Fermented Papaya Research

 

Oxidative Stress in Patients with Alzheimer's Disease: Effect of Extracts of Fermented Papaya Powder

Mario Barbagallo, Francesco Marotta, and Ligia J. Dominguez, “Oxidative Stress in Patients with Alzheimer’s Disease: Effect of Extracts of Fermented Papaya Powder,” Mediators of Inflammation, Article ID 624801, in press.

[Article references]

Abstract

Brain tissue is particularly susceptible to oxidative stress (OS). Increased production of reactive oxygen species (ROS), reduced antioxidant systems, and decreased efficiency in repairing mechanisms have been linked to Alzheimer’s disease (AD). Postmortem studies in AD patients’ brains have shown oxidative damage markers (i.e., lipid peroxidation, protein oxidative damage, and glycoxidation). Fermented papaya (FPP, a product of Carica papaya Linn fermentation with yeast) is a nutraceutical supplement with favorable effects on immunological, hematological, inflammatory, and OS parameters in chronic/degenerative diseases. We studied 40 patients (age 78.2 ± 1.1 years), 28 AD patients, and 12 controls. Urinary 8-OHdG was measured to assess OS. Twenty AD patients were supplemented with FPP (Immunage, 4.5 grams/day) for 6 months, while controls did not receive any treatment. At baseline, 8-OHdG was significantly higher in patients with AD versus controls (13.7 ± 1.61 ng/mL versus 1.6 ± 0.12 ng/mL, ). In AD patients FPP significantly decreased 8-OHdG (14.1 ± 1.7 ng/mL to 8.45 ± 1.1 ng/mL, ), with no significant changes in controls. AD is associated with increased OS, and FPP may be helpful to counteract excessive ROS in AD patients.

1. Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and its incidence increases with age [1]. AD is characterized by the presence of several pathological hallmarks including neuronal loss, formation of senile plaques composed by extracellular deposits of amyloid beta (Aβ) caused by an abnormal processing of amyloid-beta precursor protein (APP), intracellular neurofibrillary tangles (NFT) composed of aggregated hyperphosphorylated tau proteins in brain, proliferation of astrocytes, and activation of microglial. These features are accompanied by mitochondrial dysfunction and alterations in neuronal synapses [1]. The molecular and pathophysiological mechanisms that underlie AD still have many dark sides. Even though AD is multifactorial, its etiology and the exact mechanism that triggers the pathological alterations are still not clear. Although most studies have suggested that the Aβ peptide (amyloid cascade hypothesis) may initiate and/or contribute to the pathogenesis of AD, the mechanisms through which it causes neuronal loss, and tau abnormalities still remain poorly understood. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), including superoxide anion radical, hydrogen peroxide, hydroxyl radical, singlet oxygen, alkoxyl radicals, peroxyl radicals, and peroxynitrites, contribute to the pathogenesis of numerous human degenerative diseases [2] and have been implicated in the pathogenesis of neurodegenerative disorders including AD and Parkinson’s disease, among others [3]. The production of reactive oxygen species (ROS) seems to be involved in triggering and maintaining the degeneration cycle of AD, causing the damage of mitochondrial DNA and of the electron transport chain, which leads to an increased production of ROS [4]. Brain tissue is particularly susceptible to oxidative damage. The metabolism of brain tissue requires high energy levels and it consumes approximately 20% of the total body oxygen despite the fact that it comprises less than 2% of total body weight. It is very rich in easily oxidizable polyunsaturated fatty acids and transition metal, such as iron and ascorbate, which are key players in oxidation and facilitate the formation of oxygen free radicals. The brain is also characterized by a low content of antioxidant systems [5].

The generation of ROS, which are toxic, is a part of normal metabolism in a biological system. Free radicals are extremely reactive species, which once formed can start a series of reactions that are harmful to the cell. It is important to emphasize that even under normal conditions there is a physiological cellular production of free radicals, which is normally counterbalanced by endogenous enzymatic cellular antioxidants systems. The balance between the production of reactive oxygen species and antioxidants is essential in a biological system to prevent adverse effects of oxidative stress. The damage caused by free radicals is caused by an imbalance between their production and their neutralization by cellular antioxidant systems in the human body [6, 7]. Both systems (production and neutralization) seem to be altered in AD and these changes have been suggested to play a major role in the process of age-related neurodegeneration and cognitive decline [8]. The free radicals thus generated are known to attack macromolecules such as deoxyribonucleic acid, proteins, lipids, and carbohydrates. This leads to either onset or acceleration of degenerative disorders. The main damage occurs for integration with cellular macromolecules essential to survival, such as DNA, proteins, and polyunsaturated fatty acids (which make up the cell membrane) [9]. Thus, ROS have been shown to trigger a variety of damage to cellular DNA and RNA, causing peroxidation of membranes and neuronal damage. In addition, the alterations of oxidative metabolism may render the brain more susceptible to further damage from Aβ, which in turn has a prooxidant action [10]. Accumulating evidence suggests that brain tissues in AD patients are exposed to oxidative stress during the development of the disease [11]. Oxidative stress and the following cellular damage caused by protein oxidation, lipid oxidation, DNA oxidation, and glycoxidation are closely associated with the development of cognitive decline in AD [9, 12].

