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THE AMAZING HEALING POTENTIAL OF NATURAL NRF2 ACTIVATORS

Dr. Hank Liers, PhD natural nrf2 activators healing potential

When I first learned about Nrf2 activators in early 2012, I became quite enthusiastic about new knowledge that natural substances called polyphenolic compounds had the ability to activate this transcription factor. Once released in the cell Nrf2 can migrate to the nucleus and cause the body to endogenously produce high levels of key protective/antioxidant enzymes.

Also, I actively began the development of a product called Ultimate Protector that contains many concentrates and extracts from fruits, vegetables, and herbs. This product functions as 1) an excellent source of many Nrf2 activators, 2) a source of powerful antioxidants exhibiting an extremely high ORAC5.0 value per serving, and 3) a source of non-GMO Vitamin C.

More recently (July 2019) I have updated the product to Ultimate Protector+ that contains some exciting new ingredients that are now available on the market including SFB® (Standardized Fruit Blend) that contains among others mangosteen, goji berry, pomegranate, and apple extracts (click on the ingredient name to see detailed blog articles concerning these). In addition, I have added significant amounts of ingredients that are well known as potent Nrf2 activators and antioxidants including Green Tea extract and VinCare® whole grape extract.

 

Ultimate Protector+

New Ultimate Protector+

 

It is interesting to note that over 16 years ago I formulated a wonderful antioxidant formula called PRO-C™. PRO-C™ contains Buffered Vitamin C (in the form of powdered calcium, magnesium, and zinc ascorbates), high-potency Grape Extract (from grape pulp, skins, and seeds), Green Tea Extract, reduced Glutathione, N-Acetyl-L-Cysteine (NAC), R-Lipoic Acid, coenzyme forms of Vitamin B2 and Vitamin B6, and Selenium.

PRO-C™ has been one of the most effective products at supporting health I have ever formulated. Our current knowledge shows that PRO-C™ contains four effective Nrf2 activators, selenium needed for glutathione peroxidase functioning, Vitamin B2 and Vitamin B6 that support the effectiveness of glutathione, and antioxidants including Vitamin C and glutathione. I recently wrote a blog article titled PRO-C™ SUPER ANTIOXIDANT FORMULA that provides details concerning this formula.

My current personal list of supplements that I (and my wife) take every day includes both Ultimate Protector™ and PRO-C™. We feel gifted to have these products available to us!!

In this article, I will provide greater insight into the natural sources of Nrf2 activators and how they perform in the body.

SOME KEY ENZYMES MODULATED BY Nrf2 ACTIVATORS

Activation of Nrf2 results in the induction of many cytoprotective proteins. We have seen articles that claim over 200 different enzymes can be produced in the body by Nrf2 activators, but have also seen reference that over 4,000 enzymes may be produced!  Examples of some of the key enzymes are shown below:

  • NAD(P)H quinone oxidoreductase 1 – a prototypical Nrf2 target gene that catalyzes the reduction and detoxification of highly reactive quinones that can cause redox cycling and oxidative stress.
  • Superoxide dismutases (SOD) – enzymes that catalyze the dismutation of superoxide (O2) into oxygen and hydrogen peroxide. Thus, they are an important antioxidant defense in nearly all cells exposed to oxygen where superoxide is one of the main reactive oxygen species. SOD is known to provide powerful antinflammatory activity.
  • Glutamate-cysteine ligase which is the rate-limiting step in the synthesis of glutathione (GSH), a very powerful endogenous antioxidant. Glutamate-cysteine ligaseis a characteristic Nrf2 target gene, which establish Nrf2 as a regulator of glutathione, one of the most important antioxidants in the body.
  • Heme oxygenase-1 (HO-1) is an enzyme that catalyzes the breakdown of heme into the antioxidant biliverdin, the anti-inflammatory agent carbon monoxide, and iron. HO-1 is a Nrf2 target gene that has been shown to protect from a variety of pathologies, including sepsis, hypertension, atherosclerosis, acute lung injury, kidney injury, and pain.
  • The glutathione S-transferase (GST) family includes cytosolic, mitochondrial, and microsomal enzymes that catalyze the conjugation of GSH with endogenous and xenobiotic electrophiles. After detoxification by GSH conjugation catalyzed by GSTs, the body can eliminate potentially harmful and toxic compounds. GSTs are induced by Nrf2 activation and represent an important route of detoxification.
  • The UDP-glucuronosyltransferas (UGT) family catalyze the conjugation of a glucuronic acid moiety to a variety of endogenous and exogenous substances, making them more water soluble and readily excreted. Important substrates for glucuronidation include bilirubin, and acetaminophen. Nrf2 has been shown to induce UGT1A1 and UGT1A6.
  • Multidrug resistance-associated proteins  (Mrps) are important membrane transporters that efflux various compounds from various organs and into bile or plasma, with subsequent excretion in the feces or urine, respectively. Mrps have been shown to be upregulated by Nrf2 and alteration in their expression can dramatically alter the pharmacokinetics and toxicity of compounds.

NATURAL FOODS AND FOOD EXTRACTS PROMOTE THE EXPRESSION OF Nrf2

The March 2011 Epub Biochemical Basis for Functional Ingredient Design from Fruits reports: “Functional food ingredients (nutraceuticals) in fruits range from small molecular components, such as the secondary plant products, to macromolecular entities, e.g., pectin and cellulose, that provide several health benefits.  In fruits, the most visible functional ingredients are the color components anthocyanins and carotenoids.

“In addition, several other secondary plant products, including terpenes, show health beneficial activities.  A common feature of several functional ingredients is their antioxidant function. For example, reactive oxygen species (ROS) can be oxidized and stabilized by flavonoid components, and the flavonoid radical can undergo electron rearrangement stabilizing the flavonoid radical.  Compounds that possess an orthodihydroxy or quinone structure can interact with cellular proteins in the Keap1/Nrf2/ARE pathway to activate the transcription of antioxidant enzymes.

“Carotenoids and flavonoids can also exert their action by modulating the signal transduction and gene expression within the cell. Recent results suggest that these activities are primarily responsible for the health benefits associated with the consumption of fruits and vegetables.”

One of the interesting aspects of the extensive research that has been conducted is the fact that many of the polyphenols that have been shown to activate Nrf2 have been used in natural healing formulas for many years. For example, an article in a November 2010 production titled Nutraceutical antioxidants as novel neuroprotective agent expands on the classes of “antioxidant” compounds that are neuroprotective and operate either via direct antioxidant action or via the keap1-Nrf2 pathway:

“A variety of antioxidant compounds derived from natural products (nutraceuticals) have demonstrated neuroprotective activity in either in vitro or in vivo models of neuronal cell death or neurodegeneration, respectively. These natural antioxidants fall into several distinct groups based on their chemical structures: (1) flavonoid polyphenols like epigallocatechin 3-gallate (EGCG) from green tea and quercetin from apples; (2) non-flavonoid polyphenols such as curcumin from tumeric and resveratrol from grapes; (3) phenolic acids or phenolic diterpenes such as rosmarinic acid or carnosic acid, respectively, both from rosemary; and (4) organosulfur compounds including the isothiocyanate, L-sulforaphane, from broccoli and the thiosulfonate allicin, from garlic.

“All of these compounds are generally considered to be antioxidants.  They may be classified this way either because they directly scavenge free radicals or they indirectly increase endogenous cellular antioxidant defenses, for example, via activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) transcription factor pathway. Alternative mechanisms of action have also been suggested for the neuroprotective effects of these compounds such as modulation of signal transduction cascades or effects on gene expression. Here, we review the literature pertaining to these various classes of nutraceutical antioxidants and discuss their potential therapeutic value in neurodegenerative diseases.”

DIETARY FLAVONOIDS AS NRF2 ACTIVATORS

One of the ways dietary flavonoids work to confer their multiple health effects is via the keap1-Nrf2 pathway.  That is substances which are both themselves antioxidants and activators of the keap1-Nrf2 pathway produce significant results through keap1-Nrf2 and activating the body’s own antioxidant and defensive systems.

Flavonoids are a large family of polyphenolic compounds synthesized by plants. Many of the common dietary flavonoids are shown in Table 1 below along with their common food sources.

