2. Nutraceuticals: Classification and Biological Potential
The term “nutraceutical” was coined into existence in 1989 by Dr. Stephen DeFelice from the word nutrition and pharmaceutical, and it refers to the food or part of food that provides health benefits, including prevention and treatment of diseases beyond its nutritional functions
[12]—how a biologically or pharmacologically active substance (drug) alters a living organism, influencing the synthesis of proteins and the genetic material (DNA), translates into the mechanism of action
[13]. So, what is the distinction between a drug and a nutraceutical? The primary objective of a drug is to address conditions with curative possibilities, and its fundamental origin is from natural medicinal herbs, manufactured by chemical, computer-aided drug design techniques or biological origins
[14].
Sometimes, a drug acts on the intended targets in testing and design, contemplating toxicity, with additional benefits or side effects derived from binding to unproven targets
[15]. “Nutraceuticals” are assigned to those bioactive compounds having a physiological effect intended to prevent and treat diseases or disorders other than deficiency conditions
[16]. Salicylic acid, a compound originating in the white willow bark, is one of the most renowned, having been employed by the Phoenicians and ancient Greeks as an antiseptic and analgesic two millennia ago
[17]. Since then, various properties of salicylic acid have been discovered, benefiting health as an antipyretic, anti-inflammatory, antibacterial, and anti-acne agent, including keratolytic and hemolytic properties that allow exfoliation of the skin where an accumulation of necrotic tissue is abundant, stimulating the regeneration of keratinocytes of the epidermis as the uppermost layer of the skin
[17][18].
The biological contribution of nutraceuticals is extensive and includes the prevention or treatment of diseases in humans and animals and multiple benefits that help strengthen health. Therefore, nutraceuticals can be studied or classified from different angles to better understand their functioning in the body and the source that contains them. One classification includes three physiological stages that may limit its oral bioavailability
[19]. Namely, (I) bio-accessibility (release, solubilization, and interactions), (II) absorption (mucous layer, close-junction transport, bilayer permeability, active transporters, and affluent transporters), and (III) transformation (degradation and metabolism).
There are other reports published
[20][21], in which the authors present a classification of nutraceuticals from different perspectives:
(a) The source of origin: plants (garlic, aloe vera, ginger, containing organic acids, salts, tannins, and hormones), animals (oils and proteins), microorganisms (proteins, amino acids, vitamins, probiotics, prebiotics, dietary supplements, and peptides). (b) Traditional nutraceuticals: fruits (phenolic compounds, tannins, vitamins, and terpenes), vegetables (minerals, vitamins, organic acids, carotenes, and terpenes). (c) Non-traditional nutraceuticals: fortified foods (juices, cereals, vitamin additives, and minerals), originated by biotechnological processes (bread; alcoholic beverages such as beer, wine, pulque, tequila, mezcal, and apple or cane vinegar; production of amino acids and other bioceutical derivatives), or recombinant genetic engineering (production of enzymes and obtaining new nutraceutical pathways). (d) Chemical nature: herbs or spices, nutrients, phytochemicals, enzymes, terpenes (vegetables, fruits, and citrus fruits), phenolic compounds (coffee, spices, seeds, pulp and bunches of grapes, cocoa, red fruits, tea leaves, mango, banana, and spinach), and minerals (legumes, vegetables, some fruits, and spices). Nutraceuticals such as omega-3 are reported to have more than one mechanism of action. (e) The mechanism of action: their principle is to maintain and improve the physiological properties of an organism, and they are used in specific medical conditions with varied effects such as anti-inflammatory (ginger and orange peel extract), antimicrobial, osteoprotective, anti-glycemic/antihypertensive (blueberries), antioxidant (broccoli extracts), and anti-hypercholesterolemic (as the β-glucan contained in oats)
[22]; however, in some cases their toxicity, and synergy, or competition are still unknown. This fatty acid has an anti-inflammatory, anticoagulant, and antithrombotic activity
[23]. It is naturally in oily fish, shellfish, grains such as soy, canola, and flaxseed, walnut, to name a few.
Some widely studied bioactive compounds that have been shown to have anti-inflammatory, neuroprotective, and antioxidant activity, or as cofactors in important metabolic pathways. Here, the information is directed to those nutraceutical compounds that have a biological contribution to health, to the foods that contain them, and to therapeutic use, helping in the prevention or treatment of diseases, according to reported data.
2.1. Vitamins
Vitamin C. This vitamin represents a redox system comprising 2 L-isomers: ascorbic acid (vitamin C) in the reduced state and dehydro-ascorbic acid (DHA) in the oxidized form. Most of its functionality in the human body is related to its role as an electron donor; hence, it is active and is stable in tissues. It is used as a cofactor or antioxidant; it is oxidized and becomes unstable
[24]. Vitamin C intake as part of one’s diet has a positive effect on many illnesses such as the common cold, cardiovascular illnesses, and certain types of cancer, in addition to age-related macular degeneration, cataracts, diabetes, rheumatoid arthritis, and even has a protective effect on periodontal tissues, reducing severe cases of periodontitis
[25]. For many biosynthetic and gene regulatory enzymes, this vitamin plays a crucial role in immunomodulation because it stimulates neutrophil migration to the site of infection and enhances phagocytosis and oxidant generation
[24][26].
