development, functions, and growth of the human organism is referred to as its nutrient function [19].

According to Table 2, these nutrition claims provide information on the number of calories and nutrients in a food.

Nutrient claims: nutritional properties that are implied
The calorific value or energy:	a. provides
	b. offers at a higher or lower rate or
	c. does not offer
The elements or other materials:	a. contains
	b. includes either in greater or less amounts or
	c. does not include

Table 2.

The EFSA defines nutrient claims [18].

As an illustration of calorific content, a serving of carrots has 30 calories. As an illustration of nutrition, this product has trace or lowered levels of nuts.

Three categories of health claims exist behavioral health claims, function health claims, and health claims pertaining to the growth and operations of the body. Functional health claims on food labels that pertain to developing strong bones, maintaining a healthy weight, and eye health are common. Claims that nutrients or other substances modify or improve human physiological functions—for example, calcium improving bone density—are referred to as enhanced function or other function claims [19].

Claims about reducing risk factors in the course of an illness development are referred to as risk reduction claims. Reductions in disease risk claims include those that could lower the chance of contracting specific illnesses, including how fruits and vegetables digest, which could lower the chance of developing cancer [19]. These assertions are critical for gathering empirical proof before releasing the product to the market. If a risk reduction claim appears on a label, it will typically state, lowers blood pressure as higher levels of blood pressure are a risk factor for hypertension. Lastly, statements on children’s development are function health statements made with children in mind. Like general function health claims, one that relates to children’s development might be that vitamin D is necessary for optimal bone growth and development in children.

3. Beneficial ingredients in functional foods

The term “functional ingredients of functional foods” simply refers to chemicals found in vitamin functional foods that have the ability to regulate human body function by stimulating enzyme activity or through other mechanisms. Vitamin functional foods should, in general, include functional ingredients that match their activities, guarantee the lowest effective quantity of those ingredients, and, if needed, restrict the maximum limit of those ingredients [20]. Its attributes, which include sensory, nutritional, and safety qualities, meet the legal requirements for food and have completed the required functional testing on humans or animals. Additionally, there should be tight defining procedures, highly explicit components and contents, and appropriate objects.

It simply states that it “refers to the functional ingredients in functional foods” and describes the chemicals found in vitamin functional foods that are “substances capable of regulating human body function through activating enzyme activity or other means” [20]. Vitamin functional foods often need to include functional components that match their functions, guarantee the minimum effective quantity of functional ingredients, and, if needed, set a maximum limit on the number of effective ingredients. It has passed the required functional experiments on humans or animals and possesses the sensory, nutritional, and safety features of a legal food [20]. In addition, the applicable objects and their effective components and contents should be clearly defined, with exact defining methods, and so forth. Customers are now used to choosing certain functional foods according to their personal health concerns. Understanding the main functional components of functional foods and their functions is, therefore, essential.

4. Functional food: sources and classification

The sources of origin of functional foods are divided into four categories: plant, animal, microbial, and miscellaneous (such as algae, mushrooms, and other substances). Functional foods, no matter where they come from, target a number of health issues, including women’s and cardiovascular health, aging, diabetes mellitus, cancer, and immune system enhancement.

4.1 Plants-based healthy (functional) foods

Functional meals generated from plants can be categorized as primary or secondary metabolites. Primary metabolites are essential plant components for growth, whereas secondary metabolites play a role in plant survival tactics but are not necessary for growth.

4.1.1 Flaxseed

The products made from flaxseed include whole seed, ground flaxseed, flaxseed oil, partially defatted flaxseed meal, fully defatted flaxseed meal (from solvent extraction), extracts from flaxseed mucilage, flaxseed hulls, flaxseed oleosomes, and extracts from flaxseed alcohol. Each of these products has been linked to particular health benefits. Although each fraction contains more than one bioactive component, publications frequently neglect the presence of many bioactive chemicals in flaxseed fractions or attribute the observed impact to a single component.

Whole flaxseed is widely recognized as a healthful food with anticancer properties. Flaxseed eating has been shown to provide several health benefits in controlled experimental diets [21, 22]. In female rat mammary glands, dietary flaxseed flour decreases epithelial cell proliferation and nuclear abnormalities. This research suggests that flaxseed may slow the progression of breast cancer [23]. Furthermore, flaxseed lignan has been shown to inhibit breast tumor growth in the later phases of carcinogenesis [24]. In male Fisher 344 rats, the incidence of azoxymethane-induced aberrant crypt foci development is decreased by supplementing with 14% flaxseed oil and 20% flaxseed meal [25]. Similarly, it has been demonstrated that substituting 15% of the maize meal and 15% of the flaxseed oil in a basal diet dramatically reduced the number and size of tumors in the colon and small intestine of male Fisher 344 rats. According to the authors’ findings, flaxseed oil and meal are useful chemopreventive agents [26].

Flaxseed oil has a higher concentration of the omega-3 fatty acid a-linolenic acid. However, the study studies have focused on lignan, a fiber component. Plant lignans are used by bacteria in the GI tract to synthesize two essential mammalian lignans, enterodiol, and enterolactone [27, 28]. Because natural enterodiol and enterolactone are equivalent to synthetic estrogens, they were discovered to have lower estrogenic and antiestrogenic actions. It may play a key role in lowering the risk of estrogen-dependent malignancies.

However, no investigations have been recorded to date to confirm the idea. Some rodent studies found that it reduced the risk of colon and mammary gland tumors [29], as well as lung cancer [30]. Flaxseed has also been proven to reduce CVD risk by lowering total and LDL cholesterol [31] as well as platelet aggregation [32]. Furthermore, the benefits of flaxseed on cancer risk reduction were investigated. It was discovered that eating 10 g of flaxseed each day generated some hormonal changes associated with a lower risk of breast cancer [33]. According to Adlercreutz et al., urine lignan levels were lower in postmenopausal breast cancer patients compared to controls who ate a regular diet [34].

4.1.2 Tomatoes

Tomatoes are high in lycopene, and a carotenoid found in the fruits that plays a significant role in cancer prevention [35]. Eating tomatoes on a regular basis lowered the chances of developing prostate cancer [36].

Higher lycopene levels in serum or tissue were also associated with a lower risk of malignancies such as breast, digestive system, cervix, bladder, skin [37], and lung [38]. Lycopene’s antioxidant activity is the primary cause for its cancer-preventive impact. In numerous biological systems, lycopenes are highly efficient against singlet O₂ [39]. Lycopene’s radical scavenging ability has also been linked to a lower risk of myocardial [40]. The rich matrix of chemicals found in tomatoes provides numerous health benefits to humans. Table 3 lists the various classes of bioactive chemicals and their health advantages.