Table 1: Common Dietary Flavonoids

Flavonoid Subclass Dietary Flavonoids Some Common Food Sources
Anthocyanidins  Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin Red, blue, and purple berries; red and purple grapes; red wine
Flavonols  Monomers (Catechins) Catechin, Epicatechin, Epigallocatechin, Epicatechin gallate, Epigallocatecin gallate Dimers and Polymers: Theaflavins, Thearubigins, Proanthocyanidins Catechins: Teas (particularly green and white), chocolate, grapes, berries, apples Theaflavins, Thearubigins: Teas (particularly black and oolong) Proanthocyanidins: Chocolate, apples, berries, red grapes, red wine.
Flavanones Hesperetin, Naringenin, Eriodictyol Citrus fruits and juices, e.g., oranges, grapefruits, lemons.
Flavonols Quercetin, Kaempferol, Myricetin, Isorhamnetin Widely distributed: yellow onions, scallions, kale, broccoli, apples, berries, teas.
Flavones Apigenin, Luteolin Parsley, thyme, celery, hot peppers.
Isoflavones Daidzein, Genistein, Glycitein Soybeans, soy foods, legumes.

In addition to flavonoids many other plant based substances appear to produce health benefits through hormetic effects mediated by Nrf2.  The December 2011 publication Nutritional antioxidants and adaptive cell responses: an update reports: “Many plant antioxidants, intaken through the daily diet or plant-derived dietary supplements, have been shown able to prevent free radical-related diseases by counteracting cell oxidative stress. However, it is now considered that the in vivo beneficial effects of these phytochemicals are unlikely to be explained just by their antioxidant capability.

“Several plant antioxidants exhibit hormetic properties, by acting as ‘low-dose stressors’ that may prepare cells to resist more severe stress. In fact, low doses of these phytochemicals activate cell signaling pathways (being the most prominent examples the modulation of the Nrf2/Keap1 pathway, the NF-κB pathway and the Sirtuin-FOXO pathway) but high doses are cytotoxic.

“Herein we review the adaptive responses induced by the most known plant hormetic antioxidants, which are sulforaphane, resveratrol, curcumin, flavonoids, green tea catechins and diallylsulphides [in garlic], as well as the molecular mechanisms involved in such responses. Furthermore, this review outlines that the hormetic properties of these bioactive plant antioxidants might be successfully employed for realizing health-promoting dietary interventions especially in the field of neurodegenerative diseases and cancer.”

 

Ultimate Protector+

INTERESTING FACTS REGARDING NRF2 ACTIVATORS

1) An interesting fact is that Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain. 

2) Another important fact is that the well-known nutrition supplement lipoic acid is a potent activator of Nrf2 and thus increases Gluthatione levels, which may explain its protective effect against diabetic co-morbidities. Additionally, the nutritional supplements tocotrienols (active forms of Vitamin E) and N-Acetyl-L-Cysteine (NAC) are also effective Nrf2 activators!

3) We have observed that the natural plant substances with the highest ORAC5.0 values appear to be among the most effective Nrf2 activators. For example, see the table below. In particular, note that Curcumin (98%), Grape Seed Extract, Green Tea Extract, and Reservatrol which are commonly used for their excellent Nrf2 activator effects are the most powerful in-vitro antioxidants . Please note that Ultimate Protector is over 50% more powerful as an antioxidant than the best single plant ingredient.

TABLE 2: ORAC5.0™ COMPARATIVE RESULTS

Ingredient Peroxyl Radical Hydroxyl Radical Peroxy-nitrite Radical Super-
oxide Radical
Singlet O2 Radical Total ORAC5.0
Curcumin 98% 5,750 8,920 906 597 66,290 82,500
Bilberry 25% 7,000 25,000 1,000 16,000 5,000 54,000
Cocoa 10,000 28,000 1,000 11,000 2,000 52,000
Grape Seed Extract 17,000 47,000 1,000 25,000 4,000 94,000
Green Tea Extract 11,000 41,000 2,000 56,000 3,000 113,000
Coffee Berry Extract 5,000 29,000 1,000 1,000 2,000 38,000
Mangosteen 4,000 8,000 1,000 18,000 4,000 35,000
Pine Bark 7,000 23,000 1,000 17,000 2,000 50,000
Resveratrol 12,000 50,000 1,000 8,000 22,000 93,000
ULTIMATE PROTECTOR+ TBD TBD TBD TBD TBD TBD
Results are expressed in micro mole TE/g
4) Here is a list of the ingredients in ULTIMATE PROTECTOR+: USP-grade non-GMO Vitamin C, SFB® standardized fruit blend (~50% polyphenols, high-ORAC powder: 9,000 µmole TE/g) from Grape, Cranberry, Pomegranate, Blueberry, Apple, Mangosteen, Bilberry, Chokeberry, and Goji Berry), Curcumin (standardized extract with 95% curcuminoids), Trans-Resveratrol (98% from Giant Knotweed), Green Tea Extract (93% polyphenols, 50% EGCG), VinCare® Whole Grape Extract (>80% polyphenols, ORAC>19,000 µmole TE/g), Calcium Malate, Magnesium Malate, and Bioperine® (a patented black pepper extract that enhances absorption of all ingredients and is a known Nrf2 activator).

NEUROPROTECTION BY POLYPHENOL STIMULATION OF THE NRF2 / ARE PATHWAY 

Below are two abstracts that discuss how modulation of the Nrf2/ARE pathway by food polyphenols can provide neuroprotection through the activation of the heme-oxygenase enzyme.

Modulation of Nrf2/ARE pathway by food polyphenols: a nutritional neuroprotective strategy for cognitive and neurodegenerative disorders. (Oct. 2011)

ABSTRACT

In recent years, there has been a growing interest, supported by a large number of experimental and epidemiological studies, for the beneficial effects of some phenolic substances, contained in commonly used spices and herbs, in preventing various age-related pathologic conditions, ranging from cancer to neurodegenerative diseases. Although the exact mechanisms by which polyphenols promote these effects remain to be elucidated, several reports have shown their ability to stimulate a general xenobiotic response in the target cells, activating multiple defense genes.

Data from our and other laboratories have previously demonstrated that curcumin, the yellow pigment of curry, strongly induces heme-oxygenase-1 (HO-1) expression and activity in different brain cells via the activation of heterodimers of NF-E2-related factors 2 (Nrf2)/antioxidant responsive element (ARE) pathway. Many studies clearly demonstrate that activation of Nrf2 target genes, and particularly HO-1, in astrocytes and neurons is strongly protective against inflammation, oxidative damage, and cell death. In the central nervous system, the HO system has been reported to be very active, and its modulation seems to play a crucial role in the pathogenesis of neurodegenerative disorders.

Recent and unpublished data from our group revealed that low concentrations of epigallocatechin-3-gallate, the major green tea catechin, induces HO-1 by ARE/Nrf2 pathway in hippocampal neurons, and by this induction, it is able to protect neurons against different models of oxidative damages. Furthermore, we have demonstrated that other phenolics, such as caffeic acid phenethyl ester and ethyl ferulate, are also able to protect neurons via HO-1 induction. These studies identify a novel class of compounds that could be used for therapeutic purposes as preventive agents against cognitive decline.

The major green tea polyphenol, (-)-epigallocatechin-3-gallate, induces heme oxygenase in rat neurons and acts as an effective neuroprotective agent against oxidative stress. (Aug. 2009)

ABSTRACT

Oxidative stress induced by hyperglycemia is a key factor in the pathogenesis of diabetic complications, such as neuropathy. Recently, green tea catechins have received much attention, as they can facilitate a number of antioxidative mechanisms and improve glycemic control. The aim of this study was to investigate the cytoprotective effects of (-)-epigallocatechin-3-gallate (EGCG) against oxidative stress damage in a cell line of rat neurons. The role of heme oxygenase 1 (HO-1) induction by EGCG and the transcriptional mechanisms involved were also evaluated.

Immortalized rat neurons (H 19-7) were exposed to various concentrations of EGCG (10-200 microM). After treatments (6 or 24 hours), cells were harvested for the determination of heme oxygenase activity, mRNA levels, and protein expression. Nuclear levels of Nrf2, a transcriptional factor involved in HO-1 activation, were also measured. Neurons were pretreated for 12 hours with EGCG 50 microM or EGCG 50 microM + zinc protoporphyrin IX 10 microM and then exposed for 2 hours to 50 mmicro/mL glucose-oxidase before cell viability was determined.

In cultured neurons, elevated expression of HO-1 mRNA and protein were detected after 6 hours of incubation with 25-100 microM EGCG, and its induction relates with the activation of Nrf2. Interestingly, pre-incubation (12 hours) with EGCG 50 microM resulted in an enhanced cellular resistance to glucose oxidase-mediated oxidative damage; this cytoprotective effect was considerably attenuated by zinc protoporphyrin IX, an inhibitor of heme oxygenase activity.