Because free radicals and oxidative DNA damage may have a central role in age-related diseases such as AD, a protection from oxidative stress, and subsequent DNA damage may represent a basic approach for elongation of healthy age and treatment of such age-related diseases. In vitro antioxidant such as N-acetylcysteine or genetic disruption of the DNA damage response pathway by checkpoint kinase deletion can rescue many deficits and eventually elongates significantly lifespan [13]. These observations further indicate the important role of mitochondria, ROS, and DNA damage in aging and neurodegenerative diseases. In the past, randomized controlled intervention studies in AD, with antioxidants, such as selegiline or vitamin E, have produced modest but significant results [14]. Fermented papaya preparation (FPP), produced by fermentation of Carica papaya Linn by using yeast, is a food supplement that possesses beneficial and potent antioxidant properties that may be helpful against age-related and disease-related increase in oxidative stress [15]. FPP exhibits anti-inflammatory, antioxidant, and immunostimulatory action and induction of antioxidant enzymes [16].

In neurological conditions, oral administration of FPP in mice attenuated the reduction of short- and long-term memory induced by scopolamine [17]. Because of the above-described role of free radicals in the pathophysiology of chronic neurodegenerative diseases, it has been suggested a possible role for the antioxidant action of FPP in counteracting the oxidative stress associated with these conditions [15]. Therefore, we conducted the present study aiming to explore the effects of oral FPP on oxidative stress in AD patients.

2. Methods

We have measured oxidative stress in patients with initial or mild AD compared to age-matched control patients without AD. We have also tested the ability of FPP to reduce the excessive production of free radicals in patients with AD [12]. Oxidative stress was assessed by means of an enzyme immunoassay for the measurement of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the urine. Detection of 8-OHdG, a nucleic acid modification predominantly derived from hydroxide attack of guanidine, allows for assessment of more immediate oxidative damage [18]. We studied 40 patients (23 women and 17 men, mean age years) evaluated at the Alzheimer Evaluation Units of the University Hospital of Palermo. Twenty-eight patients were recruited after being diagnosed with early mild AD according to the criteria of the DSM-IV and NINCDS-ADRDA, while the other 12 were control patients of the same age.

The patients were not being treated with any other neurotrophic drug during the whole duration of the study. The 28 AD patients were divided into two groups; participants in group 1 ( patients) were treated for 6 months with a supplement of FPP (known commercially as Immunage, prepared by fermenting the Carica Papaya Linn at the Osato Research Institute, Gifu, Japan) at a dose of 4.5 grams per day p.o. in a single dose. Patients of group 2 (8 AD patients) did not receive any treatment.

3. Results and Discussion

The clinical characteristics of the study participants are shown in Table 1. At baseline, 8-OHdG was significantly higher in patients with AD versus controls (  ng/mL versus  ng/mL, , Figure 1). In group 1, supplementation with FPP significantly reduced 8-OHdG levels (from  ng/mL to  ng/mL, , Figure 2), while 8-OHdG did not change significantly in group 2 (not supplemented), showing a nonsignificant trend towards an increase (from  ng/mL to  ng/mL, ). In the 20 patients treated with FPP, oxidative stress as measured by 8-OHdG was reduced in all but one patient (Figure 3). There were no significant changes in clinical MMSE evaluation and/or on any other laboratory parameters examined.

Table 1: Clinical characteristics of study patients.
Figure 1: 8-Hydroxy-2′-deoxyguanosine (8-OHdG) level in patients with Alzheimer’s disease and in controls.
Figure 2: 8-Hydroxy-2′-deoxyguanosine (8-OHdG) level in patients with Alzheimer’s disease (group 1) before and after fermented papaya powder (FPP) supplementation.
Figure 3: 8-Hydroxy-2′-deoxyguanosine (8-OHdG) level in each of the 20 patients with Alzheimer’s disease (group 1) before and after fermented papaya powder (FPP) supplementation.