Class	Compound	The main impacts
Carotenoids	Lycopene	Inhibition of cancer (breast, colorectal, prostate, endometrial, oral, pancreatic, and lung)
	β-Carotene	Photo oxidant damage prevention
		Atherosclerosis inhibition and myocardial infarction prevention
	Lutein	Improved endogenous damage and repair resistance to DN
		Eye health protection and symptom improvement in ARMD
Vitamins	Vitamin E	Inhibition of lipid peroxidation and cardiovascular illnesses
		Decreasing risks of advanced prostate cancer and type II diabetes
	Vitamin C	LDL oxidation inhibition and monocyte adhesion
	Folates	Monitoring homocysteine metabolism
		Lowering the risk of neural tube defects
Phenolics	Flavonoids	Anti-inflammatory intestinal activity
		TNF-alpha inhibition-mediated inflammation
	Phenolic acids	DNA oxidation protection and antitumor activity against carcinogenesis in the colon
	Tannins	Adipogenesis inhibitors
		Antibacterial, antiviral, cardiovascular, anticarcinogenic action

Table 3.

Chemical components identified in tomatoes and their health effects [41].

4.1.3 Apples

Apples include a variety of chemicals, including hydroxycinnamic acids, dihydrochalcones, flavonols, catechins, triterpenoids, oligomeric procyanidins, and anthocyanins (red apples). The bioactive chemicals found in apples and apple products have been linked to a reduction in the risk factors for CVD, asthma and pulmonary dysfunction, diabetes, obesity, and cancer. The chemical oligomeric procyanidins contained in apple juice, apple peel, and apple extracts were responsible for the cancer-prevention effect [42]. It has been processed by a variety of methods, including antimutagenic activity, carcinogen metabolism regulation, antioxidant activity, anti-inflammatory processes, signal transduction pathway modulation, antiproliferative, and apoptosis-inducing activities.

Additionally, a number of observational studies have shown a beneficial link between eating apples and a decreased chance of contracting certain chronic illnesses or passing away from them [43]. The major underlying biological effects that have been attributed to the compounds present in apples include:

4.1.3.1 Antioxidant properties of apples

Many chronic diseases, including diabetes, obesity, cancer, hypertension, and cardiovascular disease, are linked to oxidative stress [44]. Oxidative stress occurs as a result of cells’ failure to regulate the generation and use of reactive oxygen (or nitrogen) species (ROS). Innate cellular antioxidants that act through various mechanisms and at different stages to maintain cellular redox homeostasis typically tightly control the process of ROS generation, whether it occurs endogenously in normal metabolism and mitochondria or exogenously from xenobiotics and the environment. According to Anwar et al. [45], this process comprises enzymes, proteins, vitamins, carotenoids, polyphenols, and minerals.

4.1.3.2 Apple consumption for the prevention of cardiovascular diseases

Cardiovascular diseases (CVDs), which include coronary heart disease, stroke, atherosclerosis, hypertension, cerebrovascular disease, and others, continue to be the world’s leading health problem and cause of death, accounting for about 18 million deaths in 2017 alone [46]. This massive health burden necessitates immediate disease management techniques to reduce prevalence and mortality. In prospective cohort studies, dietary flavonoids were found to have an inverse connection with CVD-associated mortality, confirming the notion that eating fruits and vegetables on a regular basis may help reduce the risk of developing CVD. In clinical trials, apple consumption reduced atherogenic cholesterol levels [47], improved endothelial function [48], and decreased bone mass index [49]. These collective research findings may be critical in the prevention of CVD. I.

4.1.3.3 Apple supplementation to manage cancer

Cancer is a significant health and economic burden on humans, ranking second in the global cause of mortality ranking and anticipated to overtake ischemic heart disease for first place by 2060 [50]. Polyphenol-rich fruits and plant extracts have been proposed as chemopreventive drugs due to their multiple pharmacological modes of action aimed at preventing carcinogenesis. Apple eating on a regular basis has been demonstrated to benefit various types of cancer.

Colorectal cancer outcomes have been observed to be alleviated by apple polyphenols, flavonoids [51], phloretin [52], and polysaccharides [53]. Apple anthocyanin—cyanidin-3-O-galactoside—was recently shown to diminish the emergence of the precancer indices measured in the study in the azoxymethane (rat carcinogenesis) model. Cell cycle arrest, suppression of cell migration and invasion, apoptosis, antiangiogenesis, anti-inflammatory, and antioxidant are all claimed mechanisms of action against cancer [54].

4.1.3.4 Protection of the gastrointestinal tract (GIT) with apple intake

The impact that apple components have on the human gut flora is a significant additional way in which they improve human health. It has been shown that pectin fiber and apple proanthocyanidins interact with the gut microbiota, altering its makeup to provide advantageous effects [55]. For example, a drop in the Firmicutes/Bacteroidetes ratio accompanied by an increase in Akkermansia in the cecum was linked to apple procyanidin intake, which was demonstrated to reduce obesity in mice [56]. The anti-inflammatory properties of apples associated with metabolic syndrome relief are thought to be attributable to gut microbiota modification. Pectin has been shown to induce the commensal bacteria Faecalibacterium prausnitzii in the human colon, which has anti-inflammatory properties [55].

4.1.3.5 Apple consumption against type 2 diabetes and obesity

Apple supplementation in diabetes or obese rodent diets [57] and in vitro tests [58] showed an improvement in the diabetic indices assessed. These antidiabetic effects, due primarily to the polyphenol ingredient, were reported to occur by inducing beige adipocyte formation in inguinal white adipose tissue. Other methods include insulin resistance and hyperglycemia reduction, oxidative stress and inflammation reduction, and suppression of glucosidase enzyme activity.

4.1.4 Oats

Whole grains of oats have been extensively examined as a source of beta-glucans and may have a possible influence on decreasing the likelihoods of coronary heart disease (CHD). Kelly et al. investigated the effect of consuming whole grain foods on CHD, and the trials were carried out on individuals who had previously been diagnosed with CHD or who had risk factors for CHD [59]. According to the findings, eating oatmeal can lower total and LDL cholesterol levels, potentially lowering the risk of CHD. It was also shown that the high content of glucan in oats was responsible for lowering the postprandial glycemic response of glucose in type 2 diabetic patients.

4.1.5 Garlic

Garlic (Allium sativum) is widely regarded as an important herb for its therapeutic properties [60]. Garlic has anticancer, antihypertensive,, and cholesterol-lowering activities [61]. Allicin, one of garlic’s primary ingredients, is responsible for its chemopreventive properties. Garlic contains 26–30% inulin, a nondigestible polysaccharide, in fresh garlic cloves and 77% in dried garlic. It is the component that gives it its prebiotic function. Consuming garlic and inulin supplements may influence the formation of microflora, particularly in diets high in fat, carbohydrates, and dietary fiber [62]. Table 4 provides an overview of the many biological processes involved in garlic.

