Endogenous Antioxidants are the Potent First Line of Defense against Reactive Oxygen Species

image_pdfimage_print

The Oxygen Paradox

The ‘Oxygen Paradox’ states that life on earth requires oxygen for its existence and is required in metabolism and respiration, yet oxygen is also a highly reactive molecule that produces reactive oxygen species that can damage the organism.  1    Oxygen Paradox relates directly to the fact that each oxygen atom has one unpaired electron in its outer valence shell, and molecular oxygen has two unpaired electrons. Thus atomic oxygen is a free radical and molecular oxygen is a (free) bi-radical.

The mitochondria provides the cell with a source of energy through oxygen reduction and thus generates 36 molecules of adenosine triphosphate (ATP).  In this respiratory chain, about 0.4 to 4% of the oxygen is not correctly converted to water due to electron leakage which gives rise to reactive oxygen species (ROS). 

As a result of energy production in the body, the human organism is continuously producing ROS. 

Despite the negative connotation of ROS, ROS at low levels and concentration are important to human physiology and contribute to:  2

  • Initiating and regulating apoptosis
  • Activation of transcription factors (NFkB, p38-MAP kinase, etc.)
  • Expression of genes coded for antioxidant enzymes

Problems arise in the organism when there is excessive ROS that are not quenched by a strong antioxidant system.  This is known as oxidative stress, discussed below.

Reactive oxygen species (ROS)

Reactive oxygen species (ROS) (also known as Free Radicals) are chemically reactive molecules containing oxygen that are formed as a natural byproduct of normal metabolism.  There are a number of ROS that have been identified:

  • Alkoxyl free radicals
  • Dinitrogen trioxide
  • Hydrogen Peroxide free radicals
  • Hydroxyl free radicals
  • Lipid peroxide
  • Lipid peroxyl
  • Nitric oxide
  • Nitrogen dioxide
  • Peroxyl free radicals
  • Peroxynitrite free radicals
  • Phenoxyl free radicals
  • Polyunsaturated Fatty Acid free radicals
  • Semiquinone free radicals
  • Singlet Oxygen free radicals
  • Sulfoxide free radicals
  • Superoxide free radicals
  • Tocopheroxyl free radicals

Source of ROS

The source of ROS can be found in two areas:

  • Endogenous ROS (from “inside” the body)
    • Endogenous ROS is produced intra-cellularly through multiple mechanisms in:
      • cell membranes
      • mitochondria
      • peroxisomes
      • endoplasmic reticulum
  • Exogenous ROS (from “outside” the body)
    • Exogenous ROS is produced from:
      • pollutants
      • tobacco
      • smoke
      • drugs
      • xenobiotics
      • radiation
      • prolonged exposure to sunlight
      • excessive exercise
      • heat shock

ROSChart

Figure 1:  ROS pathway of cellular destruction

Oxidative Stress

Oxidative stress is defined as an imbalance between ROS and the biological system to defend itself from the ROS and repair the damage to the cell.  Essentially oxidative stress occurs when there is an excess of free radicals and which cells cannot adequately destroy the excess of free radicals formed.  For example, hydroxyl radicals and peroxynitrite in excess can damage cell membranes and lipoproteins by a process called lipid peroxidation.  4 

Figure 2:  Oxidative Stress

Oxidative stress from oxidative metabolism causes damage to the cell, including:  5

  • damage of DNA
  • oxidations of polyunsaturated fatty acids in lipids (lipid peroxidation)
  • oxidations of amino acids in proteins
  • oxidatively deactivate specific enzymes by oxidation of co-factors

 

An external file that holds a picture, illustration, etc. Object name is 0071.f1.jpg

Figure 3:  Major sources of free radicals in the body and the consequences of free radical damage.

(Source:  Antioxidants in health and disease, J Clin Pathol. 2001 Mar;54(3):176-86.)

ROS are particularly damaging to the mitochondria.  The function of the mitochondria is to regulate processes inside the cell, and include:

  • ATP production  
  • calcium homeostasis and modulation  
  • amino acid and nitrogen metabolism 
  • apoptotic cell death 
  • ROS generation and detoxification 
  • heme and iron–sulfur center biosynthesis

Mitochondria, in their normal process of generating ATP, produce ROS.  The mitochondrial ROS, as well as ROS from other sites within or outside the cell, cause damage to mitochondrial components and initiate degradative processes.  6

Mitochondria contain a series of well-defined and tightly controlled antioxidant defense systems, which work synergistically to intercept ROS, thereby minimizing oxidative damage. Disruption of these antioxidant defenses may result in extensive oxidative damage to mitochondria.