Numerous alterations of oxidative metabolism such as increased production of ROS metabolites and/or a reduction in the efficiency of antioxidant systems and repair capability of damaged molecules are present in AD and have been connected to its onset. Mitochondrial oxidative damage has been found to be excessive in the brains of aged people, especially AD patients and AD-like transgenic animal models. The damage caused by oxidative stress is one of the earliest pathophysiological events in the development of AD; it also seems to precede the formation of amyloid plaques and neurofibrillary tangles. Markers of DNA damage, particularly oxidative DNA damage, have been largely found in brain regions, peripheral tissues, and biological fluids of AD patients. Moreover, there is evidence that oxidative damage is one of the earliest detectable events within the progression from a normal brain to dementia [9, 19]. Almost one decade ago, a decrease in the DNA base excision repair activity was observed in postmortem brain regions of AD individuals, leading to the hypothesis that the brain in AD might be subjected to the double insult of increased DNA damage, as well as deficiencies of DNA repair pathways [20]. Autopsy studies on brain tissue from AD patients’ brain tissue from AD patients have confirmed the presence of numerous signs of oxidative stress, such as Aβ-induced oxidative DNA damage and mitochondrial dysfunction, together with an increase in lipid peroxidation, proteins, and glycides oxidation [21], and a reduction of the antioxidant enzyme systems [22]. In vitro studies have shown that the neurotoxic properties of Aβ may be mediated by oxygen radicals. Amyloid deposits are associated with an overexpression of markers of oxidative stress, increased structural abnormalities of mitochondria, and mitochondrial DNA damage [23].

Age is the greatest risk factor for AD. Aging and chronic diseases are themselves associated with an increase in oxidative stress. The concentrations of oxidative-damaged proteins, lipids, and DNA have been reported to increase with age. This increase of oxidative stress during the aging process may contribute in part towards neurodegeneration in AD. The temporal association of the age related increased levels of ROS with the formation of the senile plaque provides further evidence that aging-induced alterations in brain oxidative status may be a major factor in triggering enhanced production and deposition of Aβ in AD [19].

We have previously shown that chronic diseases, such as diabetes mellitus type 2 or cardiovascular conditions, accelerate the age-dependent increase in oxidative stress [24]. A further derangement in oxidative stress balance may be caused by chronic inflammation of aging. Aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as inflammaging [25]. Aging and chronic disease create a cascade of events that can be best characterized as an asymptomatic inflammatory process. This cascade of events is mediated by cytokine interleukins 1 and 6 (IL-1alpha, and IL-6), nitric oxide (NO), and oxidative stress [26]. Inflammation has been suggested to be another responsible factor in AD and is presumed to be mediated through the cross talk among the amyloid, astrocytes, and microglia [27]. These reactions lead to altered neuronal function and the inflammatory injury. Thus, in patients with AD we have recently shown an increase of oxidative stress [12] and an alteration of the immunoinflammatory responses, with an increased cytokine production, that may have a potential causal role in contributing to an augmented oxidative stress [28]. Several studies have shown that Aβ may produce an increase in oxidative stress via several mechanisms, either increase in ROS production, decrease in the enzyme activities involved in the antioxidant defense system, or altering mitochondria function. Nerve cell insults caused by Aβ brain deposition may itself induce oxidative changes [29], and metals concentrated in amyloid deposits, such as copper, may as well contribute to the oxidative insults observed in AD-affected brains. Several studies suggest that Aβ increases oxidative stress by increasing lipid peroxidation measured by increased levels of thiobarbituric acid-reactive substances in brain [29]. In addition to lipids, it has been suggested that ROS-mediated reactions with proteins lead to oxidative damage of proteins and DNA in the brain tissue [30]. The accumulation of oxidative stress metabolites present in old age may itself cause an increase susceptibility of the brain to damage from neurotoxic peptides such as soluble or fibrillar Aβ. As the accumulation of Aβ can in turn cause a further production of ROS, it is still unclear whether the excess of oxidative stress is a primary or secondary event in AD. Although there are accumulating evidences suggesting that oxidative stress may be an early event in the onset of AD, this aspect seems to be of relative importance, as the production of ROS, even if secondary, is in turn detrimental to the brain tissue and can further contribute to neuronal damage [31]. This suggests that any effort to the removal and/or prevention of ROS formation may be useful in people with AD [29]. For example, when Aβ has started to aggregate and deposit in the brain, this protein elicits a neuroinflammatory response via the activation of microglia and astrocytes [32, 33]. Following the initial neuroinflammatory response, the neurotoxic by-products of inflammation cause additional oxidative damage to cells. Similarly, the hyperphosphorylated tau fibrils create cytoskeletal stresses and promote neuronal dysfunction [34].