Living things in action (biological activity)	Action mechanism
Antioxidant activity	After taking 80–4000 mg of garlic per day for two to four weeks, the blood SOD levels rise, resulting in a reduction in malondialdehyde and an increase in overall antioxidant capacity
	The phytochemicals included in garlic may raise GSH levels in cells and encourage the production of antioxidant enzymes, such as catalase or SOD
	Ajoene’s antioxidant activity is mediated, among other things, by Nrf2 activation, which controls GCL expression and raises GSH levels. Similarly, by increasing the expression of GCL and HO-1 and activating the Nrf2 pathway, AGEs may lessen the oxidative stress experienced by endothelial cells
	AGEs conduct antimutagenic, anticarcinogenic, and reparative functions on damaged structures in addition to playing an antioxidant role against damage to DNA structures produced by UV radiation
	Allicin inhibits oxidative stress reactions brought on by many stimuli via controlling apoptosis and the Nrf2 pathway
Anti-inflammatory activity	Inhibition of IL-17 release was seen in mononuclear cells treated with garlic extracts; After treating mononuclear cells with garlic extract, IL-14 production remained unaffected
	Following alliin administration, there has been evidence of a decrease in adipocyte IL-6 and MCP-1 release, as well as an increase in the expression of genes related to the inflammatory response
	The components of garlic have the potential to regulate the inflammatory response that T helper cells trigger
	Components of garlic have the ability to block NF-κB, which can lessen the inflammatory response caused by, among other things, TNF-α, IL-1, IL-6, MCP-1, and IL-12
	TNF-α, IL-6, and IL-12 production are all decreased by AGE
Antimicrobial activity	Garlic has been shown to have antifungal action against both Candida albicans and Penicillium funiculosum
	Studies on Bacillus cereus, Staphylococcus aureus, Micrococcus spp., Escherichia coli, Klebsiella spp., Proteus spp., Aspergillus versicolor, Penicillum citrinum, and Penicillium expansum have demonstrated the antibiofilm and antibacterial properties of garlic extracts
	It has been demonstrated that garlic has antiviral effect by inhibiting viral DNA synthesis and retrotranscription
	The influenza A (H1N1) virus is inhibited from penetrating and proliferating by garlic extract
	HIV-1 inhibitory action is exhibited by garlic compounds such as glutamyl cysteine, DATS, allin, or allicin
	Garlic, together with its flavonoid and organosulfur components, inhibits the pathogen’s 6 LU7 protein, which is responsible for its antiviral effects against SARS-CoV-2 infection
	Garlic helps treat COVID-19 disease by boosting immune system cells and reducing the release of leptin and proinflammatory cytokines
	Human lung epithelial cells treated with garlic-derived DATS showed reductions in viral load, increases in viral gene expression, and decreases in proinflammatory cytokine expression
	Garlic’s ajoene suppresses the influenza A (H1N1) virus’s NA protein, which triggers the start of a viral infection
Immuno-modulatory activity	It has been demonstrated that the protein fraction and AGE from garlic activate macrophages, natural killer cells, and lymphocytes
	Depending on the dose taken, consuming garlic and its derivatives has been demonstrated to have immunomodulatory effects

Table 4.

Crucial discoveries on garlic’s biological activities [63].

Note: GSH, glutathione; SOD, superoxide dismutase; NA, neuraminidase; DATS, diallyl trisulfide; Nrf2, nuclear factor erythroid 2-related factor 2; GCL, glutamate-cysteine ligase; AGE, aged garlic extract; HO-1, heme oxygenase-1; HIV-1, human immunodeficiency virus type 1; IL, interleukin; MCP-1, monocyte chemotactic protein; TNF-α, tumor necrosis factor α; NF-κB, nuclear kappa B transcription factor.

4.1.6 Almond

Free radicals have been shown to cause oxidative damage to proteins, lipids, and nucleic acids [64]. Antioxidant enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase, are essential for scavenging oxidants and averting cell damage, but they are not enough. As a result, biological macromolecules are vulnerable to oxidative damage [65]. Several epidemiological studies suggest that eating foods high in natural antioxidants enhances plasma antioxidant capacity and lowers the risk of some, but not all, malignancies, heart disease, and stroke [66].

According to one study, eating almonds may boost antioxidant defense in the body and lower the risk of CVD and cancer. These positive effects were linked to the polyphenols found in almond shells. These polyphenols were discovered to increase quinone reductase activity, and it should be noted that the effect was dependent on polyphenol quantities, extraction process, and vitamin present.

The nutritional value of the almond fruit is associated with its kernel. When the fruit matures, the hull splits open and is separated from the shelled almond (the full natural almond). The skin, or seed coat, is removed from the kernel and discarded during some industrial almond processing. These skins are not removed when making roasted almonds and other appetizers.

Almonds are commonly consumed as a snack and as an ingredient in a wide range of processed meals, particularly bakery and confectionery goods [67]. These nuts have been demonstrated to increase levels of high-density lipoprotein cholesterol while lowering levels of low-density lipoprotein cholesterol in humans [68] and to reduce the incidence of colon cancer in rats [69]. Strong free radical-scavenging abilities are exhibited by whole almond seed extracts, which include the brown skin, shell, and green shell cover (hull) [70, 71]. The presence of flavonoids and other phenolic compounds in nuts may be linked to these functions.

4.1.7 Broccoli and leafy green vegetables

Broccoli is a member of the Brassicaceae family. It contains vitamins C and E, as well as soluble fiber, diindolylmethane, and selenium. According to epidemiological research, regular consumption of cruciferous vegetables is connected with a lower risk of cancer. The anti-cancerous qualities of cruciferous vegetables have been linked to high amounts of glucosinolates, which may be found in the cell vacuoles of leafy vegetables [72].

A collection of natural and synthetic isothiocyanates was found to have anti-cancerous effects in animals [28]. A specific form of isothiocyanate, identified as sulforaphane in broccoli, was responsible for lowering the risk of cancer. A collection of natural and synthetic isothiocyanates was found to have anti-cancerous effects in animals [73]. A specific form of isothiocyanate, identified as sulforaphane in broccoli, was responsible for lowering the risk of cancer.

Sulforaphane was discovered to be a crucial source of an enzyme known as quinone reductase. Furthermore, broccoli diindolylmethane acts as a major controller of the innate immune response system, with antiviral, antibacterial, and anticancer activities.

Several experimental studies have indicated the potential benefits of vegetable consumption in the prevention and management of CVD. A range of bioactive components, including vitamins, essential minerals, dietary fiber, botanical proteins, and phytochemicals, have been linked to the cardioprotective effects of vegetables, including potatoes, soybeans, sesame, tomatoes, Dioscorea, and onions [74]. Moreover, blood pressure reduction, lipid metabolism modification, blood glucose regulation, antioxidation, anti-inflammation, anti-platelet, endothelial function enhancement, and attenuation of myocardial damage are possible cardioprotective advantages. Moreover, the mechanisms of action can involve controlling pertinent gene expression, signaling pathways, enzyme activity, and a number of other CVD risk markers (Table 5).

