Bioactive Compounds Of Edible Fruits With Their Anti-Aging Properties: A Comprehensive Review To Prolong Human Life Part 2

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3.2.1. Phenolic Acids

Phenolic acid is abundantly present in fruits and is separated into two main classes: hydroxybenzoic acid and hydroxycinnamic acid. Most of the berries, particularly blackberries, raspberries, blueberries, cranberries, apples, oranges, and cherries are rich in both hydroxybenzoic and hydroxycinnamic acid [99,100]. The most prevalent hydroxybenzoic acids are vanillic, syringic, gallic, protocatechuic, and p-hydroxybenzoic acids, while the corresponding hydroxycinnamic acids are sinapic, p-coumaric, ferulic, and caffeic acids. These derivatives vary in methoxylations and hydroxylations patterns of their aromatic rings. Phenolic acids are mostly present in bound forms and serve as a potent antioxidant because of the reactivity of phenol moiety; a hydroxyl substituent on the aromatic ring [101]. A few derivatives of hydroxybenzoic acids are presently used as additives to decrease nutrient oxidation and to improve the nutritional value of fruits. A wide array of phenolic compounds have the potential to scavenge ROS including hydroxyl radicals and superoxide radicals, which decrease lipid peroxyl radicals and prevent lipid peroxidation. Phenolic acids act as a powerful anti-radical agent because of their redox properties, which makes them efficient hydrogen donors and metal chelators [101]. The phenolic content of several fruits is listed in Table 3.

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Research on the structural activity of phenolic acids and their derivatives revealed that the derivatives of hydroxycinnamic acid had greater antioxidant ability in comparison to that of benzoic acid counterparts [104]. This potential was because of the existence of a propanoic side chain in cinnamic derivatives; the conjugated double bond in their side chains has an intense effect on the phenoxyl radical by resonance, thereby improving the antioxidant power. Gallic acid is also a powerful antioxidant, found abundantly in strawberries, raspberries, red grapes, grapefruit, cranberries, and blackberries, and also in juices made from these fruits [75]. The antioxidant activity of gallic acid is triple times more than that of vitamin E or C, representing that three hydroxyl groups of gallic acid can independently act as electron acceptors [77]. Derivatives of gallic acid, thus, also act as a strong antioxidant with a free hydroxyl group that is responsible for radical scavenging and apoptosis of cancer cells. The most intriguing benefits of gallic acid have been evaluated on the skin [105]. In the case of prostate cancer cells, gallic acid prevents multiplication and the death of cells. Phenolic acids have been reported to possess various useful therapeutic activities like anti-inflammatory, anti-viral, anti-bacterial, anti-allergic, anti-cancer, anti-mutagenic, and anti-melanogenic activities J77,106. Ruifeng et al. [l07I conducted an experiment to evaluate whether chlorogenic acid could ameliorate the inflammation response in lipopolysaccharide-induced mice mastitis. The findings revealed that chlorogenic acid significantly decreased the production of tumor necrosis factor-alpha (TNF-α), and interleukins(IL-1β, IL-6) against lipopolysaccharide-induced mastitis. The western blot analysis indicated that chlorogenic acid could suppress the expression of toll-like receptor(TLR4), the phosphorylation of nuclear factor kappa B (NF-kB), and the inhibition of NF-kB (IkB) induced by lipopolysaccharide, and thus highlights the anti-inflammatory response.

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3.2.2. Flavonoids

Flavonoids are diverse and the most studied group of polyphenols found abundantly in several fruits like blackberries, blueberries, raspberries, blackcurrants, strawberries, grapes, cranberries, apples, cherries, etc. Currently, more than 8000 flavonoids are recognized, some of which are responsible for the fascinating colors of the leaves, flowers, and fruits [108]. Phenolic compounds obtained from natural sources are considered much safer in terms of having no side effects than synthesized chemicals [109,110]. Synthetic antioxidants are involved in triggering diseases in humans beyond certain concentrations ]111. In fruits, flavonoids are found in glycosides or acyl glycosides form, while methylated, acylated, and sulfate molecules are rare and present in low concentrations. The flavonoid content in various fruits is listed in Table3. The common basic structure of flavonoids comprises two aromatic rings that are joined to each other by three carbon atoms and forms a closed oxygenated heterocyclic pyran ring [112]. Flavonoids are classified into six subclasses based on differences in the type of heterocycle present in this group: flavanols (blueberries and apples), flavonols(grapes), and flavanones (citrus fruits), flavones, isoflavones, and anthocyanins (grapes and berries)[113,114]. Flavonols, flavonols, and anthocyanins are ubiquitous and possess strong antioxidant properties, which mainly depend on the position and number of hydroxyl groups present within their structure. Flavonoids also exert a wide variety of biological actions namely antibacterial, antioxidant, anti-inflammatory, anti-hyperlipidemic, and hepatoprotective activities [115].