If not properly maintained and regulated, oxidative stress can create and produce a variety of chronic and degenerative diseases.  It can also contribute to the aging process and some acute pathologies.

An external file that holds a picture, illustration, etc. Object name is IJBS-4-89_F1.jpg

Figure 4:  Disease pathologies produced from oxidative stress

(Source: Free Radicals, Antioxidants in Disease and Health, Int J Biomed Sci. 2008 Jun; 4(2): 89–96. PMCID: PMC3614697)

Antioxidant System

In the human organism, there exists a highly evolved complex and sophisticated antioxidant system that acts to protect the cells and organs of the body.  The human organism contains a complex network of endogenous and exogenous systems including enzymes and metabolites that work synergistically and interactively to neutralize free radicals.  7  8  9

The antioxidant system is designed to work in two ways:  10

  • Prevent ROS from being formed (chain-breaking)
    • With chain-breaking, when a free radical releases or steals an electron, a second free radical is formed. The last one exerts the same action on another molecule and continues until either the free radical formed is stabilized by a chain-breaking antioxidant (vitamin C, E, carotenoids, etc), or it simply disintegrates into an inoffensive product.
  • Remove ROS before they can damage vital components of the cell
    • For the preventive way, an antioxidant enzyme like superoxide dismutase, catalase and glutathione peroxidase can prevent oxidation by reducing the rate of chain initiation, e.g., either by scavenging initiating free radicals or by stabilizing transition metal radicals such as copper and iron.

An external file that holds a picture, illustration, etc. Object name is 0071.f2.jpg

Figure 5:  Antioxidant defenses against free radical attack. Antioxidant enzymes catalyze the breakdown of free radical species, usually in the intracellular environment. Transition metal binding proteins prevent the interaction of transition metals such as iron and copper with hydrogen peroxide and superoxide producing highly reactive hydroxyl radicals. Chain breaking antioxidants are powerful electron donors and react preferentially with free radicals before important target molecules are damaged. In doing so, the antioxidant is oxidized and must be regenerated or replaced. By definition, the antioxidant radical is relatively unreactive and unable to attack further molecules.

(Source:  Antioxidants in health and disease, J Clin Pathol. 2001 Mar;54(3):176-86.)

The Antioxidant system in the human organism has a number of categories based on its location and function. 

These categories include:  11

  • Endogenous antioxidants (“inside the body”)
    • Enzymatic antioxidants (Primary antioxidants)
    • Non-enzymatic antioxidants 
  • Exogenous antioxidants (“outside the body”) (Secondary antioxidants)
  • Water-soluble antioxidants
  • Lipid-soluble antioxidants

Endogenous Antioxidants

Endogenous antioxidants are broken down as either enzymatic or non-enzymatic antioxidants.

Enzymatic antioxidants

There are a number of enzymatic antioxidants identified: 

  • Superoxide dismutase (SOD)
  • Catalase
  • Glutathione peroxidase (GPx)
  • Glutathione reductase (GRx)
  • Glutaredoxin,
  • Thioredoxin,
  • Thioredoxin reductase (TrxR)
  • Peroxiredoxin (PRx)
  • Sulfiredoxin

However, 3 or 4 of these enzymatic antioxidants are considered as the main enzymatic antioxidants.  These 4 include:

  • Superoxide dismutase (SOD) (copper/zinc and manganese-dependent)
  • Catalase (CAT) (iron-dependent)
  • Glutathione peroxidase (GPx) (selenium-dependent)
  • Glutathione reductase (GRx)

Enzymatic antioxidants are also known as primary antioxidants, since they are the first line of defense against ROS. 

Primary-antioxidants enzymes serve as our body’s most potent defense against free radicals and harmful inflammatory reactions. Instead of the four main enzymatic antioxidants, science states that the are only 3 primary-antioxidants:

  • Superoxide dismutase (SOD)
  • Catalase (CAT)
  • Glutathione Peroxidase (GPx)

Thanks to their complementary and synergic mechanism of action against free radicals, SOD, CAT and GPx prevent the development of oxidative stress.

wps_clip_image-26930

Figure 6:  Primary and Secondary antioxidants (© Bionov)

(Source:  Bionov)

Primary antioxidants have high catalytic properties and are involved in the elimination of millions of free radicals. Contrary to primary antioxidants, secondary antioxidants quench only one free radical and are quickly exhausted with no possibility of renewal. In this way, secondary antioxidant reserves can become quickly saturated and oxidative stress uncontrolled.

wps_clip_image-27025

Figure 7:  Quenching ability of Primary and Secondary antioxidants (© Bionov)

(Source: Bionov

Non-enzymatic antioxidants

The endogenous non-enzymatic antioxidant systems are the second line of defense against free radical damage. It has been known that non-enzymatic antioxidants can act synergistically with enzymatic antioxidants.