Effects that protect the heart (cardioprotective)	Techniques (mechanisms)
Regulate lipid metabolism	Reduce TC, TG, TAG, VLDL-C, TC/HDL-C ratio, and the development of atherosclerotic plaque; raise LDL-C/TG and VE/TG ratios; impede the activity of fatty acid synthase and ACAT; adjust the expression of ACAT and sterol regulatory element-binding protein-2 and its downstream genes; and inhibit fatty acid synthase and ACAT activity
Lower blood pressure	Reduce sympathoexcitation, decrease ACE activity and the hypothalamic MR-ATIR pathway, enhance protein kinase C-β II activity, alter the relative telomere length of peripheral leucocytes, upregulate the expression of NOS, and block K^+- and Ca^2+-induced contractions
Anti-inflammatory	Diminish leukocyte adhesion induced by TNF-α, lower NF-κB and IL-6, and prevent AM expression
Improve endothelial function	Reduce the thickness of the artery intima-media and endothelin, boost NO, enhance the protein profiles of apolipoprotein A–I and apolipoprotein J, block the endothelin-converting enzyme, and lessen DNA damage
Antioxidant	Scavenge free radicals (NO, superoxide, hydroxyl, TBARS); increase endogenous aortic H2S production; improve SOD, catalase, GPx, carnitine palmitoyltransferase-1, and paraoxonase 1 activity
Attenuate myocardial damage	Reduce MDA, water content leakage, infarct size, and increase cyclic guanosine monophosphate; block the activity of aspartate transaminase, lactate dehydrogenase, creatine kinase, and CPKMB; modify the activity of protein kinase A, p38, and phosphodiesterase-5; block the expression of Bad, Bax, caspase-8, caspase-9, and caspase-3, as well as aquaporin 4, and reduce MDA, water content leakage, and infarct size; increase phosphor (p)-Akt, p-Bad, p-Erk1/2, Bcl-2, p-JAK2, and p-STAT3
Regulate blood glucose	Reduce the activities of α-amylase and α-glucosidase; enhance hemoglobin A1c and elevated fasting blood sugar levels
Anti-platelet	Extend APTT, TT, PT, bleeding time, and clotting time; block c-Jun N-terminal kinase signaling pathways, ESRK, factor VIII, MAPK, and factor VIII activities

Table 5.

The mechanisms involved in the cardioprotective effects of vegetables [74].

4.1.8 Citrus fruits

Citrus fruits are high in nutrients such as vitamin C, folate, and fiber. The antioxidant capabilities of flavonoids, in addition to vitamin C, are particularly important. It was also shown that citrus fruits serve an important function in lowering the risk of many cancers. Citrus fruits’ anticancer properties were linked to a class of phytochemicals known as limonoids [75]. The cancer-prevention effect and discovered that it was effective against both spontaneous and chemically-induced rodent tumors [76].

Citrus bioactive compounds, particularly flavonoids, carotenoids, terpenes, and limonoids, have antioxidant activity, and thus have potential applications against obesity [77], inflammatory diseases [78, 79, 80], atherosclerosis [81], neurodegenerative diseases [82, 83], and cancer [84, 85] (Table 6). The pancreatic lipase (PL) enzyme is important in the breakdown of triglycerides in the gastrointestinal tract, and inhibiting it can help with obesity by reducing fat absorption [77]. Citrus peel extracts of grapefruit, pomelo, kumquat, mandarin, and ponkan were shown to contain the most hesperidin, neohesperidin, naringin, narirutin, and eriocitrin [77]. Interestingly, in this investigation, hesperidin, the most dominant flavonoid in ponkan peel extract, demonstrated the strongest pancreatic lipase inhibitory activities, implying a possible application in the management of obesity.

Compounds (bioactive and doses)	Experimental system	Disease target	Mechanism of action
PMF nobiletin (10–50 μM)	LPS-stimulated RAW264.7 cells	Inflammatory diseases	Reduce release of NO, increase expression of iNOS and COX-2, increase autophagy, activation of the IL-6/STAT3/FOXO3a signal pathway
Flavanones (10 μM)	Caco-2 cells stimulated with IL-1	Bowel diseases	Decrease IL-6, IL-8, and NO release
Hesperetin and gardenin A (5–10 μM	PMA/ionomycin-induced EL-4 murine T-lymphoma cell cells	Asthma	Reduce ROS and IL-5 production, decrease NFAT activity and IL-5 secretion, ↑HO-1 through enhance Nrf2, PPARγ, PI3K/AKT, or ERK/JNK signaling
Pectin oligosaccharides (5 mg/mL)	LPS-stimulated human macrophages	Atherosclerosis	Increase Immune responses, reduce TNF-α, IL-6, IL-10, and NF-κβ mRNA, increase cholesterol efflux via LXRα and ABCA1, and ABCG1 pathway, decrease cholesterol synthesis via reduce HMGCR
Limonene (1–100 mg/mL)	Aβ1–42 triggered toxicity in primary cortical neurons	Alzheimer’s disease (AD)	Decrease AchE, ROS production, voltage-gated K^+ channel KV3.4 hyperfunction, and phosphorylated ERK
Flavanone-rich mandarin juice extract (0.001–1 mg/mL)	6-hydroxydopamine (6-OHDA)-stimulated SH-SY5Y human neuroblastoma cells	Parkinson’s disease (PD)	Reduce ROS and NO, restored SOD and CAT activity, ↓caspase 3 activity, increase Bcl-2 mRNA, decrease p53 and Bax mRNA, restored mitochondrial membrane potential, decrease oxidative DNA damage, balanced α-synuclein, LRRK2, parkin, PINK1, and DJ-1 mRNA levels
Limonoids (Fortunellon and nomilin; 30 μM)	HeLa cells	Cancer (Cervical)	Increase adriamycin-dependent cell death
Limonin, nomilin, and limonexic acid (20–60 μM)	Human pancreatic Panc-28 cells	Cancer (pancreatic)	Decrease cell proliferation (IC50 values <50 μm after 72 h), increase cleavage of caspase-3, mitochondrial membrane potential, increase Bax/Bcl2 expression, and p21, decrease COX-2, NF-κβ, and IL-6
Naringenin (62.5–2000 μM)	Human A549 lung epithelial cells and primary human monocyte-derived dendritic cells	Zika virus infection	Decrease replication or assembly of viral particles
Naringin- and hesperidin-rich junos peel extract (0.5 mg/mL)	Human lung basal epithelial NCI-H460 cells exposed to H2O2	Oxidative stress-induced diseases	Decrease p53, cytochrome c, and Bax proteins
Phase-II flavanone metabolites (2–100 μM)	Pancreatic β-cell MIN6 cells exposed to cholesterol	Oxidative stress-induced diseases	Decrease oxidative biomarkers (superoxide anion, H2O2, and MDA), decrease SOD and GPx, increase insulin secretion, decrease apoptosis
β-cryptoxanthin from mandarin oranges; IC50—4.5 μM (24 h treatment)	HeLa cells	Cancer (cervical)	Decrease Bcl-2 mRNA, increase Bax, caspase-3, -7, and -9 mRNA, nuclear condensation and disruption of the integrity of the mitochondrial membrane, activation of caspase-3 proteins, nuclei DNA damage, and apoptosis

Table 6.

