Author: jessica zanovello
Date: 11/02/2013


Virginia Quarà
Jessica Zanovello

The modern pharmaceutical industry based on synthetic chemistry severed the historical connection between plants, food and medicines. But now the trend is inverted: there has been an increasing appreciation and understanding of the link between dietary fruit and vegetable intake and improved health in humans.
Multi-component botanical therapeutics hold several advantages over conventional drugs that may earn them a more prominent place in the medicine of the future. They can deliver mixtures of multi-functional molecules with potentiating and synergistic effects and pleiotropic targeting at a reasonable cost and with fewer regulatory constraints. They are well suited for long-term disease prevention in an era of genetic testing and increased life expectancy. So they also provide additional vehicles for delivering health and wellness.

“Eat an apple on going to bed and you'll keep the doctor from earning his bread” (or the more popular version “an apple a day keeps the doctor away”), addressing the health effects of the fruit, was first mentioned more than a century ago, and it is still widely used today.
Everyone has heard this old adage and we all know we should eat more fruit. But why apples? Do they contain specific benefits?
The widespread and growing intake of apples and apple juice and their rich phytochemical profile suggest their important potential to affect the health of the populations consuming them.
Exposure to apple products has been associated with beneficial effects on risk, markers, and etiology of cancer, cardiovascular disease, diabetes, asthma and Alzheimer’s disease. Recent work suggests that they may also be associated with improved outcomes related to cognitive decline of normal aging, weight management, pulmonary function, bone health and gastrointestinal protection. They also reduce tooth decay by cleaning one's teeth and killing off bacteria and aid to regulate inflammatory and immune response, by their content of vitamin C.

A Comprehensive Review of Apples and Apple Components and Their Relationship to Human Health, 2011

Apple nutrient and phytochemical composition
The apple is the pomaceous fruit of the apple tree, (Malus, species domestica, family Rosaceae). It is one of the most widely cultivated tree fruits. Apples grow on small, deciduous trees, which originated in Western Asia, where its wild ancestor, Malus sieversii, is still found today. Apples have been grown for thousands of years in Asia and Europe, and were brought to North America by European colonists. They have been present in the mythology and religions of many cultures, including Norse, Greek and Christian traditions. In 2010, the fruit's genome was decoded, leading to new understandings of disease control and selective breeding in apple production.

Apples and apple juice contain nutrient as well as non-nutrient components, including dietary fiber (pectin), minerals, vitamins and phytochemical compounds, such as, flavonoids, isoflavonoids, and phenolic acids.
With the exception of protein levels, fiber, and natural vitamin C contents, the average nutrient composition of apples and apple juice is quite similar: an apple contains zero cholesterol, fat and sodium, it has a low calorie count of 80 and it is a good source of complex carbohydrates.
Instead, content and composition of phenolic compounds, which are distributed in the peel, core and pulp, vary strongly in dependence of the apple variety, area of cultivation, and time and year of harvest.
The total polyphenol content of apples represents about 0.01 to 1% of the fresh weight. the most abundant subclasses include flavonoids (60% of all polyphenols), phenolic acids (30% of total polyphenols) and carotenoids. More than 4000 flavonoids have been identified and all share a common carbon skeleton structure (C6-C3-C6). They are further divided into different classes based on molecular structure, several of which are present in significant quantities in apples, including flavonols (quercetin glycosides, phloridzin ), oligomeric procyanidins (composed of epicatechin units), anthocyanidins, as well as dihydrochalcones and hydroxycinnamic acids (chlorogenic acid).
Cider apples are particularly rich in polyphenols. Consequently, freshly squeezed apple juice from cider apples has highest levels of the four major classes of apple constituents, whereas commercially available clear juice (often made from concentrates) is very poor in polyphenols. In addition to polyphenols, apple peel contains considerable amounts of lipophilic triterpenoids, which are concentrated in the cuticular wax layer. The most abundant triterpene is ursolic acid, with antiproliferative activity.

So apples are one of the main sources of dietary flavonoids. When compared to many other commonly consumed fruits , apples have the second highest level of antioxidant activity. They also ranke the second for total concentration of phenolic compounds, and perhaps more importantly, apples have the highest portion of free phenolics when compared to other fruits .This means that these compounds are not bound to other compounds in the fruits, and the phenolics may be more available for eventual absorption into the bloodstream.
Out of 10 varieties commonly consumed, Fuji apples had the highest total phenolic and total flavonoid compounds, Red Delicious apples have also a quite high antioxidant activity.