In animal models, administration of antioxidant vitamins increases mitochondrial SOD, GPx and catalase activity and significantly decreases MDA and carbonyl group levels, and thus prevents rupture of mitochondrial membrane.  12 

Since they are produced “inside” the body, non-enzymatic antioxidants work by interrupting free radical chain reactions.

The non-enzymatic antioxidants include: 

  • Thiols (glutathione, lipoic acid, N-acetyl cysteine)
  • L-arginine
  • NADPH and NADH
  • Ubiquinone (coenzyme Q10)
  • Melatonin
  • Uric acid
  • Bilirubin
  • Metal Binding Proteins
    • Albumin (copper)
    • Ceruloplasmin (copper)
    • Metallothionein (copper)
    • Ferritin (iron)
    • Myoglobin (iron)
    • Transferrin (iron)

Exogenous Antioxidants

Exogenous antioxidants are dietary or nutrient antioxidants that are not produced in the body but provided by food or supplements.  Most antioxidants found in foods and supplements are of the non-enzymatic type. They boost your enzymatic antioxidant defense system by doing a “first sweep,” disarming the free radicals, which helps prevent depletion of your enzymatic antioxidants. 13 

Exogenous antioxidants are also known as secondary antioxidants.  Exogenous antioxidants such as vitamins, carotenoids, polyphenols, minerals, are only able to increase the antioxidant enzymes activity, that is to say their recruitment in the blood circulation. Secondary exogenous antioxidants can’t boost the tissue expression of primary antioxidant enzymes. Consequently, they can’t prevent a depletion of enzymatic antioxidants, but only activate their release in the blood to correct oxidation.

Exogenous antioxidants include:

  • Vitamin E
  • Vitamin C
  • Beta carotene and other carotenoids and oxycarotenoids, e.g., lycopene and lutein
  • Trace metals (selenium, manganese, zinc)
  • Polyphenols and flavonoids (4,000 flavonoids have been identified and classified)
  • Omega-3 and omega-6 fatty acids

AntioxidantChart

Figure 8:  Enzymatic and Non-Enzymatic Antioxidant System

The other two categorizations of antioxidants is whether they are water-soluble (hydrophilic) or lipid-soluble (hydrophobic).

Lipid-Soluble Antioxidants

The lipid-soluble antioxidants are located in the cell membrane and protect the cell membrane from oxidative damage.  Lipid-soluble antioxidants protect cell membranes from lipid peroxidation. 

Lipid-soluble antioxidants include:

  • Vitamin E  (tocopherol and tocotrienols)
  • Vitamin A
  • Carotenoids
  • Ubiquinol  (CoQ10)

Water-Soluble Antioxidants

The water-soluble antioxidants are located inside (cytosol) and outside the cell. Water-soluble antioxidants react with oxidants in the cell cytosol and the blood plasma,

Water-soluble antioxidants include:

  • Vitamin C
  • Polyphenols
  • Glutathione

Lipid and Water-Soluble Antioxidants

There are also antioxidants that are both water-soluble and lipid soluble. 

They include:

  • R-Alpha-lipoic acid 
  • Astaxanthin

Analysis of Four Main Enzymatic Antioxidants

The four main enzymatic antioxidants include:

  • Superoxide dismutase (SOD)
  • Catalase
  • Glutathione peroxidase (GPx)
  • Glutathione reductase (GRx)

Antioxidant Enzyme

Location in tissue
SOD

   Cu/Zn SOD

Cytosol, Nucleus

   MN SOD

Mitochondria

   EC SOD

Extracellular fluid

Catalase

Peroxisomes

Glutathione Peroxidase

Cytosol, Mitochondria

Glutathione Reductase

Cytosol, Mitochondria

Superoxide Dismutase (SOD)

SOD, the first line of defense against free radicals, catalyzes the dismutation of superoxide anion radical (O2•–) into hydrogen peroxide (H2O2) by reduction.

wps_clip_image-26721

Figure 9:  SOD dismutates superoxide anion radical 

There are two categories of SOD:

  • Cellular SOD
  • Extracellular SOD

Cellular SOD is of two types based on the location in the cell:

  • Mitochondrial SOD (also known as manganese-containing SOD or Mn-SOD) is an endogenous form of SOD that exists only inside the mitochondria of cells
  • Cytoplasmic SOD (also known as copper-zinc SOD; Cu-Zn SOD; SOD1 or Cu-Zn-containing SOD) is an endogenous form of SOD that exists inside the cell (i.e. it is intracellular, existing in the cytoplasm) but outside the mitochondria

Extracellular SOD (also known as ECSOD;  Copper-Zinc SOD; Cu-Zn SOD; SOD1 or Cu-Zn-containing SOD) is an endogenous form of SOD that exists outside the cell.