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Flavonoids in citrus can suppress phosphodiesterase and kinase activation implicated in the initiation phase of inflammation. These enzymes can affect protein kinases and proinflammatory TNF-o expression. Some flavonoids can suppress the induction of endothelial cell adhesion molecules that are activated by cytokines. Inflammatory responses are also suppressed by impeding the monocytes, leukocytes, and neutrophils' adhesion to injured regions, thus highlighting the anti-inflammatory impact [116,117]. Flavonoids also reduce the risk of coronary heart disease by averting low-density lipoproteins (LDLs) from oxidizing, reducing the ability of the platelets in the blood to clot, and improving coronary vasodilatation [118]. Flavonoids can act in various developmental stages of malignant tumors by inactivating carcinogens, protecting DNA against oxidative damage, suppressing mutagenic genes, and enzyme expression accountable for triggering pro-carcinogenic substances, and triggering the systems accountable for xenobiotic detoxification [119]. cistanche tubulosa extract Most of the studies have shown a structural-functional relationship, indicating that anti-proliferative, enzyme-inhibition and antioxidant activities of flavonoids are reliant upon specific structural motifs [120-122].

Anthocyanins

Anthocyanins are the pigments that usually occur in nature, inhabiting a unique position in the group of polyphenols[123]. They are broadly distributed in a large number of fruits and vegetables and a great concentration of anthocyanins is observed in cranberries, blackcurrants, strawberries, bilberries, raspberries, blackberries, blueberries, and chokeberries [124,125]. They also constitute an immense group of colored water-soluble pigments that give the fruit purple, blue, and red colors [55]. However, anthocyanins are not solely responsible for the fruit color but are often used as a natural pigment in the food industry. Over 600 anthocyanins have been recognized in nature to date, but only six anthocyanins are widely found in fruits: malvidin, pelargonidin, peonidin, delphinidin, cyanidin, and petunidin [126,127]. The overall anthocyanin content in several fruits is mentioned in Table 3. Anthocyanins are also known as effective natural antioxidants [1281. The chemical structure of anthocyanin determines its efficacy as an antioxidant agent. The antioxidant activity of anthocyanin is allied with free hydroxyl numbers around the pyrone ring. Larger the hydroxyl number larger the antioxidant activity [129]. The anthocyanins have indicated characteristics that suppress free radical formation, reduce the threat of various age-linked diseases like cancers, and CVD, and improve aging and memory[130]. In the case of fruits, anthocyanins are found mostly in the outer layer of the pericarp. Cyanidin-3-glucoside is the main anthocyanin that is present in maximum fruits. Anthocyanins include aglycones and their glycosides—anthocyanidins and anthocyanins, and also form different complexes [131].

Anthocyanins vary in terms of the hydroxyl groups number in a molecule, their methylation degree; place, form, and a number of sugar molecules attached, number, and form of aromatic and aliphatic acids attached to sugars. In berries, anthocyanins are present in different glycoside forms i.e., mono-, di- or tri-, where residues of glycosides are commonly substituted at C3 or rarely, at the C5 or C7 position [56]. The most predominant sugars are sophorose, sambubiose, rutinose, arabinose, rhamnose, galactose, and glucose 132l. The glycoside residues of anthocyanin are frequently acylated by ferulic, p-coumaric, caffeic acid, and by acetic or malonic acid, p-hydroxybenzoic acid [131,133].

Anthocyanins exert several biological properties like anti-tumor, anti-inflammatory, antioxidant, anti-diabetic, anticancer, and neuroprotective ]134]. A researcher [135] experimented to assess the chemopreventive effect of anthocyanin-rich black currant skin extract with concentrations of 100 and 500 mg/kg against diethyl nitrosamine-initiated hepatocarcinogenesis in rats for 18 weeks. The findings showed a decrease in iNOS expression, 3-nitrotyrosine, abnormal lipid peroxidation, and protein oxidation in a dose-dependent manner. Mechanistic studies have shown that black currant skin extract upregulated the gene expression of a number of carcinogens detoxifying and hepatic antioxidant enzymes, like uridine diphosphate-glucuronosyltransferase isozymes, glutathione S-transferase and NAD(P)H: quinone oxidoreductase in diethylnitrosamine-initiated animals. This treatment significantly raised mRNA and protein expressions of nuclear factor E2-related factor 2(Nrf2), providing evidence of a synchronized activation of the Nrf2-regulated antioxidant pathway, which results in the activation of multiple housekeeping genes. Moreover, the anti-inflammatory activity of anthocyanins can be attributed to their antioxidant property which results in the down-regulation of the redox-sensitive nuclear factor-B signaling pathway [136].