Citrus fruit bioactive chemicals’ health effects have been proven utilizing in vitro experimental models [86].

4.1.9 Berries

Berries are high in anthocyanin and antioxidants, and they contain a number of anti-CVD, oxidative stress, and inflammatory properties. Berries have also been linked to improved neuronal and cognitive brain processes, ocular health, and genomic DNA integrity. Zafra-Stone et al. investigated the effect of combined berry extracts and discovered that the extracts performed a number of tasks such as strong oxygen radical quenching capability, antiangiogenic, and antiatherosclerotic activity [87].

Global study indicates that berries are an essential part of a healthy diet. Berries are rich in phytochemicals known as antioxidants, which help shield the body from a variety of illnesses and conditions, as well as the damaging effects of free radicals, which cause age-related chronic diseases. Berries: Berries are used to treat sore throats, nausea, aphtha, stomatitis, diabetes,, cancer, inflammation, and dysentery [88, 89]. Berries are also used as leaves (Table 7).

Berries	Phytochemicals	Biological properties
Blackberry	Rich in fiber, cyaniding-3-O-glucoside, polyphenols, manganese, folate, antioxidants, and vitamin C High tannin content and salicylate content	Combats the damage caused by free radicals; antiseptic, antibacterial/viral, anticancer; lowers cholesterol; slows down the aging process; acts as an analgesic and pain reliever; strengthens blood vessels
Cranberry	Rich in calcium, iron, folate, magnesium, manganese, vitamins C and A Has a higher phenolic content than the other berries that were investigated	Diuretic, antibacterial, and antiseptic; improves digestion; clears fat from lymphatic system; and supports cardiovascular health
Blueberry	Rich in vitamin C, B complex, E, A, and antioxidants High in manganese, iron, zinc, and selenium Includes lutein, zeaxanthin, and beta-carotene	Anti-inflammatory, antidiabetic, and anticancer Prevents macular degeneration and weight loss Prevents Alzheimer’s disease; aging indicators are reversed; circulation is protected and improved; cholesterol is decreased
Bilberry	Rich in vitamins C, E, and manganese Rich in anthocyanins and flavonols Includes zeaxanthin, lutein, and carotenoid	Healthy for gums, mouth, and eyes Strengthens arteries, protects blood vessels, boosts circulation, and has potent anti-inflammatory properties
Blackcurrant	High in anthocyanins, calcium, zinc, magnesium, potassium, vitamins A, B2, and gibberellic acids.	Has anti-inflammatory qualities, cleanses and lowers blood cholesterol, and enhances the function of the kidneys, liver, pancreas, and spleen in addition to digesting
Raspberry	Rich in vitamins C, B, u-3, fibers, gallic acid, and ellagic acid and acts as a strong antioxidant Contains folate, iron, potassium, copper, and lutein	Increases metabolic rate, which burns fat, has anticancer, antibacterial, and protects damage from free radicals excellent for eye strength and health
Elderberry	Rich in vitamins C, A, and B Contains high amounts of flavonoids and carotenoids High in calcium and iron	Enhances digestion, strengthens the immune system, helps with arthritic problems, improves breathing and asthma, and guards against free radical damage to DNA

Table 7.

A comparative analysis of the biological characteristics and bioactive components of berries [90].

4.1.10 Tea

Tea ingredients have been extensively investigated for their diverse actions with a particular emphasis on the polyphenolic chemicals found in green tea [91]. The polyphenol content of fresh tea leaves was changed up to 30% (dry weight basis). Catechins are the most essential and prevalent polyphenol in tea. It is made up of epigallocatechin-3-gallate, epicatechin-3-gallate, and epicatechin.

Several studies have suggested that green tea may reduce the risk of CVD and cancer, as well as have an effect on bone health, cognitive function, tooth problems, and kidney stones. Dreosti et al.’s findings validated the anti-cancerous action of tea components [92]. Tannins found in green tea have been shown to have high antioxidant activity according to a study conducted by [93].

4.1.11 Grapes

Polyphenols, such as resveratrol, phenolic acids, anthocyanins, and flavonoids, are powerful bioactive chemicals found in grape extracts. Grapes have been demonstrated to reduce the risk factor associated with inflammatory disorders, such as CVD. Grapes or grape juice have a favorable effect on CVD risk factors due to their capacity to lower LDL cholesterol levels and platelet aggregation [94]. Trans-resveratrol, a phytoalexin found in grape skins, is another chemical identified in red wine [95]. Resveratrol’s estrogenic characteristics have been linked to a reduction in cancer risk factors [96].

4.2 Animal-derived functional foods

Plant-derived functionally active chemicals abound. Nonetheless, animal diets contain a variety of physiologically active components that have been shown to improve health [97]. Functional foods derived from animals, known as zoochemicals, contain glucosamine and chondroitin sulfate, conjugated linolenic acid, small peptides, whey, and casein. Alpha-linolenic, docosahexaenoic (DHA), and eicosapentaenoic (EPA) fatty acids are all omega-3 fatty acids. Soy and canola oils, walnuts, and flaxseed are all good sources of alpha-linolenic acid. Fatty fish, such as salmon, are the primary source of EPA and DHA. Linolenic, gamma-linolenic, and arachidonic fatty acids are all omega-6 fatty acids. Some vegetable oils, nuts, and whole grains are good sources of these fatty acids. Omega-3 and 6 fatty acids operate as functional meals by boosting immunity, reducing inflammation, and guarding against neurological disorders.

A fatty liver may develop as a side effect of conjugated linolenic acid, and a fatty acid present in milk that is said to operate as a functional food by reducing the risk of cancer and adipose differentiation [98]. Small peptides and milk proteins, such as whey and casein, have comparable functions as functional meals since they are readily absorbed and digested while also aiding in muscle growth.

4.2.1 Meat and meat products

Meat and meat products are typically regarded as high-protein sources. It is also a good source of fatty acids, iron, zinc, vitamin B12, and folic acid [99]. Diets high in lean meat may influence the reduction of plasma cholesterol levels [100]. The current focus of study is on conjugated linoleic acid (CLA), which was discovered to have anticarcinogenic properties in 1987 [101]. CLA denotes a blend of linoleic acid (C18:2, n-6) isomers with conjugated double bonds rather than a normal methylene-interrupted structure [38]. Ruminant animals, such as cattle and lamb, are high in CLA.