In contrast with many other vitamins, the content of vitamin C in various foods is high (10–100 mg/100 g), in some cases, reaching units of grams per 100 g of fresh weight. Most people get much of their daily vitamin C intake through regular fresh fruits and fruit juices, as illustrated in
Figure 1 [24].
Figure 1. Chemical formulas for nutraceutical compounds such as Vitamins (
![Foods 12 03262 i001](/media/item/202309/64f83895704c1foods-12-03262-i001.png)
), Minerals (
![Foods 12 03262 i002](/media/item/202309/64f838958d581foods-12-03262-i002.png)
), and Plants (
![Foods 12 03262 i003](/media/item/202309/64f83895e533dfoods-12-03262-i003.png)
) lie to dietary source.
Vitamin D: The classical function, which involves mineral balance and skeletal maintenance, has been known for many years. With the discovery of vitamin receptors in various tissues, several other biological functions of this vitamin are recognized today. Its activity is explored in several human disorders such as cancer, diabetes, hypertension, cardiovascular disease, and immunological and dermatological alterations. Vitamin D occurs in two primary forms: vitamin D2 or ergocalciferol synthesized by ultraviolet B (UV-B) irradiation of the ergosterol contained in yeast, fungi, and a few natural foods, fortified food, and supplements. Vitamin D3 or cholecalciferol is obtained through a photochemical reaction in the skin and diet via the intake of animal-based foods (cod liver oils and oily fish)
[27].
Vitamin E (
α-tocopherol): It has been recognized as an essential lipophilic antioxidant in humans protecting lipoproteins, polyunsaturated fatty acid (PUFA), and cellular and intracellular membranes from damage for a long time
[28]. One of the more interesting effects of this nutraceutical is its use in the treatment of Alzheimer’s disease. Vitamin E’s tocopherol and tocotrienol isoforms have multiple properties, including potent antioxidant and anti-inflammatory characteristics and influences on immune function, cellular signaling, and lowering cholesterol. In general, nuts and vegetable oils are rich in tocopherols, whereas barley, oat, palm oil, rice bran, rye, and wheat germ are rich in tocotrienol. In addition, natural sources of both vitamin E isomers are also in other daily foods, i.e., fruits, seafood, cheese, and eggs.
Retinoic acid (
RA): RA is a metabolite made from vitamin A and is the driving force behind many of vitamin A’s characteristics. It has been documented that its three isomers, 9-cis, 13-cis, and all-trans RA, have diverse capabilities to modulate cellular growth and differentiation. Other abilities of these isomers to regulate cellular growth and differentiation may be attributable to differences in affinities to their nuclear receptors
[29].
2.2. Minerals
Selenium: It is most easily absorbed in organic compounds and in the presence of vitamins A, D, and E. The primary sources of selenium in the diet are foods such as cereals, meat, dairy products, seafood, and nuts (
Figure 1). Rich sources of selenium are sea salt, eggs (only in the case of Se-yeast supplementation of feed), giblets, yeast (containing selenium), bread, mushrooms, garlic, asparagus, and kohlrabi (enriched with this element)
[30].
Zinc: Among the various food products, red meat, some seafoods, dairy products, nuts, seeds, dried legumes, and whole-grain cereals are considered good dietary sources of zinc. It is an essential trace element or a micronutrient essential for the growth and reproduction of all higher plants, animals, and humans. It is vital for the functionality of over 300 enzymes, stabilization of DNA, and gene expression. In addition, it plays a key role during physiological development and fulfils an immune function. The properties of zinc, such as toxicity, teratogenicity, carcinogenicity, and immunological, are relevant to cancer prevention
[31].
2.3. Plants
Silymarin: This compound is derived from the leaves of milk thistle (
Silybum marianum),
Figure 1. The main bioactive components of silymarin are flavonolignans: silybin, silicristin, silidianin, isosilibin, dehydrosilibin, and some flavonoids, taxifolin
[3]. The mixture of silybin A and silybin B (1:1) is the main active ingredient (approximately 50%) of silymarin. Silymarin flavonolignans are agents that typically possess antioxidant, anti-inflammatory, immunomodulatory, and hepatoprotective properties
[32][33]. Consequently, silymarin has been suggested to be incorporated as a complementary treatment for inflammatory liver diseases including cirrhosis, hepatitis, alcoholic fatty liver disease, and non-alcoholic fatty liver disease (NAFLD)
[32]. It is also known as a neuroprotective agent against many neurological disorders including Alzheimer’s and Parkinson’s diseases and cerebral ischemia. Recent studies reported its antiviral activity against various viruses, including flaviviruses (from hepatitis C and dengue), togavirus (i.e., Chikungunya and Mayaro), influenza virus, human immunodeficiency virus, and that of hepatitis B
[33].