The cofactors for SOD are:

  • copper
  • zinc
  • manganese
  • iron

Since SOD is an antioxidant enzyme and a large protein, without adapted protection and guaranteed bioactivity, it cannot be consumed in the diet or as a dietary supplement.  Despite the fact that SOD is found in a number of foods like:

  • bovine liver
  • horseradish
  • cantaloupe

there is no evidence that ingestion of unprotected SOD or SOD-rich foods can have any physiological effects, since all ingested SOD is broken down into amino acids before being absorbed.

However, there are certain natural substances that have been identified that may have the capacity of activating or enhancing the production of SOD in the body.  These natural substances are listed in the Table below:

Substances that may enhance the function or production of Superoxide Dismutase

CategorySubstanceDescriptionReference
Amino Acids
TaurineHomocysteine induces ER stress and reduces the secretion and expression of EC-SOD in VSMCs, leading to increased oxidative stress in the vascular wall. Taurine restores the secretion and expression of EC-SOD by ameliorating ER stress induced by homocysteine.1
Carbohydrates
LentinanLentinan increased the pathologically low SOD activity of erythrocytes and lymphocytes of patients with cirrhosis of the liver. No significant antioxidant (free radical scavenger) effect has been observed in NADPH-induced and Fe3+-stimulated lipid peroxidation and in xanthine-xanthine oxidase system.2
Elements
Molecular hydrogen (H2)Molecular hydrogen also triggers the activation or upregulation of additional antioxidant enzymes (e.g. glutathione, superoxide dismutase, catalase, etc.)3
Foods
Garlic In the plasma fraction and erythrocyte hemolysate, MDA levels were found to be significantly lower, but erythrocyte GSH-Px and SOD activities were significantly higher in the second samples relative to the first ones. 3
Aged Garlic Extract (AGE)AGE caused both dose- and time-dependent increases in intracellular GSH level, glutathione disulphide (GSSG) reductase and superoxide dismutase (SOD) activity while GSSG level was decreased. These results suggest that the antioxidant effect of AGE may be due to its modulation of the GSH redox cycle and SOD activity in vascular endothelial cells.4
Aloe veraExtracts from the parenchymatous leaf gel and the rind of the Aloe vera plant (Aloe barbadensis Miller) were shown to contain seven electrophoretically-identifiable superoxide dismutases (SODs).5
Herbs
AshwagandhaWhile 15 days treatment with ashwagandha root powder did not produce any significant change, 30 days treatment produced a significant decrease in lipid peroxidation, and an increase in both superoxide dismutase and catalase.6
Bacopa MonneiriBacopa monniera caused a dose-related increase in SOD, catalase and glutathione peroxidase activities, in all the brain regions investigated, after 14 and 21 days. 7
Ginko BilobaThe objective of this study was to examine the influence of Ginkgo biloba exocarp polysaccharides(GBEP) on serum superoxide dismutase(SOD) activity and malondialdehyde(MDA) level in mice under different states. GBEP significantly enhanced SOD activity and decreased MDA content in S180 bearing mice.8
Korean GinsengMutations of the AP2 binding sites in the heterologous promoter and natural context systems abolished the transcriptional activation by ginsenoside Rb2. These results suggest that the SOD1 gene was greatly activated by ginsenoside Rb2 through transcription factor AP2 binding sites and its induction.9
Parsley (Apigenin)The intervention with parsley seemed, partly, to overcome this decrease and resulted in increased levels of GR and SOD.10
Hormones
MelatoninMelatonin stimulates a number of antioxidative enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase.11
Lipids
Ginsenoside Rb2Mutations of the AP2 binding sites in the heterologous promoter and natural context systems abolished the transcriptional activation by ginsenoside Rb2. These results suggest that the SOD1 gene was greatly activated by ginsenoside Rb2 through transcription factor AP2 binding sites and its induction.12
Minerals
CopperCu supplementation (2 mg/day, 4 weeks) increased erythrocyte Cu-zinc (Zn) superoxide dismutase (SOD) activity levels in 18 of 23 rheumatoid arthritis (RA) patients receiving gold or methotrexate (mean increase 21%). 13
ManganeseManganese is an essential element for superoxide dismutase14
ZincMeasurements performed at the end of the study showed that groups 1 and 3 (zinc-supplemented groups) had the highest GSH level, GPx, and SOD activities and zinc level (p < 0.01). 15
Nootropics
CentrophenoxineSix week administration of centrophenoxine (once a day in doses of 80 mg/Kg and 120 mg/Kg) to the experimental animals produced increases in the activity of SOD, GSH-PER and GSSG-RED in particulate fractions from all the three brain regions. In the soluble fractions, however, only SOD and GSH-PER activity was increased.16
DeprenylThe results of our deprenyl study suggests the possibility that the protection of catecholaminergic neurons by an upregulation of SOD and CAT activities plays a significant role in the life span of animals.17
HydergineSOD and CAT activities were higher in the aged animals and were further increased with hydergine treatment. The increase in SOD levels caused by hydergine treatment in the aged animals were the most prominent in the hippocampus and in the corpus striatum.18
Polyphenols
PycnogenolPycnogenol treatment caused an increase in superoxide dismutase levels in cells that were pretreated with pycnogenol.19
Resveratrol Resveratrol also increased in a dose-dependent way brain superoxide dismutase, catalase and peroxidase activities. 20
SilymarinIt was concluded that silymarin treatment in a concentration achievable by in vivo treatment (10 micrograms/ml) significantly increased the SOD activity of both the erythrocytes and lymphocytes of patients with liver disease, whereas the SOD expression of the lymphocytes enhanced to a considerable extent.21
Vitamins
Vitamin E (alpha and gammas tocopherols)Both α- and γ-tocopherol decreased arterial superoxide anion generation, lipid peroxidation and LDL oxidation (all p < 0.05 vs. control), and increased endogenous SOD activity (p < 0.05). The effects of γ-tocopherol were more potent than those of α-tocopherol (p < 0.05).22