CLA was proven to be helpful in preventing stomach malignancies in mice, abnormal colonic crypt foci in rats, and mammary carcinogenesis in rats in research investigations [102]. CLA’s usefulness in changing body composition was also investigated, and the findings revealed that it acts as an agent in lowering fat levels and increasing lipolysis in adipocytes [103].

According to several research, proper CLA consumption may reduce the occurrence of colon cancer [104]. CLA has also been shown to have anti-oxidative and immunological modulatory effects. Carnosine (−alanyl-L-histidine) and anserine (N-alanyl-1-methyl-L-histidine) are two histidyl dipeptides that have anti-oxidative properties in meat. Chicken meat has a carnosine content of 500 mg/g and a higher anserine content than carnosine. These peptides have the ability to chelate metals such as copper [105]. According to research findings, these chemicals operate as a resistance to numerous illnesses and health problems related with oxidative stress [106].

4.2.2 Fish

Fish is a good source of omega-3 (n-3) fatty acids, which are a type of polyunsaturated fatty acid (PUFA). It contains eicosapentaenoic acid (EPA; C20:5, n-3) and docosahexaenoic acid (DHA; C22:6, n-3) among other things. Because of their diverse health benefits, these PUFAs have received a lot of attention in seafood research [107]. There has also been research on the role of PUFAs in the prevention of many diseases such as CVD [108], high blood pressure [109], blood clotting [110], and cancer [111].

The potential of n-3-PUFAs to modify the lipid fractions in the membrane, producing changes in metabolic and signal transduction pathways, is responsible for their health advantages [112]. DHA is essential for the correct functioning and development of the brain and central nervous system. It is also critical in the development of these systems in newborns and expectant mothers [113]. Several studies have found that n-3 PUFAs can help prevent dementia. A study conducted by the Nehru Science Centre in Mumbai discovered that a DHA-rich diet slows the progression of neurological diseases in senior people. Tan et al. confirmed the protective effect of an EPA/DHA-enriched diet against brain aging [114].

Another study, by Virtanen et al. [115], suggested that circulating n-3 PUFAs may be linked to a lower risk of certain subclinical brain abnormalities. Antihypertensive peptides termed angiotensin I-converting enzyme (ACE) inhibitors are also found in fish [116]. ACE molecules have been discovered in fish waste hydrolysates. Kitts and Weiler proposed viable bioprocess methods for separating these peptides [117]. ACE peptides contribute to blood pressure reduction by limiting the vasoconstrictor effects of angiotensin II and supporting the vasodilatory effects of bradykinin [118]. The antihypertensive impact of ACE inhibitors extracted from fish muscle in their review [119]. Fish protein hydrolysates (FPHs) treated with enzymes have the potential to be employed as cardioprotective (anti-atherogenic) components in nutraceuticals or pharmaceuticals [120].

4.2.3 Egg

Eggs are often not regarded as functional foods due to their detrimental impact on blood serum cholesterol levels. According to Hasler’s study, frequent egg consumption may have no effect on cholesterol levels [98]. Eggs are high in protein, sphingolipids, choline, n-3 PUFA, and lutein/zeaxanthin. As a result, the egg may be viewed as a critical component in transforming the face of functional foods [98].

Apart from dairy products and soybean, eggs are a major source of sphingolipids [121]. Sphingolipids have been linked to biological processes such as growth regulation, differentiation, and death. According to animal research, sphingolipid supplementation slows colon carcinogenesis, lowers blood LDL cholesterol levels, and raises HDL cholesterol levels [121]. Choline is contained in eggs at a concentration of 2000 mg, which is enough to meet the daily dietary limit recommended by the National Academy of Sciences in 1998 [122]. Choline is being studied for its health benefits related with cognitive function, particularly in early brain development. Eggs are also a good source of lutein and zeaxanthin, which have been linked to a lower risk of age-related macular degeneration, the leading cause of permanent blindness in the United States [123]. Numerous studies have documented the immunomodulatory properties of egg proteins and their generated peptides, which take place through a range of pathways (Table 8) [124].

Protein	Enzymes used for making peptides	Mechanism of activity
Phosvitin	Trypsin	Decreased release of TNF-α from murine RAW 264.7 cells caused by LPS Increased proinflammatory cytokine production and macrophage phagocytic activity in the absence of LPS stimulation Inhibited TNF- and LPS induced IL-8, IL-12, and MCP-1 expression in HT-29 cells
Ovalbumin	Pepsin, chymotrypsin	Increased TNF-α release Cytokine production was impacted by heat-denatured ovalbumin A rise in IL-12, IL-17, and IL-10 production and a fall in IL-4 production
		Peptides (OA 77–84, OA 126–134) increased in macrophage phagocytic activity
Ovotransferrin	Thermolysin, pepsin	Activated nitrite, MMP, and IL-6 synthesis An increase in proinflammatory cytokine production through the MAPK pathway
		IRW prevented endothelial cells from producing MCP-1, VCAM-1, and ICAM-1 in response to TNF-α
		IRW suppressed the translocation of p50 and p65 (related to the NF-κB pathway)
Ovomucin	Alcalase, pronase-papain	Inhibited TNF-mediated NF-κB pathway Suppressed TNF-induced ICAM-1 expression Stimulated macrophage activity by increasing H2O2 generation and IL-1 production
Cystatin		Stimulated NO production in mouse peritoneal macrophages Induced the synthesis of TNF-α and IL-10 Upregulated IL-6 and IL-8 production in gingival fibroblasts
Lysozyme		Improved chronic sinusitis and bronchitis Stimulated immunoglobulin production Enhanced IgM translation Lysozyme-galactomannan conjugate (LGC) enhanced proinflammatory cytokine production via JNK, ERK, and NF-κB pathway
Livetin	Pepsin, alcalase	Suppressed the production of proinflammatory cytokines
IgY		Reduced the rise in IFN-γ and TNF-α and the drop in IL-10 in the model of Salmonella Typhimurium infection in mice

Table 8.

Peptides and proteins from eggs that have immunomodulatory properties [124].

4.2.4 Milk and milk products

The effects of milk and milk products on human health have been widely established, and this may be attributed to bioactive chemicals in milk and probiotic bacteria found in fermented milk products. Milk, in addition to nutrients such as protein, carbs, and fats, contains a variety of bioactive elements such as immunoglobulins, enzymes, antimicrobial peptides, oligosaccharides, hormones, cytokines, and growth factors [125].

Lactose, milk’s sugar component, has been transformed to lactic acid, which lowers the pH and changes the physical properties of casein. As a result, it enhances digestibility, boosts calcium utilization, and inhibits bacterial development. Lactulose is a byproduct of milk thermal processing that enhances an individual’s health by allowing probiotic bacteria (bifidobacteria and lactobacilli) to thrive on their own [126]. Other polysaccharides and their hydrolyzed derivatives, such as kefiran, one of the components in kefir, are also present in sour dairy products. Kefir provides numerous health benefits, including protection against metabolic disorders, atherosclerosis, allergic illnesses, TB, cancer, and gastrointestinal disorders [127].