Apple phytochemicals and their health benefits, 2004

We decided to give an overview of the positive association, demonstrated in several observational studies, between apple components and reduced risk of chronic diseases and the underlaining biochemical pathways.


There is growing evidence that dietary variables may be related to cognitive decline in normal aging and also influence the risk and course of neurodegenerative diseases of aging.
It has been suggested that reactive oxygen species (ROS) are the main cause of cellular aging as they can damage and cross-link DNA, proteins, and lipids. The presence of apple components, in particular polyphenols, prevents ROS accumulation.
The higher efficiency of apples appears to be strictly related to the presence of oligomeric proanthocyanidins, epicatechin and procyanidin B2.
The best-described property of flavonoide is their capacity to act as antioxidants. Body cells and tissues are continuously threatened by the damage caused by free radicals and reactive oxygen species. Free radicals can attract various inflammatory mediators, contributing to a general inflammatory response and tissue damage.
The antioxidant-defense mechanisms of the body include enzymes such as superoxide dismutase, catalase, and glutatione peroxidase. The increased production of reactive oxygen species during injury results in consumption and depletion of the endogenous scavenging compounds. Flavonoids may have an additive effect to the endogenous scavenging compounds and can increase the function of the endogenous antioxidants, interfaring with different free radical–producing systems, such as:

  • Direct radical scavenging
    Flavonoids are oxidized by radicals, resulting in a more stable, less-reactive radical. In other words, flavonoids stabilize the ROS by the high reactivity of their hydroxyl group. Radicals are made inactive, according to the following equation:

Flavonoid(OH) + R• --> flavonoid(O•) + RH

where R• is a free radical and O• is an oxygen free radical.
Selected flavonoids can directly scavenge superoxides, whereas other flavonoids can scavenge peroxynitrite. Epicatechin is also powerful radical scavenger.
By scavenging radicals, flavonoids can inhibit LDL oxidation in vitro. This action protects the LDL particles and, theoretically, flavonoids may have preventive action against atherosclerosis.

  • Nitric oxide
    Several flavonoids, including quercetin, result in a reduction in ischemia-reperfusion injury by interfering with inducible nitric-oxide synthase (NOS) activity. Nitric oxide is produced by several different types of cells, including endothelial cells and macrophages. Although the early release of nitric oxide through the activity of constitutive NOS is important in maintaining the dilation of blood vessels, the much higher concentrations of nitric oxide produced by inducible NOS in macrophages can result in oxidative damage. In these circumstances, activated macrophages greatly increase their simultaneous production of both nitric oxide and superoxide anions. Nitric oxide reacts with free radicals, producing the highly damaging peroxynitrite and resulting in irreversibile damage to the cell membrane. When flavonoids are used as antioxidants, free radicals are scavenged and therefore can no longer react with nitric oxide, resulting in less damage. Interestingly, nitric oxide can be viewed as a radical itself, and it is was reported that nitric oxide molecules are directly scavenged by flavonoids.
  • Xanthine oxidase
    The xanthine oxidase pathway has been implicated in the oxidative injury to tissues, especially after ischemia-reperfusion. Both xanthine dehydrogenase and xanthine oxidase are involved in the metabolism of xanthine to uric acid. Xanthine dehydrogenase is the form of the enzyme present under physiologic conditions, but its configuration is changed to xanthine oxidase during ischemic conditions. In the reperfusion phase (ie, reoxygenation), xanthine oxidase reacts with molecular oxygen, thereby releasing superoxide free radicals. At least 2 flavonoids, quercetin and silibin, inhibit xanthine oxidase activity, thereby resulting in decreased oxidative injury.
  • Iron chelation
    When reactive oxygen species are in the presence of iron, lipid peroxidation results. Specific flavonoids are known to chelate iron, thereby removing a causal factor for the development of free radicals. Quercetin in particular is known for its iron-chelating and iron-stabilizing properties. Direct inhibition of lipid peroxidation is another protective measure.

Apple Can Act as Anti-Aging on Yeast Cells, 2012

Flavonoids: a review of probable mechanisms of action and potential applications, 2001