In this study, we demonstrated that EGCG, the major green tea catechin, induced HO-1 expression in cultured neurons, possibly by activation of the transcription factor Nrf2, and by this mechanism was able to protect against oxidative stress-induced cell death.

 

The following review article abstract shows how natural products containing Nrf2 activator/antioxidant ingredients might be used to support health and anti-aging.

Nrf2/ARE Signaling Pathway: Key Mediator in Oxidative Stress and Potential Therapeutic Target in ALS (July 2012)

REVIEW ARTICLE

Abstract: Nrf2 (nuclear erythroid 2-related factor 2) is a basic region leucine-zipper transcription factor which binds to the antioxidant response element (ARE) and thereby regulates the expression of a large battery of genes involved in the cellular antioxidant and anti-inflammatory defence as well as mitochondrial protection. As oxidative stress, inflammation and mitochondrial dysfunctions have been identified as important pathomechanisms in amyotrophic lateral sclerosis (ALS), this signaling cascade has gained interest both with respect to ALS pathogenesis and therapy. Nrf2 and Keap1 expressions are reduced in motor neurons in postmortem ALS tissue.

Nrf2-activating compounds have shown therapeutic efficacy in the ALS mouse model and other neurodegenerative disease models. Alterations in Nrf2 and Keap1 expression and dysregulation of the Nrf2/ARE signalling program could contribute to the chronic motor neuron degeneration in ALS and other neurodegenerative diseases. Therefore, Nrf2 emerges as a key neuroprotective molecule in neurodegenerative diseases.

Our recent studies strongly support that the Nrf2/ARE signalling pathway is an important mediator of neuroprotection and therefore represents a promising target for development of novel therapies against ALS, Parkinson’s disease (PD), Huntington’s disease (HD), and Alzheimer’s disease (AD). Simultaneous blockage of disease-specific broad toxic signaling cascades in motor neurons and glia may ultimately lead to more efficient neuroprotection in ALS. Stimulation of defense mechanisms that modulate neuroprotective genes which affect both neuronal and glial functions is a novel therapeutic approach and holds great promise. A key molecule to affect a variety of defense mechanisms is the transcription factor Nrf2 which activates the Nrf2/ARE signaling program. Nrf2 acts as master regulator of the cellular antioxidant response by stimulation of over 250 phase II genes that should be referred to as “prolife genes” since they save cells from death.

Nrf2 activation can at once regulate the expression of multiple cytoprotective enzymes that are capable of simultaneous inhibition of major pathogenic pathways described in ALS such as oxidative stress, neuroinflammation, and mitochondrial dysfunction. Decreased Nrf2 expression was found in motor neurons in ALS postmortem brain and spinal cord. We have established the proof-of-concept that the Nrf2/ARE program is a viable target with excellent therapeutic potential for ALS. While there are still multiple gaps of knowledge on the path from Nrf2 dissociation to nuclear localization and its action as transcription factor, activation of the Nrf2 signaling cascade represents a novel and unique attempt to find a cure for ALS and other neurodegenerative diseases by fortifying the intrinsic defense mechanisms of neurons.

CONCLUSION

In this article I have shown how foods such as fruits, vegetables, herbs, and their extracts can stimulate extremely powerful protective enzymes in the body that work to keep us healthy. I strongly suggest that our readers eat an organic diet that emphasizes these foods and highly recommend the use of nutritional supplements such as Ultimate Protector+ and PRO-C™ that can further support the activation of the Nrf2 pathways in the body!

SOURCES

BLOG ARTICLES

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PREVENTING FREE RADICAL DAMAGE WITH ULTIMATE PROTECTOR+

Back in 2012, I learned about Nrf2 activators and was excited about pursuing the development of a supplement that would incorporate the new knowledge we were learning into a effective product for preventing free radical damage. At that time, I published two articles: New Directions for Preventing Free Fadical Damage and Natural Phytochemical Nrf2 Activators for Chemoprevention. I started working on a new Nrf2-activator formula I called Ultimate Protector that incorporated many of the ideas contained in these articles. The product was introduced November 2012.

More recently, in early 2019, I decided to upgrade the product using new information and ingredients. The upgraded product is called Ultimate Protector+. In this article, I provide new details of our design logic and product ingredients. I expect the new formula to be released in July 2019.

Ultimate Protector+

Ultimate Protector+ is new and improved!

PREVENTING FREE RADICAL DAMAGE WITH ULTIMATE PROTECTOR+

Ultimate Protector+™ is a unique cell protection formula that simultaneously meets the needs for high levels of non-GMO Vitamin C, full spectrum antioxidants (high ORAC values), and protective enzyme activators (Nrf2 activators) in a single product. This potent combination of characteristics distinguishes the formula because no other single product available today offers such complete protection. This is the single best formula for preventing free radical damage that is available.

Ultimate Protector+™ provides extremely high levels of natural antioxidants, including high levels of ingredients such as polyphenols, flavonoids, anthocyanidins, oligomeric proanthocyanidins, catechins, curcuminoids, pterostilbene, resveratrol, chlorogenic acid, punicalagins, zeaxanthin and other carotenoids that act powerfully as antioxidants. These antioxidants come from more than 12 plant-based ingredients with demonstrated free-radical quenching capacity. These “exogenous” food-based antioxidants (supplied from outside the body) provide you with immense oxidative defenses that can be used to defend against free-radical assault.

Ultimate Protector+™ contains USP-grade non-GMO Vitamin C , SFB® standardized fruit blend (~50% polyphenols, high-ORAC powder: 9,000 µmole TE/g) from Grape, Cranberry, Pomegranate, Blueberry, Apple, Mangosteen, Bilberry, Chokeberry, and Goji Berry), Curcumin (standardized extract with 95% curcuminoids), Trans-Resveratrol (98% from Giant Knotweed), Green Tea Extract (90% polyphenols, 50% EGCG), VinCare® Whole Grape Extract (>80% polyphenols, ORAC>19,000 µmole TE/g), Calcium Malate, Magnesium Malate, and Bioperine® (a patented black pepper extract that enhances absorption of all ingredients and is a known Nrf2 activator).

Ultimate Protector+™ is contained in a capsule suitable for vegetarians (i.e., a veggie cap) and contains no magnesium stearate.

NUTRITIONAL CONSIDERATIONS AND APPLICATIONS

Ultimate Protector+™ satisfies three distinct needs:

1) The need for a non-GMO Vitamin C product. That is, a Vitamin C formula that avoids protein from genetically modified sources such as corn, potatoes, or beets.

2) The need for a single, powerful antioxidant formula for preventing free radical damage. That is, a single, easy-to-take antioxidant formula offering a broad range of extremely high-ORAC plant source antioxidants. These antioxidants should protect against the full range of free radicals found in the human body including: superoxide anion (O2·-), peroxyl radicals (ROO·), hydroxyl radicals (HO·), singlet oxygen (1O2), and peroxynitrite (ONOO-).

3) The need for a supplement providing a full spectrum of Nrf2 activators. That is, a supplement providing a wide range of natural Nrf2 transcription factor activators that allow the body to make its own antioxidant enzymes (e.g., superoxide dismutase (SOD), catalase, hemeoxygenase, and glutathione peroxidase). Scientific research has shown that these are found naturally in many fruits, vegetable, and herbs. These ingredients provide a wide range of Nrf2 activators that result in significantly high levels of the endogenously produced antioxidant enzymes.

The ways Ultimate Protector+™ satisfies these three needs are discussed below:

1) NON-GMO VITAMIN C / ASCORBIC ACID

High-quality, USP grade Vitamin C has been obtained historically from corn, potatoes, and/or beets. Unfortunately, many of these sources have to a large extent gone to genetically modified (GMO) variants. However, with highly refined production methods and the use of PCR testing, we have been able to obtain final products that are free from GMOs.

In nature, Vitamin C is found generally in plant sources containing polyphenols. Vitamin C and polyphenols work together to provide a high level of antioxidant protection and they support the function of each other in the process. For example, Vitamin C is needed by the body to produce collagen and certain polyphenols (especially oligomeric proanthocyanidins) (OPCs) crosslink the collagen and make it stronger.

2) EXTREMELY HIGH ORAC SOURCES

Free radicals are reactive species that can have adverse effects on normal physiological functions. Studies associate the five major types of free radicals (i.e., hydroxyl, peroxyl, peroxynitrite, singlet oxygen, and superoxide anion) with health conditions such as cardiovascular disease, hypertension, breakdown of vital proteins, chronic inflammation, Alzheimer’s disease, and certain cancers. Avoiding free radical damage is the goal.