Oxidative stress-induced cell damage and inflammation are implicated in a variety of age-related diseases other than neurodegenerative disorders (such as cancers, diabetes, arthritis, and cardiovascular dysfunctions) and aging. All these conditions could potentially benefit from functional nutraceutical/food antioxidant supplements. Antioxidant defenses may potentially protect the body from the detrimental effects of free radicals. Physiological antioxidants in food such as fruits and vegetables provide a reasonable amount of antioxidants. Although existing knowledge is not definitive, there is rational basis to suggest that antioxidant supplementation and food plant extracts may help protect against a number of neurological diseases in which oxidative stress is implicated and may have a role in the prevention and treatment of age-related disease.

It has been suggested that substances with antioxidant properties or that enhance the endogenous defense system against free radicals may have a role in preventing the onset or in slowing the progression of AD [35]. Dietary antioxidants contribute to increased levels of cellular antioxidant ability, thus decreasing the toxicity of ROS.

FPP has been shown to reduce apoptosis related to oxidative stress and activation of inflammatory cytokines [36, 37] and to contrast the DNA damage related to the production of free radicals induced by several prooxidant substances, including iron ions, copper, benzopyrene, methylguanidine, and aluminum, among others [15,38–40].

In particular, it has been shown that FPP exerts several protective actions; it inhibits lipid peroxidation [41]; it enhances enzyme antioxidant activities such as glutathione S-transferase in hepatocytes [36] and showed remarkable hepatoprotective activity [42]. In vitro in a cellular model of AD, FPP has neuroprotective activity against β-amyloid-mediated copper neurotoxicity in β-amyloid precursor protein in a cell culture system [36]. FPP has shown protective properties against iron-mediated oxidative damage to DNA and proteins [43]. In the brain tissue, FPP has been shown to have a neuroprotective effect from oxidative damage, from lipid peroxide level, and superoxide dismutase activity in iron-induced epileptic foci of rats [41]. At the neuronal level, FPP has been shown to have a neuroprotective action, to improve the oxidative status in human neuronal cells and to protect from insults by oxidative stress linked, for example, to the cytotoxicity by aluminum in neuronal cells [44]. Neuroprotective potential evaluated in an AD cell model showed that the toxicity of the Aβ can be significantly modulated and/or reduced by FPP. In vitro FPP has been shown to protect cells by the oxidative damage related to the deposition of Aβ. Treatment with FPP increased the survival of neuronal cells, preventing apoptosis, and was able to decrease the production of hydroxyl radicals and superoxide anion in the cells, as well as decreasing nitric oxide accumulation and intracellular calcium ion [36]. Noda et al., using an ESR technique, confirmed the potent antioxidant inhibitory effect of the FPP, by demonstrating its hydroxyl radical scavenging activity, its superoxide anion radical scavenging activity (SOD-like activity), and its inhibitory effect on hydroxyl radical generation from methylguanidine [40]. At the clinical level, studies in chronic and degenerative disease conditions (i.e., thalassemia, cirrhosis, and diabetes) showed that FPP favorably modulates immunological, hematological, inflammatory, vascular, and oxidative stress damage parameters [15].

Our results suggest that FPP has antioxidant actions in AD patients and that it may be prophylactic food against the age-related and neurological diseases associated with free radical overproduction. Our data confirm that AD is associated with an increased oxidative stress and that the FPP can be useful in helping to counteract the excessive production of free radicals present in patients with AD [12]. The previous in vitro studies are promising and proven preventive action on the damage from Aβ suggesting that it would also be useful to evaluate the action of FPP in the more advanced stages of the disease and in combination with neurotrophic drugs. It would also be interesting to identify the component of FPP neurotrophic action.

In conclusion, dietary factors can modulate physiological functions (including brain function) thereby increasing the economic productivity of a population as a function of health. A greater understanding of the molecular mechanisms of neuroprotection, oxidative stress, and immune function will facilitate definition of the prophylactic potentials of diet, nutritional/food supplements, medicinal plants, and herbal extracts. Although the role of oxidative stress in aging and neurodegenerative and other related diseases is largely accepted, the value of antioxidant strategies is still debatable. This becomes more important when, apart from foods or reasonable lifestyle changes, antioxidant supplements are considered. Well-defined long-term trials are still needed to assess the efficacy of antioxidant strategies or of antioxidant-rich nutritional intervention. Future studies of longer duration and with a larger number of subjects woul0d be useful to assess the potential clinical actions of FPP and the possible relevance to the reduction of oxidative stress on the natural history of the disease.

Conflict of Interests

The authors declare that they have no conflict of interests.