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Catechins

Catechin is a polyphenolic antioxidant present in several fruits such as blueberries, strawberries, gooseberries, cherries, black grapes, and apples. Catechin term refers to the flavonoid class and flavan-3-ols/flavanols sub-class.The most important dietary catechins are gallocatechin, epicatechin (EC), epicatechin 3-gallate(ECG), epigallocatechin 3-gallate(EGCG), and epigallocatechin (EGC). In strawberries, 2-50 mg/100 g total amount of catechins are present. Cherries contain 5-22 mg/100 g catechins whereas apples contain 10-43 mg/100 g catechins but both are abundant in EGCG[137l Catechins are rich in external tissues of the fruit and are distinguished from the flavonoids containing ketones, in particular, rutin and quercetin, which endorse the antioxidant defense system.

Catechin present in cranberries is like the catechin present in green tea, that aids in protection against cancer [22]. The antioxidant action of catechin is effective against cancer, neurodegenerative and cardiovascular diseases [138]. A study conducted by researchers [139]reported that epigallocatechin gallate (EGCG), major catechin strongly inhibits an enzyme called telomerase, which is necessary for unlocking the proliferative capacity of cancer cells by upholding the tips of their chromosomes. Thus, it may be another reason for the anticancer activity of catechins. The antioxidant property of catechin proved beneficial in reducing coronary heart diseases as it decreases cytotoxicity caused by amiodarone in fibroblast cells of the lungs [140]. Catechins also show anti-inflammatory activities in bowel disease in humans by affecting oxidative stress-related cell signaling pathways, such as transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), mitogen-activated protein kinases (MAPKs), nuclear factor-kappa B(NF-KB), signal transducer and the activator of transcription 1/3 (STAT1/3) pathways [141]. Pan et al. [142]experimented to study the anti-inflammatory effects of catechins in an in vitro experiment using stimulated human nasal epithelial cells(HNEpCs) and in an ovalbumin-induced allergic rhinitis murine model. The results showed that catechin inhibited the expression of Thymic stromal lymphopoietin (a molecule that plays the main role in the development of allergy) in epithelial cells by influencing the NF-kB/TSLP pathway. Catechin effectively decreased the inflammation in allergic rhinitis. Catechins also reduce the degeneration of neurons by directly or indirectly decreasing oxidative stress, scavenging ROS, and improving antioxidant enzymes [140]. Thus, most of the benefits of catechins are achieved through the way of their antioxidant mechanism.

Quercetin

Quercetin is a natural polyphenolic compound, found abundantly in several fruits such as apples, grapes, blueberries, raspberries, cherries, and blackcurrant [82,143]. It is reported as one of the most powerful ROS scavengers in the flavonoid class and flavonol sub-class [144]. An experiment was proposed [145] to evaluate the free radical scavenging activity of flavonoids in H2O2 treated human myelogenous leukemia (K562) cells. The experimental findings revealed that quercetin and luteolin have shown the highest protective effects as compared to rutin, and apigenin towards H2O2 induced damage in leukemia cells. The antioxidant property of quercetin to scavenge free radicals is due to the presence of two antioxidant pharmacophores inside molecules that have the ideal structure for free radical scavengers [33,146]. Chondrogianni et a1.[147]described in his studies that quercetin and its derivative quercetin caprylate(QU-CAP) can revitalize senescent human fibroblasts and extend their life expectancy by activating proteasomes. It acts as an effective antioxidant that has significant pharmacological, biological, and medicinal properties. The antioxidant potential of quercetin is directly proportional to the number of free hydroxyl groups[148]. Moreover, it also exhibits potential anticancer and anti-inflammatory properties. Quercetin suppresses the production of inflammatory enzymes like lipoxygenase (LOX) and cyclooxygenase(CO.X) thus reducing the production of prostaglandins and leukotrienes, chemicals that promote inflammation [149]. The anti-inflammatory and antioxidant activities of quercetin and its derivatives contribute to the anti-aging effect since inflammation and chronic oxidative stress are considered to play a substantial part in activating the aging process [3].