SOD B®

Scientists discovered that a specific cantaloup melon variety (Cucumis melo L.) had a shelf-life three or four times longer than most ripe melons. After extensive research, scientists concluded that these melons had 15 to 20 higher levels of SOD than standard melons.

Even though this melon had higher levels of SOD, oral consumption of the melon would not provide the SOD enzyme to the blood plasma due to the stomach acid breaking apart the enzyme protein. 

Gastric-Protection

Figure 10:  SOD B® is microencapsulated in order to provide an enteric-coating protection able to inhibit SOD degradation during the digestive process. The Bionov patented C3 microencapsulation technology enables SOD B® to reach the intestinal tract with the guaranteed highest SOD activity. Once in the intestinal tract, SOD B® is released from the coating to provide its antioxidant and anti-inflammatory properties. Thanks to its expertise in coatings development, Bionov was the first to propose a natural and bioactive source of SOD for nutritional applications.  (© Bionov)

(Source:  Bionov)

The solution regarding bioavailability was provided by the French company Bionov, the world’s largest producer of natural and bioactive Superoxide Dismutase (SOD) from Cantaloup French melon (Cucumis melo L.). 

Through its coatings, Bionov preserves the SOD activity from gastric acidity, therefore protecting the bioactivity of the enzyme. The bioavailability issue has been resolved by demonstrating the inductive primary antioxidant pathway activated by SOD B® through the NRF2/ARE activation in the intestinal tract.

Way-of-Action

Figure 11:  Once released along the intestinal tract, SOD B® could be able to promote the activation of the immune system and then induce a cascade leading to the activation of macrophages in the entire body. This immune response could induce endogenous antioxidant defenses, possibly via the upregulation of Nrf2/ARE pathway. Nuclear-factor-E2 related factor (Nrf2) is a transcription factor well known to induce antioxidant enzymes synthesis in the body.  (© Bionov)

(Source:  Bionov)

Bionov has developed three (3) bioactive solutions suitable for the formulation of a large range of nutritional applications.  These three bioactive solutions include:

With SOD B Extramel®, Bionov has produced the highest source of natural and bioactive Superoxide Dismutase (SOD, 14,000 IU/g).  As demonstrated in multiparametric clinical studies, a one-month supplementation with SOD B Extramel® significantly boosts daily performances by improving stress relief, sleep quality, cognitive functions and physical tonus.

Antioxidants composition of SOD B Extramel®.