Antioxidants function as a vital line of defense against free radicals by blocking their attack on DNA, vital proteins, lipids, and amino acids. Until now, efforts to identify the effect of antioxidants on all five types of free radicals were constrained by limited testing procedures. However, new technological developments have resulted in a comprehensive testing method called the Total ORAC5.0™ assay. Because of the development of the Total ORAC5.0™ test, it is now possible to target and measure the effects of antioxidants on the five major types of free radicals found in the body.

We are currently in the process of testing Ultimate Protector+™ using this new ORAC5.0™ assay. We are confident that our formula offers protection against these five major types of free-radicals because we combine a wide range of extremely high-ORAC fruit, vegetable, and herbal blends. As soon as the results are available (in July 2019), we will update this article with the findings.

3) NRF2 TRANSCRIPTION FACTOR ACTIVATORS

In order to survive under a variety of environmental or intracellular stresses, our cells have developed highly efficient protective mechanisms to protect themselves from oxidative or electrophilic challenges. Proteins that comprise phase II detoxification and antioxidant enzymes provide an enzymatic line of defense against reactive oxygen species (ROS). These enzymes include superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione S-transferase (GST), and glutamate cysteine ligase.

Induction of phase II and antioxidant enzymes are regulated at the DNA/gene level by an antioxidant responsive element (ARE). ARE-mediated gene expression plays a central role in the cellular defense against cellular oxidative damage. Experimental evidence supports the view that induction of ARE-mediated cytoprotective enzymes is a critical and sufficient mechanism to enable protection against disease provoked by environmental and endogenous insults.

One of the key ARE-binding transcription factors is Nrf2. Induction of cytoprotective enzymes in response to ROS, electrophiles, and phytochemicals is a cellular event that is highly dependent on Nrf2 protein. By activating Nrf2 signaling, phytochemicals can increase cellular detoxification and antioxidant enzymes, thereby enhancing removal of ROS and toxic chemicals and preventing disease. Numerous research studies carried out over the last 15 years have demonstrated the effectiveness of a very wide range of Nrf2 activators extracted from fruits, vegetables, and herbs.

For example, a study with sulforaphane (an isothiocyanate present abundantly in cruciferous vegetables) shows that oral administration of this phytochemical can effectively block benzo[a]pyrene-induced forestomach tumors in mice. This protective effect was abrogated in mice that could not produce Nrf2. This supports the critical role of phase II detoxification and antioxidant enzymes in the prevention of carcinogenesis by chemopreventive agents.

Nrf2 is normally bound in the cytoplasm of cells to a protein called KEAP1. However, when an appropriate phytochemical agent attaches to a kinase receptor on the cell wall a phosphate group is released that causes the Nrf2 to be released. Also, there are other mechanisms that allow Nrf2 to be released from KEAP1. The released Nrf2 then migrates into the cell nucleus and causes an antioxidant enzyme (e.g., superoxide dismutase (SOD)) to be fabricated and released. This endogenously produced enzyme then can protect against ROS, electrophiles, and other toxic agents.

In practical experience, it has been found that a combination of multiple polyphenols works significantly better than single ingredients. In fact, in one experiment it was found that a combination of five ingredients all known to be Nrf2 activators was 18 times more effective than any single ingredient. Furthermore, it was found that this combination of five ingredients was able to increase levels of SOD by 30% and catalase by 56% after 120 days of taking the combination.

In view of the considerations above, we include a wide range of Nrf2 activators in Ultimate Protector+™. These include a large variety of freeze-dried and concentrated fruits, vegetables, and herbs. These include Grape, Cranberry, Pomegranate, Blueberry, Apple, Mangosteen, Bilberry, Chokeberry, Goji Berry), Curcumin (standardized extract with 95% curcuminoids), Trans-Resveratrol (98% from Giant Knotweed), Green Tea Extract (93% polyphenols, 50% EGCG), VinCare® Whole Grape Extract (>80% polyphenols, ORAC>19,000 µmole TE/g)

Ultimate Protector+™ includes the following phytonutrients in its array of freeze-dried and concentrated fruits, vegetables, and herbs: polyphenols, flavonoids, anthocyanins, catechins, proanthocyanins, ellagic acid, xanthines, chlorogenic acid, pterostilbenes, resveratrol, phloridzin, quercetin, zeaxanthin, carotinoids, polysaccharides, quinic acid, and more.

The phytochemical ingredients in Ultimate Protector+™ are discussed below:

1. SFB® – (Standardized Fruit Blend)

SFB® is a nutritious, non-GMO blend that provides a broad spectrum of polyphenols, anthocyanins, and other antioxidants derived from water and/or ethanol extracts of grape (Vitis vinifera), cranberry (Vaccinium macrocarpon), pomegranate (Punica granatum) with >75% polyphenols, blueberry (Vaccinium uliginosum), apple (Malus pumilla Mill), mangosteen (Garcinia mangostana), bilberry (Vaccinium myrtillis), chokeberry (Aronia arbutifolia), and goji berry (Lycium barbarum). This powder has an ORAC value in excess of 9,000 µmole TE/g and contains 50% polyphenols.

Polyphenols and anthocyanins are not all created equal. Every fruit, vegetable and herb provides its own set of unique polyphenols and anthocyanins that reside in the body for different lengths of time and in different locations, providing a range of benefits. SFB® has been designed to provide a wide range of plant polyphenols, flavonoids, anthocyanins, catechins, OPCs, zeaxanthin and other carotinoids, etc. Published research associates these plant ingredients with healthy aging, inflammation management, improved blood sugar metabolism, and cardiovascular disease management.

SFB® provides the following benefits: Superior source of natural antioxidants and Nrf2 activators, helps ameliorate the effects of premature aging, promotes cardiovascular health, promotes healthy brain function and mental acuity, promotes healthy vision, promotes healthy blood sugar levels, and is an excellent source of flavonoids and organic acids.

I have prepared detailed blog articles for the ingredients in SFB®. Below some of these are summarized and links to the articles are provided.

a) Cranberry Extract

Ultimate Protector+ Includes Cranberry

Ultimate Protector+ Includes Cranberry Extract

Cranberry extract is an especially good source of antioxidant polyphenols. In animal studies, the polyphenols in cranberries have been found to decrease levels of total cholesterol and so-called “bad” cholesterol. Cranberries may also inhibit the growth of tumors in human breast tissue and lower the risk of both stomach ulcers and gum disease.

Here is a list of the antioxidant and anti-inflammatory phytonutrients in found in cranberry extract.

Type of Phytonutrient Specific Molecules
Phenolic Acids hydroxybenzoic acids including vanillic acids;
—Phenolic Acids (cont.) hydroxycinnamic acids inculding caffeic,
—Phenolic Acids (cont.) coumaric, cinnamic, and ferulic acid
Proanthocyanidins epicatechin oligomers
Anthocyanins cyanidins, malvidins, and peonidins
Flavonoids quercetin, myricetin, kaempferol
Triterpenoids ursolic acid

OTHER CRANBERRY INFORMATION

    • Cranberries hold significantly high amounts of phenolic flavonoid phytochemicals called oligomeric proanthocyanidins (OPC’s). Scientific studies have shown that consumption of the berries have potential health benefits regarding cancer, aging and neurological diseases, inflammation, diabetes, and bacterial infections.
    • Antioxidant compounds in cranberry extract including OPC’s, anthocyanidin flavonoids, cyanidin, peonidin and quercetin may support cardiovascular health by counteracting against cholesterol plaque formation in the heart and blood vessels. Further, these compounds help the human body lower LDL cholesterol levels and increase HDL-good cholesterol levels in the blood.
    • Scientific studies show that cranberry juice consumption offers protection against gram-negative bacterial infections such as E.coli in the urinary system by inhibiting bacterial-attachment to the bladder and urethra.
    • It is known that cranberries turns urine acidic. This, together with the inhibition of bacterial adhesion helps prevent the formation of alkaline (calcium ammonium phosphate) stones in the urinary tract by working against proteus bacterial-infections.
    • In addition, the berries prevent plaque formation on the tooth enamel by interfering with the ability of the gram-negative bacterium, Streptococcus mutans, to stick to the surface. In this way cranberries helps prevent the development of cavities.
    • The berries are also good source of many vitamins like vitamin C, vitamin A, ß-carotene, lutein, zea-xanthin, and folate and minerals like potassium, and manganese.
  • Oxygen Radical Absorbance Capacity (ORAC) demonstrates cranberry at an ORAC score of 9584 µmol TE units per 100 g, one of the highest in the category of edible berries.

b) Pomegranate Extract

Ultimate Protector+ Includes Pomegranate

Ultimate Protector+ Includes Pomegranate

For thousands of years, the pomegranate has been extensively used as a source of food and medicine. Full of antioxidants, vitamin C and potassium, pomegranate has been used to control body weight, reduce cholesterol, fight against cell damage, and inhibit viral infections. Pomegranate extracts have anti-bacterial effects.