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3.2.3.Tannins

Tannins are the essential constituents that play a major part in delineating the sensory characteristics of fruits and their products. They include both ellagic acid or esters of gallic acid called hydrolyzable tannins, and condensed tannins called proanthocyanidins [150]. They are responsible for variations in the fruit color and tart taste [151]. Tannins stabilize anthocyanins, in fruits rich in them, by binding them to form copolymers. Hydrolyzable tannins are rarely found and have been present in blackberries, blueberries, strawberries, and raspberries [82,95].

Ellagic acid contains approximately 51% of the total phenolic content and occurs in free as well as in complex forms such as glucosides and ellagitannins esterified as glucose. The presence of ellagic acid and its derivatives makes the berries (cranberries, raspberries, blackberries, strawberries) and grapes consumption appropriate for possible health benefits. In addition, ellagic acid has been described to possess potent antiviral, anti-inflammatory, anti-proliferative, and antioxidant properties and also provide defense against cancer of the esophagus, lungs, and colon [152,153]. Ellagic acid has been identified in several fruits in which the total concentration of ellagic acid was computed by evaluating the concentration after acid hydrolysis of ellagic acid extracts [22]. In the case of raspberries, free ellagic acid contains a small portion of total ellagic acid, and the main source of ellagitannins is discharged by acid hydrolysis [95].

3.2.4. Stilbenes

Stilbenes are low-molecular-weight compounds found in several fruits like berries and grapes. It comprises two phenyl moieties that are linked by a two-carbon methylene bridge. Generally, stilbenes are present in low concentrations in the human diet. One of the naturally occurring and most studied polyphenol stilbenes is resveratrol [154].

Resveratrol

Resveratrol (RES) is a phytoalexin that is formed by a broad diversity of plants as a response to fungal infections, injury, UV radiation, and stress. In 1940, the first resveratrol molecule was isolated from the Veratrum grandiflorum O. Loes roots (white hellebore) and later from berry-skins, grapevines, and Vitis spp.(grapes)leaves comprising their frequent and most examined source[31,155]. Research suggests that the resveratrol molecule is one of the main factors of the French Paradox that defines an epidemiological observation that connects fewer incidences of cardiovascular diseases and longer lifespan(despite a high-fat diet) in French people with the daily consumption of red wines [3,156,157]. As red wine comprises a substantial quantity of resveratrol, it has dragged great interest in the experimental community to explore its possible health benefits, and whether the resveratrol might bestow these benefits.

Resveratrol is a polyphenolic antioxidant that belongs to the family stilbene and is synthesized by grapevine and various other plants as a response to pathogens' attack from the precursor molecules of p-coumaroyl CoA and malonyl-coenzyme A (CoA), in the existence of enzyme stilbene synthase [158]. Resveratrol is found in various fruits like grapes and Vaccinium spp.(cranberry, bilberry, and blueberry). It has also been identified in plum fruit, increasing its natural wealth profile, particularly in dietary sources [31,159].

A plethora of evidence proposed that supplementation of dietary resveratrol exerts advantageous effects on aging and various other age-related chronic diseases particularly Alzheimer's disease, cancer, diabetes, etc. [160]. In addition, it was found to prolong lifespan by 70% in Saccharomyces cerevisiae, a typical model for aging studies. Over the past two decades, resveratrol has been the subject of extraordinary studies due to its anti-aging properties. It works both as a radical scavenger, and as a chelating agent, and possesses anti-inflammatory activity [161].

4. An Insight into Pharmacological and Biological Benefits of Fruits

There is growing evidence from worldwide research that fruits are an imperative part of a balanced diet. Numerous phytochemicals from the fruits have antioxidant properties that safeguard against the detrimental effects of free radicals, which further lead to chronic pathologies linked with aging[162,163]. Fruits are also a good source of naturally occurring antioxidants which include vitamins, minerals, flavonoids, and phenolic acids. The presence of these antioxidants aids in delaying or preventing oxidative damage of biomolecules by ROS which contain reactive free radicals including hydroxyl, peroxyl, alkoxyl, superoxide, and non-radicals such as hypochlorous, hydrogen peroxide, etc. The anthocyanins in fruits are also the most studied phenolic with a large variety of bioactivities including anti-aging, anticancer, anti-inflammatory, and antioxidant properties. Antioxidants scavenge these radicals by counteracting the formation of free radicals by attaching to metal ions or suppressing the initiation and chain-breaking propagation, by quenching superoxide and singlet oxygen, and by reducing hydrogen

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peroxide[164] and thus circumventing several age-linked diseases like type 2 diabetes, inflammation, cancer, and CVD. Various pharmacological and biological properties of several fruits are described in Table 4.

This article is Antioxidants 2020, 9, 1123; doi:10.3390/antiox9111123 www.mdpi.com/journal/antioxidants