High cholesterol, obesity and diabetes are greatly influenced by diet and lifestyle and are costing a lot in health related expenses, since they are risk factor for cardiovascular disease (it has been estimated that the United States will spend 30 billion dollars per year on cholesterol treatment by statin drugs).
Apples consumption may exert protective effects on the cardiovascular system since it is consistently associated with a decrease in lipidemia. Such effect is attributed to dietary fibers and phenolic compounds (above all Flavonoids), which act by several mechanisms, including inhibition of LDL oxidation and platelet aggregation. These compounds are also able to modulate the generation of nitric oxide (NO) from vascular endothelium and to interfere with the mechanisms leading to inflammation and endothelial apoptosis, contributing to the prevention of the endothelial dysfunction, known to play a central role in the pathogenesis of cardiovascular diseases.
More recently, it has been shown that Flavonoids could interfere with the synthesis and secretion of triglyceride-rich lipoproteins (TRLs) in hepatocytes.
Apple polyphenol, in particular procyanidins (members of the proanthocyanidin, or condensed tannins, class of flavonoids), decreases the esterification of cholesterol in human enterocytes and the secretion of lipoproteins. Infact they decrease apolipoprotein B (apoB) secretion by inhibiting apoB synthesis without increasing the degradation of the newly synthesized protein. They also improve lipid homeostasis reducing the plasma levels of LDL-cholesterol and increasing antiatherogenic HDL-cholesterol.
These compounds do not interfere with cholesterol uptake or catabolism, but decrease the intracellular incorporation of [1-14C]oleic acid into cholesteryl ester. So, apple polyphenols reduced the intracellular accumulation of [1-14C]oleate incorporated into cholesteryl ester and decreased the secretion of all classes of newly synthesized lipids, resulting in a decrease in cholesteryl esters, phospholipids and TGs.
Apple polyphenols also decrease the secretion of apoB-48 and apoB-100 and, consequently, the secretion of apoB-containing lipoproteins ( respectively chylomicrons and VLDLs).
Decreased apoB secretion could be attributable to a decrease of its synthesis or to an increase of its degradation. Apple polyphenols inhibit an early step of synthesis, the incorporation of [35S]Cys/Met into apoB, and do not increase degradation.
Indeed they reduced activity and expression of ACAT2 and MTP.
The first is a Sterol O-acyltransferase, an intracellular protein located in the endoplasmic reticulum that forms cholesteryl esters from cholesterol. It catalyzes the chemical reaction:
acyl-CoA + cholesterol CoA + cholesterol ester
The latter is the microsomal triglyceride transfer protein, responsible for the assembly of apo B-containing lipoproteins (Image 1)
Image 1

But apples are also a rich natural source of phytosterols.
Phytosterols, which encompass plant sterols and stanols, are steroid compounds similar to cholesterol which occur in plants and vary only in carbon side chains and/or presence or absence of a double bond.
The ability of phytosterols to reduce cholesterol levels was first demonstrated in humans in 1953. They were subsequently marketed as a pharmaceutical treatment. Coadministration of statins with phytosterol-enriched foods increases the cholesterol-lowering effect of phytosterols, frequently used as a surrogate endpoint for beneficial effects on CVD.
Statins work by reducing cholesterol synthesis by inhibiting the rate-limiting HMG-CoA reductase enzyme. Phytosterols reduce cholesterol levels by competing with cholesterol absorption in the gut, a mechanism which complements statins. Their molecular mode of actions can be divided into two steps:
1)Stanols displace cholesterol from these micelles (cholesterol absorption occurs via the formation of micelles with bile acids) so that less cholesterol is absorbed. They need to be taken as part of a meal in order to be incorporated in the micelles.
2)Stanols work in enterocytes by activating transporter proteins (ABC, LXR) responsible for the excretion of cholesterol back into the intestinal lumen.
The fact that phytosterolaemia, a rare genetic disorder, is associated with rapid development of coronary atherosclerosis, had lead to use phytosterols levels as marker for cholesterol absorption, an atherogenic factor if it is abnormally elevated.

Polyphenols as potential therapeutical agents against cardiovascular diseases, 2005

Apple procyanidins decrease cholesterol esterification and lipoprotein secretion in Caco-2/TC7 enterocytes, 2004


Apples have a role in the neuroprotection.
Apple juice concentrate prevents the characteristic decline in acetylcholine associated with aging and oxidative stress. Because cholinergic depletion is associated with impaired memory and reduced cognitive performance, and acetylcholine reduction in particular is associated with Alzheimer’s disease(AD), there is potential importance in the ability of apple juice to maintain levels of this neurotransmitter.
Apple also may work by other mechanisms, including the ability to suppress overexpression of presenilin-1, which is linked to the production of amyloid β peptide, a hallmark of Alzheimer’s disease.
Apple juice also attenuated the neurotoxicity of amyloid β peptide. Quercetin seems to be very important in these processes: it is a flavonoid that showed protective effects against Amyloid beta-peptide (Abeta) toxicity by modulating oxidative stress, because of antioxidant propertier and capacity to increase glutathione (GSH) levels, which are reduced in Alzheimer's disease.