Epicatechin: Epicatechin is a flavonoid polyphenol from the flavanol group; it is a natural component in cocoa and its products, found in dark chocolate and green tea. Scientific evidence has shown that populations that consume substantial amounts of cocoa daily (
Figure 1) have low blood pressure and a significantly lower incidence of cardiovascular disease
[34][35]. The literature proposes that one of the main beneficial effects of epicatechin is achieved through its ability to remove reactive oxygen species (ROS) directly or indirectly by reacting chemically with ROS or by modulating pathways that regulate ROS-scavenging compounds and enzymes, respectively
[35][36].
Epicatechin can also combat diseases such as diabetes mellitus and cancer with an inflammatory component. Epicatechin interferes with cancer signaling, making cells more susceptible to apoptosis, an effect that could be used to sensitize cancer cells to radiation or chemotherapy treatment. In addition, epicatechin appears to inhibit the proliferation of Hodgkin lymphoma cells and Jurkat T cells by inhibiting the binding of NF-κB to DNA in these cells
[34][35].
Curcumin: A yellow pigment is the main component of turmeric, the rhizome of
Curcuma longa XU
[37]. At the molecular level, it exhibits anti-inflammatory activity through the suppression of various cellular signaling pathways, including NF-κB, STAT3, Nrf2, ROS, and COX-2. Numerous studies have indicated that curcumin is a very potent antimicrobial agent and is active against various chronic diseases, including multiple types of cancers, diabetes, obesity, in addition to cardiovascular, lung, neurological, and autoimmune diseases
[38][39].
Resveratrol: 3,5,4′-trihydroxystilbene is a naturally occurring phytochemical. Its trans-isomer glycosylated form is found in plants as
Polygonum cuspidatum, fruits including grapes and berries, peanuts, and red wine,
Figure 1. Its use as a nutraceutical has been studied in both animal and human models, including clinical trials, in people with obesity, metabolic syndrome, heart disease, and cancer, among others; however, to date, there are no specific recommendations on the dose and duration of supplementation
[32][40]. Resveratrol is a compound with antioxidative properties and is considered for treatment of neurodegenerative diseases characterized by elevated levels of oxidative damage in, for example, Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis
[41].
Previously mentioned, resveratrol may improve or assist in the treatment of metabolic syndrome. There is scientific evidence of the anti-inflammatory effect of resveratrol. This compound inhibits the production of pro-inflammatory cytokines and the activity of cyclo-oxygenases (COX-1 and COX-2) and inducible nitric oxide synthase
[40][42].
Oroxylin A: This is a natural flavonoid isolated from
Scutellaria baicalensis and widely used in traditional oriental medicine. It exhibits several beneficial effects, including anti-inflammatory, anti-cancer, antiviral, and antibacterial activity
[43][44][45][46][47]. Oroxylin A has exerted inhibition of cell growth and induces apoptosis in various cancer cells. Oroxylin A can help treat colitis, allergy, and liver damage; these anti-inflammatory effects are attributed to the regulation of the NF-κB regulatory pathway with the consequent recruitment of immune cells and release of cytokines
[44][47][48].
Quercetin: Another flavonoid present in fruits, vegetables, tea, and red wine (
Figure 1), quercetin has shown beneficial health effects as an antioxidant and having anti-inflammatory, anti-allergic, and anti-thrombotic effects, with vasodilatory actions
[37][49]. Quercetin reduced systolic blood pressure and plasma-oxidized LDL concentrations, evidencing that quercetin may safely protect against cardiovascular disease
[50]. Due to its biological properties, quercetin was tested for treatment of neurodegenerative diseases, by evaluating the effect on signaling events of dopaminergic neuronal models and further testing its efficacy in the MitoPark transgenic mouse model of Parkinson’s disease
[51].
Apigenin: It is abundant in fruits and vegetables; it has antioxidants, anti-inflammatory, and anti-cancer effects. It exerts a protective effect against oxidative stress-related diseases, including metabolic disorders, obesity, neurodegenerative diseases, and cancer
[35][52][53][54]. Obesity represents a significant health issue; the administration of apigenin in obese mice increased levels of NAD
+ coenzyme, causing a global decrease in the acetylation of proteins, improving the homeostasis of glucose and lipids
[55]. Also, the use of apigenin against colon cancer shows a time- and dose-dependent cell cycle arrest in the G2/M phase in colon carcinoma cell lines
[35].
Genistein: Obtained from soy-based foods, genistein is a phytoestrogen compound that can bind to estrogen receptors
[56][57]. Besides cancer treatment, biological potential in cognitive function has also been studied in cardiovascular and skeletal health. Genistein has neuroprotective and memory-enhancing effects. Its potential is attributed to antioxidant, anti-inflammatory, and cholinesterase inhibitory activities. Genistein helps treat breast cancer due to its estrogen receptor antagonist activity, induces apoptosis, and promotes synergistic inhibitory effects when combined with anticancer drugs
[57].