Antioxidants Level (per g)
Superoxide dismutase 14,000 U
Catalase 1550 U
Glutathione peroxydase 155 U
Co-enzyme Q10 0.08 mg
Lipoic acid 0.03 mg
Glutathione 0.33 μg
Glutathione disulfide 4.78 μg
Carotenoids 0.54 μg
Vitamin A 15.5 μg
Vitamin E 0.37 μg
Vitamin C 7.78 μg
Selenium 0.004 μg
Total phenolics 0.54 mg GAE 1

1 GAE: gallic acid equivalents.

(Source:  Nutrients. 2014 Jun; 6(6): 2348–2359.)

Contrary to SOD-like compounds, SOD B Extramel® is a source of natural and bioactive SOD and allows the stimulation of tissue expression of SOD, as well as Catalase & Glutathione Peroxidase, restoring the body’s endogenous primary antioxidant defenses for prolonged periods. SOD B Extramel® is backed by strong scientific evidence contrary to SOD-like molecules which are scarcely supported by scientific research.

SOD B Extramel® acts by inducing the expression of the body’s endogenous antioxidant defenses, as demonstrated in several proprietary studies. Numerous health benefits have been demonstrated following an SOD B Extramel® administration both after topical and oral administration.  14

Catalase

Catalase converts hydrogen peroxide into water and oxygen (using iron and manganese cofactors), as a result of the dismutation by SOD.   Catalase exhibits an extremely high reaction rate that is capable of decomposing millions of hydrogen peroxide molecules every second.  Catalase is found in:

  • peroxisomes
  • red blood cells
  • extracellular spaces

In the human body, catalase levels are highest in the liver and red blood cells and comparatively low in the heart and brain. Catalase serves many functions in the human body including:

  • modulating inflammation
  • mutagenesis
  • apoptosis

Catalase cannot be consumed in the diet or as a dietary supplement.  However, there are certain natural substances that may enhance the production of catalase in the body.  These natural substances are listed in the Table below:

Substances that may enhance the function and production of Catalase

CategorySubstanceDescriptionReference
Elements
Molecular hydrogen (H2) Molecular hydrogen also triggers the activation or upregulation of additional antioxidant enzymes (e.g. glutathione, superoxide dismutase, catalase, etc.)1
Herbs
AshwagandhaActive glycowithanolides of Ashwagandha administered once daily for 21 days, induced a dose-related increase in catalase activity in frontal cortex and striatum.1
Bacopa monniera Bacopa monniera caused a dose-related increase in SOD, catalase and glutathione peroxidase activities, in all the brain regions investigated, after 14 and 21 days.2
Ginko BilobaGinkgo biloba extract prepared from the leaves of Ginkgo biloba with 50% diluted alcohol was found to locally induce catalase enzyme activity in the epidermis after topical application, and also to systemically increase the activity of catalase in the liver, heart and kidney of Sprague Dawley rats.3
Green TeaHPLC analysis revealed that Longjing green tea catechin extract (GTC) contained 62% epigallocatechin gallate (EGCG), 19% epigallocatechin (EGC), 9% epicatechin gallate (ECG), and 7% epicatechin (EC). Accordingly, SOD and catalase activities in OR wild type increased by 40 and 19%, respectively. RT-PCR analysis indicated that the genes for copper-zinc containing SOD (CuZnSOD), manganese containing SOD (MnSOD), and catalase were upregulated. 4
Hormones
MelatoninMelatonin has been shown to either stimulate gene expression for the antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) or to increase their activity.5
Lipids
Ursolic AcidUrsolic acid has been found to increase catalase activity in mouse livers.6
Fish oilsIncreased life span was partially associated with decreased body weight, blunting renal proinflammatory cytokine (interferon-gamma, interleukins-10 and -12 and tumor necrosis factor-alpha) levels and lower nuclear factor-kappaB (NF-kappaB). Reductions in NF-kappaB were preceded by enhanced superoxide dismutase, catalase and glutathione peroxidase activities.7
Polyphenols
PycnogenolPycnogenol caused a concentration-dependent enhancement of H2O2 and O-2-clearance. Itincreased the intracellular GSH content and the activities of GSH peroxidase and GSH disulfide reductase. it also increased the activities of SOD and CAT. The results suggest that pycnogenol promotes a protective antioxidant state by upregulating important enzymatic and nonenzymatic oxidant scavenging systems. 8
Nootropics
DeprenylContinued subcutaneous infusion of deprenyl for 3 weeks caused a 2-3-fold increase in activities of both Cu Zn- and Mn-SOD and a 50-60% increase in CAT activities in striatum and substantia nigra but not in hippocampus, cerebellum or the liver. 9
HydergineHydergine or vehicle was administered systemically to young (3 months) and aged (18 months) Sprague-Dawley rats for 20 days and 24 h after the termination of the treatment, superoxide dismutase (SOD) and catalase (CAT) activities were determined in some brain regions. SOD and CAT activities were higher in the aged animals and were further increased with hydergine treatment. 10

Glutathione Peroxidase

Glutathione Peroxidase mainly detoxifies free H2O2 and lipid peroxides using reduced glutathione (GSH) as a cofactor.  Selenium is considered particularly important in protecting the lipid environment against oxidative injury, as it serves as a cofactor for Glutathione peroxidase.  Thus to function properly, glutathione peroxidase requires glutathione and selenium. Its main role is to eliminate lipid peroxides resulting from the action of oxidative stress molecules on polyunsaturated fatty acids.