Pomegranates are rich in ellagic acid, gallic acid, lignans, polyphenols and other bioactive compounds, and have been shown to lower blood pressure and enhance vascular function. Furthermore, it can offset some of the negative effects of medications and chemicals. These compounds occur naturally in its peel, seeds, leaf and juice. The seeds are high in p-coumaric acid, plant sterols, tannins and fatty acids. In addition to their antihypertensive effects, they may help reduce blood sugar levels.

Pomegranate fruit is a rounded berry with a thick reddish skin covering approximately 200–1400 white to deep red or purple seeds. Pomegranate seeds are edible and hold strong antioxidant and anti-inflammatory properties due to their high content of hydrolysable tannins and anthocyanins. As compared to the antioxidant activity of vitamin E, β-carotene, and ascorbic acid, the pomegranate antioxidants appear unique due to combinations of a wide array of polyphenols, having a broader range of action against several types of free radicals. As compared to the recognized antioxidants in red wine and green tea, anthocyanins from pomegranate fruit possess significantly higher antioxidant activity.

Pomegranate has been used in various medicinal systems of medicine for the treatment and therapy of a multitude of diseases and ailments. In the ancient Indian medicinal system, i.e., in Ayurvedic medicine, the pomegranate was considered to be a whole pharmacy unto itself. It was recommended to be used as an antiparasitic agent and to treat diarrhea and ulcers. The medicinal properties of pomegranate have sparked significant interest in today’s scientific community as evidenced by the scientific research relating to health benefits of pomegranate that have been published in last few decades.

Studies have shown that pomegranate and its constituents can efficiently affect multiple signaling pathways involved in inflammation, cellular transformation, hyperproliferation, angiogenesis, initiation of tumorigenesis, and eventually suppressing the final steps of tumorigenesis and metastasis. The pomegranate constituents are shown to modulate transcription factors, pro-apoptotic proteins, anti-apoptotic proteins, cell cycle regulator molecules, protein kinases, cell adhesion molecules, pro-inflammatory mediators, and growth factors.

c) Chokeberry (Aronia)

Ultimate Protector+ Includes Chokeberry

Ultimate Protector+ Includes Chokeberry

HEALTH BENEFITS OF CHOKEBERRY (ARONIA)

Aronia melanocarpa (black chokeberry) has attracted scientific interest due to its deep purple, almost black pigmentation that arises from dense contents of polyphenols, especially anthocyanins. Total polyphenol content is 1752 mg per 100 g in fresh berries, anthocyanin content is 1480 mg per 100 g, and proanthocyanidin concentration is 664 mg per 100 g. These values are among the highest measured in plants to date.

The plant produces these pigments mainly in the leaves and skin of the berries to protect the pulp and seeds from constant exposure to ultraviolet radiation and production of free radicals. By absorbing UV rays in the blue-purple spectrum, leaf and skin pigments filter intense sunlight, serve antioxidant functions and thereby have a role assuring regeneration of the species.

Analysis of polyphenols in chokeberries has identified the following individual chemicals (among hundreds known to exist in the plant kingdom): cyanidin-3-galactoside, cyanidin-3-arabinoside, quercetin-3-glycoside, epicatechin, caffeic acid, delphinidin, petunidin, pelargonidin, peonidin, and malvidin.All these except caffeic acid are members of the flavonoid category of phenolics.

In a standard measurement of antioxidant strength, the oxygen radical absorbance capacity or ORAC, demonstrates aronia to have one of the highest values yet recorded for a fruit — 16,062 micro moles of Trolox Eq. per 100 g. The components contributing to this high measurement were both anthocyanins and proanthocyanidins, with the proanthocyanidin level “among the highest in foods”, which may explain their potent astringent taste.

d) Goji Berry

Ultimate Protector+ Includes Goji Berry

Ultimate Protector+ Includes Goji Berry

Goji Berries contain abundant polysaccharides (LBPs, comprising 5%–8% of the dried fruits), scopoletin (6-methoxy-7-hydroxycoumarin, also named chrysatropic acid, ecopoletin, gelseminic acid, and scopoletol), the glucosylated precursor, and stable vitamin C analog 2-O-β-D-glucopyranosyl-L-ascorbic acid, carotenoids (zeaxanthin and β-carotene), betaine, cerebroside, β-sitosterol, flavonoids, amino acids, minerals, and vitamins (in particular, riboflavin, thiamin, and ascorbic acid).

The predominant carotenoid is zeaxanthin, which exists mainly as dipalmitate (also called physalien or physalin). The content of vitamin C (up to 42 mg/100 g) in goji berry (also known as wolfberry) is comparable to that of fresh lemon fruits. As to the seeds, they contain zeaxanthin (83%), β-cryptoxanthin (7%), β-carotene (0.9%), and mutatoxanthin (1.4%), as well as some minor carotenoids.

In fact, increasing lines of experimental studies have revealed that L. barbarum berries have a wide array of pharmacological activities, which is thought to be mainly due to its high LBPs content. Water-soluble LBPs are obtained using an extraction process that removes the lipid soluble components such as zeaxanthin and other carotenoids with alcohol. LBPs are estimated to comprise 5%–8% of LBFs and have a molecular weight ranging from 24 kDa to 241 kDa. LBPs consist of a complex mixture of highly branched and only partly characterized polysaccharides and proteoglycans.

The glycosidic part accounts, in most cases, for about 90%–95% of the mass and consists of arabinose, glucose, galactose, mannose, rhamnose, xylose, and galacturonic acid. LBPs are considered the most important functional constituents in LBFs. Different fractions of LBPs have different activities and the galacturonic acid content is an imperative factor for activities of LBP. The bioactivities of polysaccharides are often in reverse proportion with their molecular weights. Increasing lines of evidence from both preclinical and clinical studies support the medicinal, therapeutic, and health-promoting effects of LBPs.

e) Mangosteen

Ultimate Protector+ Includes Mangosteen

Ultimate Protector+ Includes Mangosteen

The Mangosteen extract in Ultimate Protector+ has been extracted with non-GMO food grade ethanol and distilled water. Testing has indicated the product contains over 10% polyphenols.

Mangosteen extract in obtained from the skin and whole fruit for which numerous biological activities have been reported including: antimutagenic, antibacterial, hypocholesterolemic, antioxidant, and protective against tumorigenesis.

Mangosteen contains nutrients with antioxidant capacity, such as vitamin C and folate. Plus, it provides xanthones — a unique type of plant compound known to have strong antioxidant properties. In several test-tube and animal studies, the antioxidant activity of xanthones has resulted in anti-inflammatory, anticancer, anti-aging, heart protective, and antidiabetic effects.

Additionally, some research suggests that certain plant compounds in mangosteen may have antibacterial properties — which could benefit your immune health by combating potentially harmful bacteria. In a 30-day study in 59 people, those taking a mangosteen-containing supplement experienced reduced markers of inflammation and significantly greater increases in healthy immune cell numbers compared to those taking a placebo.

f) Apple Extract

Ultimate Protector+ Includes Apple

Apples contain a large concentration of flavonoids, as well as a variety of other phytochemicals, and the concentration of these phytochemicals may depend on many factors, such as cultivar of the apple, harvest and storage of the apples, and processing of the apples. The concentration of phytochemicals also varies greatly between the apple peels and the apple flesh.

Some of the most well studied antioxidant compounds in apples include quercetin-3-galactoside, quercetin-3-glucoside, quercetin-3-rhamnoside, catechin, epicatechin, procyanidin, cyanidin-3-galactoside, coumaric acid, chlorogenic acid, gallic acid, and phloridzin. Recently researchers have examined the average concentrations of the major phenolic compounds in six cultivars of apples. They found that the average phenolic concentrations among the six cultivars were: quercetin glycosides, 13.2 mg/100 g fruit; vitamin C, 12.8 mg/100 g fruit; procyanidin B, 9.35 mg/100 g fruit; chlorogenic acid, 9.02 mg/100 g fruit; epicatechin, 8.65 mg/100 g fruit; and phloretin glycosides, 5.59 mg/100 g fruit.