[Article references]

The Effect of Fermented Papaya Preparation on Radioactive Exposure

Eitan Fibach(a), and Eliezer A. Rachmilewitz(b), Radiation Research 184(3):304-313. 2015
doi: http://dx.doi.org/10.1667/RR14000.1
(a) Department of Hematology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
(b) Department of Hematology, The E. Wolfson Medical Center, Holon, Israel

[Article references]

Abstract

Exposure to ionizing radiation causes cellular damage, which can lead to premature cell death or accumulation of somatic mutations, resulting in malignancy. The damage is mediated in part by free radicals, particularly reactive oxygen species. Fermented papaya preparation (FPP), a product of yeast fermentation of Carica papaya Linn, has been shown to act as an antioxidant. In this study, we investigated the potential of FPP to prevent radiation-induced damage. FPP (0-100 μg/ml) was added to cultured human foreskin fibroblasts and myeloid leukemia (HL-60) cells either before or after irradiation (0-18 Gy). After 1-3 days, the cells were assayed for: intracellular labile iron, measured by staining with calcein; reactive oxygen species generation, measured with dichlorofluorescein diacetate; apoptosis, determined by phosphatidylserine exposure; membrane damage, determined by propidium iodide uptake; and cell survival, determined by a cell proliferation assay. DNA damage was estimated by measuring 8-oxoguanine, a parameter of DNA oxidation, using a fluorescent-specific probe and by the comet assay. These parameters were also assayed in bone marrow cells of mice treated with FPP (by adding it to the drinking water) either before or after irradiation. Somatic mutation accumulation was determined in their peripheral red blood cells, and their survival was monitored. FPP significantly reduced the measured radiation-induced cytotoxic parameters. These findings suggest that FPP might serve as a radioprotector, and its effect on DNA damage and mutagenicity might reduce the long-term effects of radiation, such as primary and secondary malignancy.

[Article references]

Papaya: A Fountain of Youth

In her article "Papaya: a Fountain of Youth",  Dr Holly Lucille ND, RN, discusses the role FPP can play in aging.

  • Reducing cell damage caused by oxidative stress from free radicals
  • Boosting the immune system

This is what she says...[Article references]

“...FPP can help by reducing oxidative stress and immune system decline. Additionally, fighting oxidative stress helps people retain their youthful appearance longer. Oxidative damage is the number one factor in facial aging.

What exactly does oxidative stress mean and what does it have to do with aging?

One theory of aging is that harmful molecules called free radicals wreak havoc in our cells. Many of our body's normal metabolic processes produce free radicals. For example, free radicals are a normal by-product in the production of ATP (the energy molecule) from glucose. Certain types of white blood cells destroy invading microbes by the production of free radicals. Free radicals are also formed by the many normal enzymatic actions that take place every minute every day.16

However, outside sources can also cause free radical formation, as well. If we are exposed to pollutants in the environment, chemicals, additives, and preservatives in the food we eat, or even direct sunlight, excess production of free radicals can occur, causing profound damage. This free radical frenzy is called oxidative stress, and is linked to almost every disease of aging including arthritis, heart disease, cataracts, Alzheimer's disease, Parkinson's disease, and cancer.16 In fact, the reason why these are called diseases of aging is because the longer we are alive, the longer we are subjected to these free radical assaults.

How does FPP affect the decline of our immune systems as we age?

Our immune systems consist of specialized tissues, organs, and cells, including several different kinds of white blood cells. Each type of white blood cell works in specific ways to keep us healthy and free of disease. They not only stand guard – on the alert for invaders – they can fight and eradicate microbes, too.28-30

However, as we age, our white blood cells become less efficient in keeping viruses and bacteria from infecting us. They often mistake invaders for good guys, like nutrients. As they age, white blood cells may recognize foreign invaders, but be too tired to fight and let them in.30,31 This age-associated immune decline also results in single cancer cells being able to “take hold" and grow into tumors. By the time the white blood cells realize their mistake, the cancer is a widespread disease.28

That’s why older members of society have more urinary tract infections, more pneumonia, more cases of bacterial meningitis, tuberculosis, herpes zoster, and much more cancer than younger adults do. Moreover, mortality rates for these diseases are often 2-3 times higher among older adults than younger people with the same disease.5,28

FPP steps in and takes charge. One kind of white blood cell, the macrophage “eats" and digests bacteria, viral particles, and free radical fragments. Research has shown that FPP helps macrophages work faster and ingest more disease causing microbes.30,31 Scientists have also discovered that FPP increases the production of a chemical protein called interleukin that’s secreted by macrophages. Interleukin plays an important part in wound healing and keeping minor infections from becoming major infections.32

Another important immune system cell is the natural killer (NK) cell, a white blood cell that is continually on the prowl for cancer cells. As the immune system ages, NK cells have trouble “seeing" cancer cells. Researchers have discovered that FPP boosts the activity of NK cells. Increased NK cell activity can result in the increased killing of cancer cells as well as cells infected by viruses. 30,31

How does FPP help protect us from free radical damage?