Glutathione peroxidase help break down hydrogen peroxide and organic peroxides into alcohols, and are particularly abundant in the liver.

Even though a standardized glutathione peroxidase is not currently available as a dietary supplement, there are identified natural substances that may enhance the production of glutathione peroxidase in the body.  These natural substances are listed in the Table below:

Substances that may stimulate the production of Glutathione Peroxidase

CategorySubstanceDescriptionReference
Foods
Aloe veraExtracts from the parenchymous leaf-gel of the Aloe vera plant (Aloe barbadensis Miller) were shown to contain glutathione peroxidase (GSHPx) activity.1
Herbs
AshwagandhaWhile 15 days treatment with ashwagandha root powder did not produce any significant change, 30 days treatment produced a significant decrease in lipid peroxidation, and an increase in both superoxide dismutase and catalase.2
Bacopa monnieraBacopa monniera caused a dose-related increase in SOD, catalase and glutathione peroxidase activities, in all the brain regions investigated, after 14 and 21 days.3
Green TeaMice studies have demonstrated the ability of green tea polyphenols to significantly increase the activity of glutathione peroxidase in the lungs, liver and small intestine.4
GingerMale adult Wistar rats were grouped into control, preventive and curative teams. The experimental teams were respectively fed on the test diet containing 2% ginger and 5% ginger, in order to measure the changes of plasma lipid peroxides (LPO) and glutathione (GSH-Px) after the experiment. The results show that ginger increased GSH-Px and reduced LPO in the rats' blood.5
Hormones
MelatoninMelatonin has been shown to either stimulate gene expression for the antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) or to increase their activity. 6
Lipids
Fish oilThis study was conducted to investigate the effect of omega-3 fatty acids on lipid peroxidation and antioxidant enzyme activities in non-insulin dependent diabetic patients. Among the erythrocyte antioxidant enzymes, the Glutathione peroxidase activity was increased (32.5 +/- 9.9 U/g Hb/min, before combined therapy vs 42.25 +/- 4.6 U/g Hb/min.7
Minerals
SeleniumSelenium is an essential trace element in humans and animals. Its only established function in humans is the antioxidant activity of glutathione peroxidase, a selenoenzyme.8
ZincThis study aims to examine the effect of zinc supplementation on free-radical formation and antioxidant system in individuals who are actively engaged in wrestling as a sport. Measurements performed at the end of the study showed that groups 1 and 3 (zinc-supplemented groups) had the highest GSH level, GPx, and SOD activities and zinc level (p < 0.01). 9
Polyphenols
CathechinsIn Se(+) cells, the remarkable cytoprotective activity of those flavonoids were confirmed, whereas none of such activity was evidenced in Se(-) cells. It was proved that the intracellular antioxidative function of flavonoids requires the interaction with GSH-PO, at least in the cells expressing the enzyme. Interestingly, the flavonoid activated GSH-PO clearly.10
QuercetinIn Se(+) cells, the remarkable cytoprotective activity of those flavonoids were confirmed, whereas none of such activity was evidenced in Se(-) cells. It was proved that the intracellular antioxidative function of flavonoids requires the interaction with GSH-PO, at least in the cells expressing the enzyme. Interestingly, the flavonoid activated GSH-PO clearly.11
Nootropics
CentrophenoxineSix week administration of centrophenoxine (once a day in doses of 80 mg/Kg and 120 mg/Kg) to the experimental animals produced increases in the activity of SOD, GSH-PER and GSSG-RED in particulate fractions from all the three brain regions. 12
Vitamins
Vitamin EVitamin E supplementation to hypercholesterolemic rats induced a significantly decrease in lipid peroxide concentrations and a significant increase in the GSH content, GSH-Px and GSH-ST activities in erythrocytes and liver. Long-term administration of vitamin E may play an important role in suppressing oxidative stress, and thus, may be useful for the prevention and/or early treatment of hypercholesterolemia.13

Glutathione Reductase

Glutathione reductase catalyzes the reduction of glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH), which is a critical molecule in resisting oxidative stress and maintaining the reducing environment of the cell.