The compounds most commonly found in apple peels consist of the procyanidins, catechin, epicatechin, chlorogenic acid, phloridzin, and the quercetin conjugates. In the apple flesh, there is some catechin, procyanidin, epicatechin, and phloridzin, but these compounds are found in much lower concentrations than in the peels. Quercetin conjugates are found exclusively in the peel of the apples. Chlorogenic acid tends to be higher in the flesh than in the peel.

Because the apple peels contain more antioxidant compounds, especially quercetin, apple peels may have higher antioxidant activity and higher bioactivity than the apple flesh. Research showed that apples without the peels had less antioxidant activity than apples with the peels. Apples with the peels were also better able to inhibit cancer cell proliferation when compared to apples without the peels. More recent work has shown that apple peels contain anywhere from two to six times (depending on the variety) more phenolic compounds than in the flesh, and two to three times more flavonoids in the peels when compared to the flesh. The antioxidant activity of these peels was also much greater, ranging from two to six times greater in the peels when compared to the flesh, depending on the variety of the apple. This work is supported a study which found that rats consuming apple peels showed greater inhibition of lipid peroxidation and greater plasma antioxidant capacity when compared to rats fed apple flesh.

Many of these phytochemicals from apples have been widely studied, and many potential health benefits have been attributed to these specific phytochemicals. The procyanidins, epicatechin and catechin, have strong antioxidant activity and have been found to inhibit low density lipoprotein (LDL) oxidation in vitro. In mice, catechin inhibits intestinal tumor formation and delays tumors onset. One study found that chlorogenic acid has very high alkyl peroxyl radical (ROO•) scavenging activity. Compared to about 18 other antioxidant compounds (including quercetin, gallic acid, α-tocopherol), chlorogenic was second only to rutin. Since ROO• may enhance tumor promotion and carcinogenesis, chlorogenic acid may add to the protective effect of apples against cancer. Chlorogenic acid has been found to inhibit 8-dehydroxy-deoxyguanosine formation in cellular DNA in a rat model following treatment with 4-nitroquinoline-1-oxide.

Quercetin is also a strong antioxidant, and is thought to have potential protective effects against both cancer and heart disease. Briefly, quercetin has been found to down regulate expression of mutant p53 in breast cancer cells, arrest human leukemic T-cells in G1, inhibit tyrosine kinase, and inhibit heat shock proteins. Quercetin has protected Caco-2 cells from lipid peroxidation induced by hydrogen peroxide and Fe2+. In mice liver treated with ethanol, quercetin decreased lipid oxidation and increased glutathione, protecting the liver from oxidative damage. Recently, it has been found that high doses of quercetin inhibit cell proliferation in colon carcinoma cell lines and in mammary adenocarcinoma cell lines, but at low doses quercetin increased cell proliferation (20% in colon cancer cells and 100% in breast cancer cells). However, low doses of quercetin (10 uM) inhibited cell proliferation in Mol-4 Human Leukemia cells and also induced apoptosis. Quercetin inhibited intestinal tumor growth in mice, but not in rats. Low levels of quercetin inhibited platelet aggregation, calcium mobilization, and tyrosine protein phosphorylation in platelets. Modulation of platelet activity may help prevent cardiovascular disease.

g) Blueberry and Bilberry Extract

wild bilberry and wild blueberry
Wild bilberry and wild blueberry provide Nrf2 activators.

The key compounds in bilberry fruit are called anthocyanins and anthocyanosides. These compounds help build strong blood vessels and improve circulation to all areas of the body. They also prevent blood platelets from clumping together (helping to reduce the risk of blood clots), and they have antioxidant properties (preventing or reducing damage to cells from free radicals). Anthocyanins boost the production of rhodopsin, a pigment that improves night vision and helps the eye adapt to light changes.

Bilberry fruit is also rich in tannins, a substance that acts as an astringent. The tannins have anti-inflammatory properties and may help control diarrhea.

Bilberries have been shown to have the highest Oxygen Radical Absorbance Capacity (ORAC) rating of more than 20 fresh fruits and berries. The antioxidant properties of bilberries were shown to be even stronger than those of cranberries, raspberries, strawberries, plums, or cultivated blueberries.

The antioxidant powers and health benefits of bilberries and blueberries can be attributed to a number of remarkable compounds contained in them, including the following:

  • Anthocyanins
    • malvidins
    • delphinidins
    • pelargonidins
    • cyanidins
    • peonidins
  • Hydroxycinnamic acids
    • caffeic acids
    • ferulic acids
    • coumaric acids
  • Hydroxybenzoic acids
    • gallic acids
    • procatchuic acids
  • Flavonols
    • kaempferol
    • quercetin
    • myricetin
  • Other phenol-related phytonutrients
    • pterostilbene
    • resveratrol
  • Other nutrients
    • lutein
    • zeaxanthin
    • Vitamin K
    • Vitamin C
    • manganese

2) Curcumin

Ultimate Protector+ Includes Curcumin

Ultimate Protector+ Includes Curcumin

We have included Curcumin (95% curcuminoids in ULTIMATE PROTECTOR™. This ingredient contains three main chemical compounds – Curcumin, Demethoxycurcumin and Bisdemethoxycurcumin – collectively known as Curcuminoids and all derived from Turmeric. Curcumin has been shown to be one of the most potent Nrf2 transcription factor activators. Studies have reported that curcumin and turmeric protect the liver against several toxicants both in vitro and in vivo. A number of reports showed the curative action of turmeric and curcuminoids. Curcumin is a potent scavenger of free radicals such as superoxide anion radicals, hydroxyl radicals, and nitrogen dioxide radicals. It exerts powerful antioxidant and anti-inflammatory properties.


3) Trans-Resveratrol (98% from Polygonum cuspidatum – giant knotweed)

giant knotweed resveratrol

Knotweed (Polygonum cuspidatum) is a major source for resveratrol.

Trans-resveratrol provides antioxidant protection, boosts cellular energy, and balances the immune system. It has been proven in studies to activate the SIRT1 longevity gene and enhance cellular productivity. Several research studies have shown that trans-resveratrol activates Nrf2 transcription factor, significantly modulates biomarkers of bone metabolism, inhibits pro-inflammatory enzymes such as COX-1 and COX-2, and exhibits cardioprotective effects, neuroprotective properties, and caloric restrictive behavior. Trans-resveratrol has shown the ability to increase the number of mitochondria thereby increasing total daily energy. Studies have shown that trans-resveratrol promotes an increase in mitochondrial function. Increased mitochondrial function translates into an increase in energy availability, improved aerobic capacity, and enhanced sensorimotor function. Trans-resveratrol has an ORAC value of 31,000 µmole TE/g.


4) Green Tea Extract

Ultimate Protector+ Includes Green Tea Extract

Ultimate Protector+ Includes Green Tea Extract

Green Tea Extract contains highly bioavailable bioflavonoid complexes that in research studies have been shown to have powerful antioxidant capability. Green tea extract is obtained from the unfermented leaves of Camellia sinensis for which numerous biological activities have been reported including: cell protective, antimicrobial, and antioxidant. The green tea extract in Ultimate Protector is extracted is extracted by non-GMO ethanol and distilled water and contains ~ 90% polyphenols and 50% epigallocatechingallate (EGCG).

Epigallocatechin gallate (EGCG) is the most abundant catechin compound in green tea. It is well established that EGCG is a potent antioxidant and anti-inflammatory agent. Epidemiological studies show that consumption of 100 or more mg of EGCG per day is beneficial, as it is the most potent Nrf2 activator among all green tea catechins. EGCG exhibits robust diffusion through bodily tissues, including the endothelium of the blood brain barrier.

EGCG has the capacity to activate Nrf2/ARE and induce Heme oxygenase-1 (HO-1) expression. Several studies have shown that EGCG can also interact with kinases, causing the disassociation of Nrf2/Keap1 complex.

Protective effects of EGCG have been reported against ischemia/reperfusion injury. Administration of EGCG showed improved neurologic scores, reduced infarct volume, and ameliorated neuronal apoptosis due to increased GSH biosynthesis (via Nrf2 activation) and decreased ROS content. By inducing the expression of Nrf2 and HO-1, EGCG increases important endogenous antioxidants in microglial cells.