FPP contains unique and powerful antioxidants. Antioxidants are molecules that neutralize free radical damage. Antioxidants do this by donating an extra electron to the free radical without becoming frenzied or worked up into a free radical themselves. Although the antioxidant has donated an electron, it has a more stable “personality" and is less reactive. This action stops the domino effect and ongoing free-radial damage.17-21

If you consider your body a temple, think of free radicals as stealing bricks from your temple’s foundation. FPP acts not only as policeman, but as a builder as well. It doesn’t just stop the theft of bricks, it helps create new ones, keeping the foundation strong and young.22-27 FPP does this by affecting superoxide dismutase (SOD) and glutathione peroxidase (GPX), the very genetic pathways that eliminate free radicals from the system. FPP is more than an antioxidant—it doesn’t turn into a pro-oxidant if you happen to take a large dose the way standard antioxidants can. Consider it an “antioxidant plus."22-27

Since aging is largely determined by how well our bodies can fight oxidative damage, using FPP can slow down the clock as it bolsters natural abilities with its own potent neutralizing activities. ...

...One scientific study showed the ability of FPP to inhibit dangerous hydroxyl and hydroxyl-like free radicals, while enhancing the production of protective superoxide.27 Other research by Dr. Lester Packer, a professor of Molecular Pharmacology and Toxicology at the University of Southern California School of Pharmacy, shows FPP to have natural iron chelating effects and prevents lipid peroxidation.36,37 And, in one randomized, double blind, placebo-controlled clinical trial, patients with cirrhosis of the liver were given FPP or a placebo. The results showed that 81.2% of the patients survived in the FPP group compared to 38.5% of participants in the placebo group.38 These studies, and many others like it, show that FPP can neutralize the effects of oxidative stress on disease states as well as slowing the normal aging process...

[Article references]

Management of Anemia of Inflammation in the Elderly

Papaya has been traditionally acknowledged as one of nature's best anti-inflammatories, as well as having other benefits for health and well being. Today, scientific studies such as the one below support this potential. This extract is from the article:

Antonio Macciò and Clelia Madeddu, "Management of Anemia of Inflammation in the Elderly," Anemia, vol. 2012, Article ID 563251, 20 pages, 2012. doi:10.1155/2012/563251

[Article references]

...5.6. Nutraceuticals

Since time immemorial, man has used plant extracts to protect himself against several diseases and also to improve his health and lifestyle. Traditional medicines have long provided front-line pharmacotherapy for many millions of people worldwide. Medicinal extracts are a rich source of therapeutic leads for the pharmaceutical industry. The use of medicinal plant therapies to treat chronic illness, including aging anemia is thus widespread and increasing. Recently, nutritional approaches have been sought more frequently to counteract both anemia and immunological dysfunction (i.e., immunosenescence) commonly found in older subjects. In fact, many aromatic, medicinal, and spice plants contain compounds that possess confirmed strong antioxidant and anti-inflammatory components that can counteract the etiopathogenetic mechanisms that induce aging anemia. No doubt, plants are serving several purposes in health, nutrition, beauty, or medicine. With technique development and recent research, it has been proved that certain nonnutritive chemicals in plants, such as terpenoids and flavonoids that were earlier thought to be of no importance to the human diet, possess antioxidant properties. In fact, the plants are susceptible to damage by active oxygen and thus develop numerous antioxidant defenses and potent antioxidants. Recent research has proved that these can also be used as antioxidants to protect our body from various chronic diseases, such as anemia, that can weaken the immune system of the body [110].

Until now, no set definition of antioxidants has existed. In simple words, “antioxidants” are a type of complex compounds found in our diet that act as a protective shield for our body against certain diseases related to oxidative stress. Oxidative damage is a significant causative factor in the development of certain human diseases, aging and related problems, and antioxidants are capable of preventing or ameliorating these processes [111]. The antioxidants are classified into the following different categories:

Enzymatic and Nonenzymatic Endogenous Antioxidants -

These antioxidants are found both in extracellular and intracellular environment and are tactically arranged within the cell to provide maximum protection against free radicals.