Certain natural substances have been identified to enhance the production of glutathione reductase in the body and are listed in the Table below:

Substances that may enhance the function of Glutathione Reductase

CategorySubstanceDescriptionReference
Foods
Garlic The effect on glutathione reductase activities of feeding garlic oil to white albino rats maintained on high sucrose and alcohol diets was studied. Whereas high sucrose and alcohol diets resulted in significant increases in the activity of glutathione reductase in liver, kidneys and serum, the presence of garlic oil restored the levels to near normal. 1
Herbs
Green TeaFollowing the oral feeding of a polyphenolic fraction isolated from green tea (GTP) in drinking water, an increase in the activities of antioxidant and phase II enzymes in skin, small bowel, liver, and lung of female SKH-1 hairless mice was observed. GTP feeding to mice also resulted in considerable enhancement of glutathione reductase activity in liver. 2
Parsley (Apigenin)The intervention with parsley seemed, partly, to overcome this decrease and resulted in increased levels of GR and SOD.3
Hormones
MelatoninMelatonin has been shown to either stimulate gene expression for the antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) or to increase their activity. 4

The Table below is a summary of the natural substances that may enhance the production of the four main enzymatic antioxidants in the body:

Summary of Antioxidant Enzymes

SubstanceSODCatalaseGlutathione PeroxidaseGlutathione ReductaseTotals
Aged Garlic ExtractX1
Aloe veraXX2
AshwagandhaXXX3
Bacopa MonneiriXXX3
CathechinsX1
CentrophenoxineXX2
CopperX1
DeprenylXX2
Fish oilsXX2
Garlic XX2
GingerXX2
Ginko BilobaXX2
Ginsenoside Rb2X1
Green TeaXXX3
HydergineXX2
Korean GinsengX1
LentinanX1
ManganeseX1
MelatoninXXXX4
ParsleyXX2
PycnogenolXX2
QuercetinX1
Resveratrol X1
SeleniumX1
SilymarinX1
TaurineX1
Ursolic AcidX1
Vitamin EXX2
ZincXX2

Nrf2 Pathway

Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor that in humans is encoded by the NFE2L2 gene.  Nrf2 regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation.

Under normal or unstressed conditions, Nrf2 is kept in the cytoplasm by a cluster of proteins that degrade it quickly. Under oxidative stress, Nrf2 is not degraded, but instead travels to the nucleus where it binds to a DNA promoter and initiates transcription of antioxidative genes and their proteins.

Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the:  15

  • kidney
  • muscle
  • lung
  • heart
  • liver
  • brain

Nrf2 Activation

Nrf2 is latent within each cell in the body, unable to move or operate until it is released by an Nrf2 activator. Once released it migrates into the cell nucleus and bonds to the DNA at the location of the Antioxidant Response Element (ARE) or also called hARE (Human Antioxidant Response Element) which is the master regulator of the total antioxidant system that is available in all human cells.

Activation of Nrf2 can be triggered by high levels of ROS and when Nrf2 is activated it opens the door for the production of the enzymatic antioxidants.

Certain natural substances in foods are powerful activators of the Nrf2 pathway.  These dietary natural substances have been shown in vitro or cell culture to activate Nrf2 and directly increase activity of phase II enzymes. 

Some of these natural substances include:

  • epigallocatechin gallate (EGCG)  16
  • resveratrol  17
  • curcumin and its metabolite tetrahydrocurcumin  18
  • cinnamaldehyde  19
  • caffeic acid phenyethyl ester  20
  • alpha lipoic acid  21
  • alpha tocopherol  22
  • lycopene  23
  • apple polyphenols (chlorogenic acid and phloridzin)  24
  • gingko biloba  25
  • chalcone  26
  • capsaicin  27
  • hydroxytyrosol from olives  28
  • allyl sulfides from garlic  29
  • chlorophyllin  30
  • xanthohumols from hops  31

 


Informational References:

Bionov

SOD B® & Cell Aging Prevention (© Bionov)

Bionov SOD B® Leaflet (© Bionov)

Bionov SOD B Extramel® Leaflet (© Bionov)

Bionov SOD B PRIMO-ANTIOXIDANT® Leaflet (© Bionov)

Bionov SOD B Dimpless® Leaflet (© Bionov)

 


Resources:

SOD by Seeking Health

ReserveAge Nutrition, French Melon, SOD Complex

ResVitale – French Melon SOD Complex

 


    Print This Post Print This Post