5) VinCare® whole grape extract (seed, pulp, and skin)

Ultimate Protector+ Includes Whole Grape Extract

Ultimate Protector+ Includes Whole Grape Extract

Whole Grape Extract contains highly bioavailable bioflavonoid complexes that in research studies have been shown to have powerful antioxidant capability. The Oligomeric Proanthocyanidins (OPCs) in grape extract are able to strengthen collagen fibers in aging or damaged connective tissue and can act as a preventative against connective tissue degradation. Some research indicates that anthocyanidins, which are found in extracts of grape seed, skin, and stems (but not in grape seed extract), can reduce oxidized glutathione while at the same time become reduced themselves. In addition, extracts of grape skin and pulp (but not those of grape seed extract) contain trans-resveratrol that has been shown to have cell protective effects.

Grape seed extract has been reported to demonstrate a remarkable spectrum of biological, pharmacological and therapeutic properties against oxidative stress. The antioxidative activities of grape seed extract have been found to be much stronger than those of vitamins C and E. Studies have indicated that grape seed extract showed a protective effect on cardiovascular disease, nephropathy, atherosclerosis, and neuropathy, among other conditions.

Vincare® contains ~80% polypnenols and has an ORAC value of about 19,000 µmole TE/g. ORAC 5.0 testing of grape seed extract exhibits one of the highest values of any tested material at about 100,000 µmole TE/g.

It has been shown that grape seed OPCs activate nuclear erythroid2-related factor2 (Nrf2), which is a key antioxidative transcription factor, with the concomitant elevation of downstream hemeoxygenase-1 (HO-1). Click here to view an excellent article entitled Proanthocyanidins [OPCs] against Oxidative Stress: From Molecular Mechanisms to Clinical Applications.

7) Bioperine®:

Bioperine® is a black pepper extract that has been shown to enhance the absorption of nutrients by 30–60 percent and makes all of the nutrients in this product more effective.

Ultimate Protector+™ will be most effective when used in conjunction with other foundational nutritional supplements that support the body’s metabolism, including Multi Two or Mighty Multi-Vite!™ (therapeutic multivitamin formulas), Omega Plus (essential fatty acids with Vitamin E), PRO-C™ (antioxidant formula), and one of our high-RNA Rejuvenate!™ superfoods.

COMPOSITION: six veggie capsules provides the following percentages of the Daily Value:

Serving Size: 6 Veggie Capsules Servings per Container: 30
Amount Per Serving Amounts % Daily Value
Vitamin C (as 100% USP-grade, non-GMO ascorbic acid) 1,500 mg 1667%
Calcium (from calcium malate) 60 mg 6
Magnesium (from magnesium malate) 60 mg 15
SFB®† (50% polyphenols, Orac: 9,000 units/gm) 180 mg *
Curcumin (95% min. curcuminoids from Curcuma longa) (root) 135 mg *
Green Tea extract (92% polyphenols, 50% EGCG) 135 mg *
Trans-Resveratrol 98% 135 mg *
Vincare®† whole grape extract (80% polyphenols, Orac: 19,000 units/gm) 135 mg *
Bioperine®†† 7.5 mg *
*
* Daily Value not established

Other ingredients: vegetarian capsule (veggie cap), microcrystalline cellulose, silica, and ascorbyl palmitate.

Directions for Use: As a dietary supplement take two capsules three times daily with food, or as directed by a health care professional.

ULTIMATE PROTECTOR Does Not Contain: wheat, rye, oats, barley, corn, gluten, soy, egg, dairy, yeast, sugar, shellfish, GMOs, wax, preservatives, colorings, or artificial flavorings.

ULTIMATE PROTECTOR+™ will be most effective when used in conjunction with other foundational nutritional supplements that support the body’s metabolism, including Multi Two or Mighty Multi-Vite!™ (therapeutic multivitamin formulas), Essential Fats plus E (essential fatty acids with Vitamin E), PRO-C™ (antioxidant formula), and one of our high-RNA Rejuvenate!™ superfoods.

†SFB® and VinCare® are registered trademark of Ethical Naturals, Inc.

†† Bioperine® is a registered trademark of Sabinsa Corporation.

ADDITIONAL RESOURCES

New Directions for Preventing Free-Radical Damage

Natural Phytochemical Nrf2 Activators for Chemoprevention

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ULTIMATE PROTECTOR+ INGREDIENTS – APPLE

Dr. Hank Liers, PhD biography about us HPDI integratedhealth formulator founder CEO scientist physicist wild bilberry and wild blueberry Ultimate Protector+ includes apple extract, as well as extracts from 12 different fruits, vegetables, and herbs. Each of these ingredients contain substances considered to be polyphenols, antioxidants, and Nrf2 activators. In this article, I explore the ingredient apple (Malus pumila mill.) extract, which is a component of SFB® – Standardized Fruit Blend from Ethical Naturals, Inc.

apple extract

Ultimate Protector+ Includes Apple

SFB® is a proprietary formula that combines extracts from Grape, Cranberry, Pomegranate, Blueberry, Apple, Mangosteen, Bilberry, Chokeberry, and Goji Berry. It is high in fruit polyphenols, flavonoids, anthocyanins, catechins, proanthocyanins, ellagic acid, xanthines, chlorogenic acid, pterostilbenes, resveratrol, phloridzin, quercetin, zeaxanthin, and quinic acid. With its diverse blend, SFB® offers over 40-50% polyphenols as well as >9,000 ORAC units in a single gram.

Polyphenols, anthocyanins and other plant elements are powerful ingredients associated with a variety of areas of human health, including healthy aging, healthy glucose metabolism, cardiovascular health, and inflammation management.

HEALTH BENEFITS OF APPLE

The Apple extract in Ultimate Protector+ has been extracted with non-GMO food grade ethanol and distilled water. Testing has indicated the product contains over 40% polyphenols. In numerous epidemiological studies, apples have been associated with a decreased risk of chronic diseases such as cardiovascular disease, cancer, and asthma.

When compared to many other commonly consumed fruits in the United States, apples had the second highest level of antioxidant activity. Apples also ranked the second for total concentration of phenolic compounds, and perhaps more importantly, apples had the highest portion of free phenolics when compared to other fruits.

APPLE PHYTOCHEMICALS

Apples contain a large concentration of flavonoids, as well as a variety of other phytochemicals, and the concentration of these phytochemicals may depend on many factors, such as cultivar of the apple, harvest and storage of the apples, and processing of the apples. The concentration of phytochemicals also varies greatly between the apple peels and the apple flesh.

Some of the most well studied antioxidant compounds in apples include quercetin-3-galactoside, quercetin-3-glucoside, quercetin-3-rhamnoside, catechin, epicatechin, procyanidin, cyanidin-3-galactoside, coumaric acid, chlorogenic acid, gallic acid, and phloridzin. Recently researchers have examined the average concentrations of the major phenolic compounds in six cultivars of apples. They found that the average phenolic concentrations among the six cultivars were: quercetin glycosides, 13.2 mg/100 g fruit; vitamin C, 12.8 mg/100 g fruit; procyanidin B, 9.35 mg/100 g fruit; chlorogenic acid, 9.02 mg/100 g fruit; epicatechin, 8.65 mg/100 g fruit; and phloretin glycosides, 5.59 mg/100 g fruit.

The compounds most commonly found in apple peels consist of the procyanidins, catechin, epicatechin, chlorogenic acid, phloridzin, and the quercetin conjugates. In the apple flesh, there is some catechin, procyanidin, epicatechin, and phloridzin, but these compounds are found in much lower concentrations than in the peels. Quercetin conjugates are found exclusively in the peel of the apples. Chlorogenic acid tends to be higher in the flesh than in the peel.

Because the apple peels contain more antioxidant compounds, especially quercetin, apple peels may have higher antioxidant activity and higher bioactivity than the apple flesh. Research showed that apples without the peels had less antioxidant activity than apples with the peels. Apples with the peels were also better able to inhibit cancer cell proliferation when compared to apples without the peels. More recent work has shown that apple peels contain anywhere from two to six times (depending on the variety) more phenolic compounds than in the flesh, and two to three times more flavonoids in the peels when compared to the flesh. The antioxidant activity of these peels was also much greater, ranging from two to six times greater in the peels when compared to the flesh, depending on the variety of the apple. This work is supported a study which found that rats consuming apple peels showed greater inhibition of lipid peroxidation and greater plasma antioxidant capacity when compared to rats fed apple flesh.

Many of these phytochemicals from apples have been widely studied, and many potential health benefits have been attributed to these specific phytochemicals. The procyanidins, epicatechin and catechin, have strong antioxidant activity and have been found to inhibit low density lipoprotein (LDL) oxidation in vitro. In mice, catechin inhibits intestinal tumor formation and delays tumors onset. One  study found that chlorogenic acid has very high alkyl peroxyl radical (ROO•) scavenging activity. Compared to about 18 other antioxidant compounds (including quercetin, gallic acid, α-tocopherol), chlorogenic was second only to rutin. Since ROO• may enhance tumor promotion and carcinogenesis, chlorogenic acid may add to the protective effect of apples against cancer. Chlorogenic acid has been found to inhibit 8-dehydroxy-deoxyguanosine formation in cellular DNA in a rat model following treatment with 4-nitroquinoline-1-oxide.