Caseins, lactoglobulin, lactalbumin, immunoglobulins, lactoferrin, and serum albumin are the protein components of milk. Protein’s health benefits are also affected by the various peptides (protein breakdown components). Casomorphins, cytokinins, immunopeptides, lactoferrin, lactoferricin, and phosphopeptides are examples of these peptides. Immunomodulation, antimicrobial activity, antithrombotic activity, and blood pressure regulation are all functions of peptides [128]. Whey proteins including lactalbumin, lactoglobulin, lactoferrin, lactoperoxidase, and immunoglobulins are found in higher concentrations in fermented dairy products. It also has a number of health-promoting properties, including anticarcinogenic action [129].

β-Lactoglobulin, one of the protein components, has been implicated in functions such as emulation and immunomodulator [130]. Aside from these functions, it can also produce other activities such as antihypertensive, antithrombotic, opioid, antimicrobial, immunomodulant, and hypocholesterolemic properties. Furthermore, all lactoglobulin-derived peptides have radical-scavenging activity [131].

Because of its minimal allergy-inducing potential, the other protein component, lactalbumin, has been used as a nutrition in newborn meals. Furthermore, it has anticancer action, immunomodulatory effects, antimicrobial activity [132], and anti-ulcerative qualities [133].

IgG1, IgM, IgA, and IgG2 immunoglobulins are found in milk. These immunoglobulins perform immunological tasks such as pathogen defense, complement activation, phagocytosis stimulation, microbe adhesion prevention, and virus and toxin neutralization. They also increase glutathione levels, which function as a powerful anti-oxidant. They also help to prevent a variety of microbial illnesses [134].

Lactoferrin is found in lower concentrations in milk and has a variety of physiological activities including iron homeostasis management, protection against various microbial infections, anti-inflammatory, and anticancer action. It can also act as an immunosuppressive, anti-inflammatory, or immunostimulant agent. Lactoferricin is one of the peptides generated during the degradation of lactoferrin, and it is the key factor in its actions. Lactoferrin and lactoferricin may have antiviral activity against hepatitis C [135], human papillomavirus [136], herpes simplex virus [137], and chronic hepatitis C [138].

Milk protein bioactive peptides are effective in lowering the chances of obesity and type 2 diabetes [139]. Bioactive peptides can also be created through fermentation in products, such as various cheese kinds and fermented milk. Biologically active peptides can be formed during cheese ripening, and these peptides have been identified in products such as comet and cheddar cheese [140]. Furthermore, when the cheese ripens, the number of bioactive peptides released by secondary hydrolysis increases. As a result, it is clear that the functioning of peptides was determined by the ripening period. Other studies have shown bioactive peptides in fermented milk products (yogurt, sour milk, and Dahi). Yogurt and milk containing cultures of Lactobacillus casei ssp. Rhamnosus strain contains ACE-inhibitory, immunomodulatory, and opioid peptides [141]. They can also be present in yogurt made from bovine milk [142] and caprine milk kefir [143].

Milk fat components, such as CLA, butyric acid, ether lipids, carotene, and vitamins A and D, have been shown to lower the risk of several malignancies [144]. Many studies have described CLA’s cancer-preventive activity, as well as its potential to prevent atherosclerosis and modulate specific aspects of the immune system [145].

Sphingolipids and their metabolite were also engaged in many health-promoting actions such as cancer prevention, antibacterial and immunomodulatory activities, and cholesterol adsorption inhibition [146]. Butyric acid is thought to be an anticancer agent, and it, along with etheric lipids, vitamins (A, D, E), and linoleic acid, form a protective layer that protects against a variety of noncommunicable diseases [147]. Caprylic and capric acid have been shown to have antiviral properties. Lauric acid (C12:0) has been shown to have antiviral and antibacterial properties [148], as well as anticaries and antiplaque activity [149].

4.3 Microbial functional foods

Probiotics, prebiotics, symbiotics, and synbiotics are examples of microbial-derived functional foods. Probiotics are naturally occurring bacteria in the gut, such as L. casei or other Bifidobacter species that enhance health [98]. Probiotics are beneficial bacteria that are found naturally in the gut, such as Lactobacillus casei and other Bifidobacter species [98]. Prebiotics are dietary elements that support the growth of probiotic microorganisms. While synbiotics combine particular probiotics and prebiotics to benefit one another, symbiotics mix probiotics and prebiotics at random. Microbially derived functional foods function by promoting the growth of beneficial bacteria and stifling the growth of pathogenic bacteria.

4.4 Miscellaneous functional foods

Some functional meals are created from a variety of components, including algae and mushrooms. Algae provide omega-3 fatty acids, which boost immunity, reduce inflammation, and protect against neurological illnesses. Mushroom-derived functional foods have antiviral, antibacterial, and anti-inflammatory effects.

4.4.1 Algae

The marine ecosystem is underutilized as a potential source of bioactive substances that could be used in industries such as pharmaceuticals, cosmetics, and food. Among marine sources, macroalgae (or seaweeds) and microalgae have received the most attention. To acquire value-added products from macro and microalgae, appropriate extraction procedures must be used [150].

In general, algae has been thought to be a rich source of nutrients, such as proteins, carbs, fiber, minerals, and vitamins, with a low-fat content. Algae has been identified as a rich source of fiber with the soluble fraction consisting primarily of sulfated galactan in the form of agar or carragenates (in red algae) and alginates, fucans, and laminarin (in brown algae). Dietary fiber consumption may have preventive effects such as lowering the risk of colon cancer, constipation, hypercholesterolemia, obesity, and diabetes. It exhibits immunological activity in addition to antioxidant activity of dietary components. Undaria pinnatifida (wakame) was discovered to have a positive effect on certain CVD [151]. This alga is mostly composed of dietary fiber (as a principal ingredient) and alginic acid, which has been shown to reduce hypertension risk factors [151].

Polysaccharides were another type of chemicals found in algae that could have an influence. Polysaccharides, which are abundant in algae, have potent antiviral properties. Of these, sulfated polysaccharides include xylofucans, alginic acid, and two species of fucans are present in Sargassum vulgare [152] while sulfated fucans (fucoidans) [153] and sulfate of galactofucan [154] in good levels in Undariapinnatifida (brown alga). These components have been demonstrated to have antiviral activity against herpes type 1 virus (HSV-1), HSV-2, and human cytomegalovirus (HCMV). Fucoidans have the potential to serve as anticoagulants and antithrombotics [155]. Porphyran, a sulfated polysaccharide, was found in the red alga Porphyra sp. It exhibits effective apoptotic activity (as measured by AGS cells from a human stomach cancer), causing carcinogenic cells to die [156].