Neuronal loss in AD is preceded by the extracellular accumulation of Aβ associated with oxidative stress and neurotoxicity. Aβ reduce neuronal Cl--ATPase activity and elevated intracellular Cl- concentrations in hippocampus neurons, probably by lowering PIP level, and this property may reflect a pro apoptotic condition in early pathophysiological profiles of AD. The activity of Cl--ATPase is attenuated by an inhibitor of PI-kinase, quercetin.
Quercetine inhibits the formation of fibrilar Aβ, destabilize fibrils, and protected cells from Aβ oxidative attack.
This flavonoid can increase the resistance of neurons against oxidative stress and exitotixcity by modulation of cell death mechanisms. Quercetin has the specific structure to prevent GSH oxidation, thereby protecting oxidative stress-induced neurotoxicity. It has been reported that quercetin can flux into brain regions. Therefore, it is possible that quercetin with beneficial antioxidant and biological functions is able to penetrate the BBB and protect brain against H2O2-induced cytotoxicity.
During oxidative stress several lipid peroxidation products are formed. Lipid peroxidation products are known to cause damage to biomembranes, proteins and other biomolecules in AD brain. These alkenals react with an immediate substrate, GSH, and these lipid peroxidation products are known to be involved in apoptosis, which may derived from GSH depletion. Glutathione protects cultured neurons against oxidative damage resulting from amyloid β- peptide. GSH can also protect brain from damage by peroxynitrite, hydroxyl free radicals, or reactive alkenals. Decreased protein oxidation was observed in neuronal cell culture treated with quercetin on incubation with Aβ. So, quercetin protect GSH from oxidative depletion and protect brain against oxidative stress.

Protective Effect of Quercetin in Primary Neurons Against Aβ (1-42): Relevance to Alzheimer's Disease, 2009

Dietary Supplementation with Apple Juice Decreases Endogenous Amyloid-β Levels in Murine Brain, 2009


Apple extracts and components, especially oligomeric procyanidins and triterpenoids, have been shown to influence multiple mechanisms relevant for cancer prevention. These include antimutagenic activity, enhanced detoxification through modulation of xenobiotic metabolism, antioxidant effects, anti-inflammatory activity by inhibition of Cox activity and NF-κB, inhibition of signaling pathways, including the EGF/EGFR-mediated activation of the MAP kinase pathway, cell growth inhibitory mechanisms and induction of programmed cell death by activation of both the death receptor and the mitochondrial pathway. Recent studies have identified as novel targets of apple products epigenetic mechanisms and modulation of innate immunity.
Epidemiological observations indicate that regular consumption of one or more apples a day may reduce the risk for lung and colon cancer.

Induction of apoptosis
Cancer chemopreventive efficacy in vivo is attributed in great part to flavonoids, above all the flavanol polymeric procyanidins (Pcy). The regular consumption of Pcy-containing foods has been associated with a reduced risk of various types of cancers, since they are able to increase the expression of pro-apoptotic mediators and prevent or delay tumor development through the activation of NF-κB and p53 transcription factors which up-regulate the expression of TRAIL-death receptors DR4 and DR5 (members of the necrosis factor receptor family).
In addition, apple procyanidins increased mitochondrial membrane permeability and cytochrome c release from mitochondria and activated caspase-3 and caspase-9 within the tumor cells, so an oral administration inhibits the proliferation of tumor cells by inducing apoptosis through the intrinsic mitochondrial pathway. It is therefore possible that the expression ratios of Bcl-2 family proteins (anti-apoptotic Bcl-2 and Bcl-xL proteins and pro-apoptotic Bax proteins) are altered by apple products.
Activation of the caspase (a family of cysteine proteases) cascade induces numerous cell changes that are markers of apoptosis, including endonucleolytic cleavage of DNA, proteolytic cleavage of nuclear and cellular proteins, cell membrane blotting and production of apoptotic bodies. Caspase-3 is a notable effecter caspase in apoptosis and represents a convergence point for two different caspase-dependent apoptosis pathways: the mitochondria -related caspase 9 damage and the death receptor-related caspase 8 pathway (Image 2).
Image 2

Implication of NF-κB and p53 in the expression of TRAIL-death receptors and apoptosis by apple procyanidins in human metastatic SW620 cells, 2010

Cancer Chemopreventive Potential of Apples, Apple Juice, and Apple Components, 2008

Apple procyanidins induce tumor cell apoptosis through mitochondrial pathway activation of caspase-3, 2007

2013-02-19T15:18:10 - Virginia Quara
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