Exogenous Antioxidants Derived from Natural and Dietary Sources -

Plants develop several antioxidants that aid in the antioxidant defense system, protecting plants against damage caused by active O2 formed by ultraviolet exposure. Certain seaweeds also function as antioxidants. Our daily diet contains vegetables, fruits, tea, wine, and other things that possess compounds rich in antioxidative properties (Table 2).

Table 2

(Click here if you are having trouble viewing this table)

Categories of antioxidants.

There are 4 types of antioxidants based on the defense mechanism.

  1. Preventive antioxidants: these suppress the free radical formation (i.e., enzymes such as peroxidase, catalase, lactoferrin, carotenoids, etc.).
  2. Radical scavenging antioxidants: these suppress the chain initiation reaction (i.e., vitamin C and carotenoids).
  3. Repair and de novo antioxidants: these comprise of proteolytic enzymes and repair enzymes for DNA and genetic materials.
  4. Enzyme inhibitor antioxidants: these induce the production and reaction of free radicals and the transport of the appropriate antioxidants to the appropriate active site.

The basic science that underlies the role of free radicals in causing cellular pathologies and the role of antioxidants in preventing this show that an imbalance between the ROS and antioxidant defense systems may lead to chemical modifications of biologically relevant macromolecules. This imbalance provides a logical pathobiochemical mechanism for the initiation and development of elderly anemia. Experimental data obtained in vivo provide evidence that antioxidants function in systems that scavenge reactive oxygen species and that these are relevant to what occurs in vivo.

The majority of the antioxidant activity is due to the flavones, isoflavones, flavonoids, anthocyanin, coumarins, catechins, and isocatechins. Spices and herbs are recognized as sources of natural antioxidants and thus play an important role in the chemoprevention of diseases and aging...

...The use of complementary medicines, such as plant extracts, in therapy varies according to the different cultural traditions...

...Also fermented papaya preparation (FPP) (a product of yeast fermentation of Carica papaya Linn) has been tested in chronic and degenerative disease conditions (such as thalassemia, cirrhosis, diabetes, and aging) and performance sports showing the ability to favorably modulate immunological, hematological, inflammatory, vascular, and oxidative stress damage parameters. Neuroprotective potential evaluated in an Alzheimer's disease cell model showed that the toxicity of the β-amyloid could be significantly modulated by FPP. FPP modulated the oxidative stress-induced apoptosis through the downregulation of the ERK, Akt, and p38 activation mediated by H2O2. FPP reduces the extent of the H2O2-induced DNA damage, an outcome corroborated by similar effects obtained in the benzo[a]pyrene treated cells [117].

Considering the etiopathogenetic mechanisms of anemia of inflammation in the elderly population, an integrated nutritional/dietetic approach with nutraceuticals that can manipulate oxidative stress and related inflammation may prevent the onset of this anemia and its negative impact on patients' performance and quality of life. Indeed, emerging evidence suggests that interventions, including nutrition, pharmacology, and physical exercise, may activate the expression of cellular antioxidant systems and play a role in preventing inflammatory processes. For these reasons, new effective interventions, based on nutrition and aimed at targeting oxidative stress and chronic inflammation, may induce an important protection. Although a large body of research has focused on individual or small numbers of antioxidants, increasing the circulating antioxidant capacity through the increased consumption of antioxidant-rich fruits and vegetables may be protective against aging-related disease. The available scientific evidence indicates that the link between oxidative stress, a proinflammatory systemic environment, and aging anemia is strong...

Acknowledgment

This work accomplished in collaboration with TEVA Italia. Work supported by the ‘‘Associazione Sarda per la ricerca in Oncologia Ginecologica-ONLUS”.

[Article references]

Applications and Bioefficacy of the Functional Food Supplement Fermented Papaya Preparation

Toxicology journal homepage: www.elsevier.com/locate/toxicol

Okezie I. Aruomaa,*, Yuki Hayashib, Francesco Marottac, Pierre Mantellob, Eliezer Rachmilewitzd, Luc Montagniere

a Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, New York, NY, USA
b Osato Research Institute, Gifu, Japan
c ReGenera Research Group for Aging Intervention, Milano, Italy
d Department of Hematology, The E. Wolfson Medical Center, Holon, Israel
e UNESCO, World Foundation AIDS Research and Prevention, UNESCO, Paris, France

[Article references]

Abstract

Fermented papaya preparation (FPP) (a product of yeast fermentation of Carica papaya Linn) is a food supplement.