Carotenoid is an important bioactive chemical found in marine sources. Apart from coloration, it has biological properties such as antioxidant, antiproliferative, anti-inflammatory, provitamin A action, and even protection against macular degeneration [157]. Some macro- and microalgae have been identified as a critical source of carotenoid (Dunaliella salina, a green microalga). Dunaliella-derived carotene is a mixture of all-trans, 9-cis, 15-cis, and other minor isomers. Haematococcus pluvialis is another microalgae researched for its carotenoid (xanthophyll) supply [158].

The EPA describes Himanthalia elongata, Undaria pinnatifida, and Porphyra sp. as rich sources of PUFA. PUFA can help prevent disorders such as coronary artery disease, thrombosis, and arteriosclerosis [159]. Sterols are another class of chemicals found in many algal species. The experiments described the efficiency of sterols in lowering blood cholesterol levels. Sterols also have a variety of pharmacological properties, including anti-inflammatory, antibacterial, antifungicidal, antiulcerative, and antitumoral action [160].

4.4.2 Mushrooms

Mushrooms are not only a source of nutrients but they have also been described as therapeutic foods, effective in illness prevention [161]. They have been shown to boost the immune system and natural defenses against a variety of ailments. By boosting leukocyte counts in the blood, enhancing immune function, enhancing appetite, decreasing pain, and halting hair loss, mushrooms will also help patients undergoing radiation and chemotherapy. In addition, mushrooms may have antioxidant, antidiabetic, hypoglycemic, antitumor, immunomodulator, antimicrobial, antiviral, antiallergic, anti-inflammatory, hepatoprotective, anticancer, and genoprotective effects [162].

Recent research into medical, pharmacological, and functional foods reveals that mushrooms have a lot to offer in terms of human health. In treatments when chemical drugs may have side effects or fail to give a complete cure, the use of mushrooms and their products may help. Mushrooms offer both nutritional and therapeutic value. Some of them have both nutritional and therapeutic characteristics and give health advantages in addition to basic nourishment, making them functional foods [163]. A scientific evidence database exists on the unique health impacts of mushrooms and their bioactive components.

5. Food intolerance and allergy

Biogenic effects of functional microorganisms are also used to create altered functional goods by replacing current components with helpful components. This is the case with gluten elimination from baked goods manufactured from cereals, specifically wheat flour. Epidemiological studies have shown that celiac disease is becoming more common, with a frequency of around 1% in Europe and the United States [164]. Currently, the only available and effective treatment is a gluten-free diet. Immunogenic peptides that cause celiac disease are produced from glutenins and, in particular, gliadins, and are high in glutamine and, in particular, proline. Because of the presence of proline imino acid, they are completely degraded and detoxified by the synergistic activity of certain peptidases [165]. Beyond medicinal applications, peptide breakdown by microbial prolyl endopeptidases has been used as an alternative to a gluten-free diet [166].

Several studies found that using selected sourdough lactic acid bacteria to make wheat and rye bread or durum wheat pasta significantly reduced the toxicity of prolamin epitopes, but the concentration of gluten in these foods remained above 6000 ppm [167, 168]. After a while, Rizzello et al. found that gluten could be successfully digested at concentrations of less than 20 parts per million by combining ten chosen lactic acid bacteria with fungal proteases, which are frequently used in the production of bread [169]. This is the lowest and strictest limit for what constitutes a gluten-free matrix. Later, Rizzello et al. discovered that combining 10 selected lactic acid bacteria with fungal proteases, which are commonly used in bread manufacturing, and traditional long-time fermentation under semiliquid conditions was highly successful in digesting gluten at concentrations below 20 ppm [169]. This is the most restrictive and lowest boundary for defining a gluten-free matrix.

The pepsin-trypsin digest of hydrolyzed wheat flour proved dangerous, according to ex vivo experiments on intestinal T-cell lines from 12 celiac patients and peripheral blood mononuclear cells (PBMCs). PBMCs also produced interferon. The proportion of individuals suffering from immunoglobulin E-mediated hypersensitivity reactions following food ingestion is increasing worldwide, accounting for around 6% of babies and children under the age of three, and approximately 3% of the adult population [170]. Gastric enzymes (pepsin, pancreatin, and trypsin) cannot breakdown allergens that enter the intestine unmodified and activate an immunological response [171].

According to several research, probiotic therapy has considerable potential for controlling the allergic inflammation associated with food allergies [172, 173]. These stories concerned food allergies brought on by consuming proteins from cow’s milk. The capacity of probiotic VSL#3 to hydrolyze wheat flour allergens was the subject of a second investigation [174]. Hydrolysis was accomplished by utilizing VSL#3 as the starter for sourdough fermentation, a design that replicated the predigestion of wheat flour proteins during food processing. Simulated gastric digestion with pepsin and pancreatin totally destroyed the immunoglobulin E binding proteins that remained in the bread produced with VSL#3. When chosen sourdough lactic acid bacteria were used in bread manufacturing, nearly identical results were obtained [175].

6. Conclusion

The current focus of nutrition research is on health promotion, disease prevention, and performance enhancement. Human nutrition depends on two factors: the condition of the intestinal microbiota of the host and the degree to which the host is fed a balanced meal. Numerous low molecular weight physiologically active compounds that are dietary, endogenous, and probiotics have comparable structures and functions, serving as general regulators of physiological, metabolic, genetic, and epigenetic processes. Modern health benefit goods must take into account food safety, quality, and an understanding of the interactions between these active substances. Recent discoveries in the fields of microbial ecology, metabolomics, epigenomics, and genomes have conclusively shown that every human is genetically distinct; his gut microbiota is also strain-specific. The findings of many studies on the function of bioactive compounds derived from various sources suggested that these compounds may improve an individual’s health. The bioactive constituents include saponins, phytic acid, isoflavones, omega-3 fatty acid, lignan precursors, lycopene, flavonols (quercetin glycosides), catechins, triterpenoids, oligomeric procyanidins, anthocyanins, β-glucan, allicin, vitamin C, soluble fiber, diindolylmethane, and selenium sulforaphane, folate, catechins, resveratrol from plants; conjugated linoleic acid and carnosine from meat and meat products; n-3 fatty acids, angiotensin, FPHs from fish; sphingolipids, choline, n-3 PUFA and lutein/zeaxanthin from eggs; lactulose, β-lactoglobulin, α-lactalbumin, immunoglobulins, lactoferrin, serum albumin, conjugated linoleic acid, butyric acid, ether lipids, β-carotene and vitamins A and D, calcium, probiotics, whey proteins, and whey peptides, from dairy products; fiber, polysaccharides, carotenoid, and PUFA from algae. These bioactive chemicals have a variety of biological roles and have been shown to reduce the risk of a variety of diseases. Furthermore, research on functional foods and functional ingredients was required to explore the stability and interaction of bioactive substances with other food elements throughout processing and storage.

Conflict of interest

The authors declare no conflict of interest.