Studies in chronic and degenerative disease conditions (such as thalassemia, cirrhosis, diabetes and aging) and performance sports show that FPP favourably modulates immunological, hematological, inflammatory, vascular and oxidative stress damage parameters. Neuroprotective potential evaluated in an Alzheimer's disease cell model showed that the toxicity of the β-amyloid can be significantly modulated by FPP. Oxidative stress trigger apoptotic pathways such as the c-jun N-terminal kinase (JNK)and p38-mitogen activated protein kinase (MAPK) are preferentially activated by pro-inflammatory cytokines and oxidative stress resulting in cell differentiation and apoptosis. FPP modulated the H2O2-induced ERK, Akt and p38 activation with the reduction of p38 phosphorylation induced by H2O2.

FPP reduces the extent of the H2O2-induced DNA damage, an outcome corroborated by similar effects obtained in the benzo[a]pyrene treated cells. No genotoxic effect was observed in experiments with FPP exposed to HepG2 cells nor was FPP toxic to the PC12 cells. Oxidative stress-induced cell damage and inflammation are implicated in a variety of cancers, diabetes, arthritis, cardiovascular dysfunctions, neurodegenerative disorders (such as stroke, Alzheimer's disease, and Parkinson's disease), exercise physiology (including performance sports) and aging. These conditions could potentially benefit from functional nutraceutical/food supplements (as illustrated here with fermented papaya preparation) exhibiting anti-inflammatory, antioxidant, immunostimulatory (at the level of the mucus membrane) and induction of antioxidant enzymes.

© 2010 Elsevier Ireland Ltd. All rights reserved.

Conflict of interest
YH and PM are affiliated with the Osato Research Institute (not for profit organization focused on biomedical research involving FPP). OIA, ER, FM and LM are actively involved in biomedical research involving fermented papaya preparation. FPP is produced by the Osato International Inc., Japan.

Acknowledgments
The authors thank Aston Martin Racing team drivers David Brabham, Darren Turner and Rickard Rydell and team members Sadie Wigglesworth and Melanie Johnson without whom the proof of concept study at the Le Mans 2007 would not have been possible. The medical assistance of Rene Kacian is acknowledged. The authors thank Drs. Catherine Garrel and Henri Faure of the University Hospital Grenoble, France for their assistance in samples analysis.

[Article references]

Management of Anemia of Inflammation in the Elderly

Antonio. Macciò and Clelia Madeddu, in collaboration with TEVA Italia, and  supported by the ‘‘Associazione Sarda per la ricerca in Oncologia Ginecologica-ONLUS”,  report on the role of plant extracts in the management of anemia - following is an extract from their article:

Antonio Macciò and Clelia Madeddu, "Management of Anemia of Inflammation in the Elderly," Anemia, vol. 2012, Article ID 563251, 20 pages, 2012. doi:10.1155/2012/563251

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“Anemia of any degree is recognized as a significant independent contributor to morbidity, mortality, and frailty in elderly patients. Among the broad types of anemia in the elderly a peculiar role seems to be played by the anemia associated with chronic inflammation, which remains the most complex form of anemia to treat. The origin of this nonspecific inflammation in the elderly has not yet been clarified. It seems more plausible that the oxidative stress that accompanies ageing is the real cause of chronic inflammation of the elderly and that the same oxidative stress is actually a major cause of this anemia...

... In fact, the plants are susceptible to damage by active oxygen and thus develop numerous antioxidant defenses and potent antioxidants. Recent research has proved that these can also be used as antioxidants to protect our body from various chronic diseases, such as anemia, that can weaken the immune system of the body [110]. Until now, no set definition of antioxidants has existed. In simple words, “antioxidants” are a type of complex compounds found in our diet that act as a protective shield for our body against certain diseases related to oxidative stress. Oxidative damage is a significant causative factor in the development of certain human diseases, aging and related problems, and antioxidants are capable of preventing or ameliorating these processes [111]....

Also, fermented papaya preparation (FPP) (a product of yeast fermentation of Carica papaya Linn) has been tested in chronic and degenerative disease conditions (such as thalassemia, cirrhosis, diabetes, and aging) and performance sports showing the ability to favorably modulate immunological, hematological, inflammatory, vascular, and oxidative stress damage parameters. Neuroprotective potential evaluated in an Alzheimer's disease cell model showed that the toxicity of the β-amyloid could be significantly modulated by FPP. FPP modulated the oxidative stress-induced apoptosis through the downregulation of the ERK, Akt, and p38 activation mediated by H2O2. FPP reduces the extent of the H2O2-induced DNA damage, an outcome corroborated by similar effects obtained in the benzo[a]pyrene treated cells [117].

Since oxidative stress-induced cell damage and inflammation are implicated in the pathogenesis of anemia of chronic inflammation, this condition could potentially benefit from functional nutraceutical/food supplements exhibiting anti-inflammatory, antioxidant, and immunostimulatory and antioxidant properties.”

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