Quercetin is also a strong antioxidant, and is thought to have potential protective effects against both cancer and heart disease. Briefly, quercetin has been found to down regulate expression of mutant p53 in breast cancer cells, arrest human leukemic T-cells in G1, inhibit tyrosine kinase, and inhibit heat shock proteins. Quercetin has protected Caco-2 cells from lipid peroxidation induced by hydrogen peroxide and Fe2+. In mice liver treated with ethanol, quercetin decreased lipid oxidation and increased glutathione, protecting the liver from oxidative damage. Recently, it has been found that high doses of quercetin inhibit cell proliferation in colon carcinoma cell lines and in mammary adenocarcinoma cell lines, but at low doses quercetin increased cell proliferation (20% in colon cancer cells and 100% in breast cancer cells). However, low doses of quercetin (10 uM) inhibited cell proliferation in Mol-4 Human Leukemia cells and also induced apoptosis. Quercetin inhibited intestinal tumor growth in mice, but not in rats. Low levels of quercetin inhibited platelet aggregation, calcium mobilization, and tyrosine protein phosphorylation in platelets. Modulation of platelet activity may help prevent cardiovascular disease.

SCIENTIFIC STUDIES ON THE ANTIOXIDANT EFFECTS OF APPLE

Below, I provide relevant scientific studies on the antioxidant effects and potential health benefits of apple.

Apple phytochemicals and their health benefits

Jeanelle Boyer1 and Rui Hai Liu1

Abstract

Evidence suggests that a diet high in fruits and vegetables may decrease the risk of chronic diseases, such as cardiovascular disease and cancer, and phytochemicals including phenolics, flavonoids and carotenoids from fruits and vegetables may play a key role in reducing chronic disease risk. Apples are a widely consumed, rich source of phytochemicals, and epidemiological studies have linked the consumption of apples with reduced risk of some cancers, cardiovascular disease, asthma, and diabetes. In the laboratory, apples have been found to have very strong antioxidant activity, inhibit cancer cell proliferation, decrease lipid oxidation, and lower cholesterol. Apples contain a variety of phytochemicals, including quercetin, catechin, phloridzin and chlorogenic acid, all of which are strong antioxidants. The phytochemical composition of apples varies greatly between different varieties of apples, and there are also small changes in phytochemicals during the maturation and ripening of the fruit. Storage has little to no effect on apple phytochemicals, but processing can greatly affect apple phytochemicals. While extensive research exists, a literature review of the health benefits of apples and their phytochemicals has not been compiled to summarize this work. The purpose of this paper is to review the most recent literature regarding the health benefits of apples and their phytochemicals, phytochemical bioavailability and antioxidant behavior, and the effects of variety, ripening, storage and processing on apple phytochemicals..

Cancer chemopreventive potential of apples, apple juice, and apple components.

 Gerhauser C1.

From: https://www.ncbi.nlm.nih.gov/pubmed/18855307

Abstract

Apples ( MALUS sp., Rosaceae) are a rich source of nutrient as well as non-nutrient components and contain high levels of polyphenols and other phytochemicals. Main structural classes of apple constituents include hydroxycinnamic acids, dihydrochalcones, flavonols (quercetin glycosides), catechins and oligomeric procyanidins, as well as triterpenoids in apple peel and anthocyanins in red apples. Several lines of evidence suggest that apples and apple products possess a wide range of biological activities which may contribute to health beneficial effects against cardiovascular disease, asthma and pulmonary dysfunction, diabetes, obesity, and cancer (reviewed by Boyer and Liu, Nutr J 2004). The present review will summarize the current knowledge on potential cancer preventive effects of apples, apple juice and apple extracts (jointly designated as apple products). In brief, apple extracts and components, especially oligomeric procyanidins, have been shown to influence multiple mechanisms relevant for cancer prevention in IN VITRO studies. These include antimutagenic activity, modulation of carcinogen metabolism, antioxidant activity, anti-inflammatory mechanisms, modulation of signal transduction pathways, antiproliferative and apoptosis-inducing activity, as well as novel mechanisms on epigenetic events and innate immunity. Apple products have been shown to prevent skin, mammary and colon carcinogenesis in animal models. Epidemiological observations indicate that regular consumption of one or more apples a day may reduce the risk for lung and colon cancer.

Apple Peel Polyphenols and Their Beneficial Actions on Oxidative Stress and Inflammation

. 2013; 8(1): e53725.
Marie Claude Denis, Alexandra Furtos, Stéphanie Dudonné, Alain Montoudis, Carole Garofalo, Yves Desjardins, Edgard Delvin, and Emile Levy
From: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553108/#

Abstract

Since gastrointestinal mucosa is constantly exposed to reactive oxygen species from various sources, the presence of antioxidants may contribute to the body’s natural defenses against inflammatory diseases.

Hypothesis

To define the polyphenols extracted from dried apple peels (DAPP) and determine their antioxidant and anti-inflammatory potential in the intestine. Caco-2/15 cells were used to study the role of DAPP preventive actions against oxidative stress (OxS) and inflammation induced by iron-ascorbate (Fe/Asc) and lipopolysaccharide (LPS), respectively.

Results

The combination of HPLC with fluorescence detection, HPLC-ESI-MS TOF and UPLC-ESI-MS/MS QQQ allowed us to characterize the phenolic compounds present in the DAPP (phenolic acids, flavonol glycosides, flavan-3-ols, procyanidins). The addition of Fe/Asc to Caco-2/15 cells induced OxS as demonstrated by the rise in malondialdehyde, depletion of n-3 polyunsaturated fatty acids, and alterations in the activity of endogenous antioxidants (SOD, GPx, G-Red). However, preincubation with DAPP prevented Fe/Asc-mediated lipid peroxidation and counteracted LPS-mediated inflammation as evidenced by the down-regulation of cytokines (TNF-α and IL-6), and prostaglandin E2. The mechanisms of action triggered by DAPP induced also a down-regulation of cyclooxygenase-2 and nuclear factor-κB, respectively. These actions were accompanied by the induction of Nrf2 (orchestrating cellular antioxidant defenses and maintaining redox homeostasis), and PGC-1α (the “master controller” of mitochondrial biogenesis).

Conclusion

Our findings provide evidence of the capacity of DAPP to reduce OxS and inflammation, two pivotal processes involved in inflammatory bowel diseases.

APPLE SUMMARY

Apple is an important fruit full of polyphenols, anthocyanins, antioxidants, and Nrf2 activators that help to make Ultimate Protector+ such an outstanding nutritional supplement.

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ULTIMATE PROTECTOR+ INGREDIENTS – MANGOSTEEN

Dr. Hank Liers, PhD biography about us HPDI integratedhealth formulator founder CEO scientist physicist wild bilberry and wild blueberry Ultimate Protector+ includes mangosteen extract, as well as extracts from 12 different fruits, vegetables, and herbs. Each of these ingredients contain substances that may be considered to be polyphenols, antioxidants, and Nrf2 activators. In this article, I explore the ingredient mangosteen (Garcinia mangostana) extract which is a component of SFB® – Standardized Fruit Blend from Ethical Naturals, Inc.

Ultimate Protector+ Includes Mangosteen

Ultimate Protector+ Includes Mangosteen

SFB® is a proprietary formula that combines extracts from Grape, Cranberry, Pomegranate, Blueberry, Apple, Mangosteen, Bilberry, Chokeberry, and Goji Berry. It is high in fruit polyphenols, flavonoids, anthocyanins, catechins, proanthocyanins, ellagic acid, xanthines, chlorogenic acid, pterostilbenes, resveratrol, phloridzin, zeaxanthin, and quinic acid. With its diverse blend, SFB® offers over 40–50% polyphenols as well as >9,000 ORAC units in a single gram.

Polyphenols, anthocyanins and other plant elements are powerful ingredients associated with a variety of areas of human health, including healthy aging, healthy glucose metabolism, cardiovascular health, and inflammation management.

HEALTH BENEFITS OF MANGOSTEEN

The Mangosteen extract in Ultimate Protector+ has been extracted with non-GMO food grade ethanol and distilled water. Testing has indicated the product contains over 10% polyphenols.

Mangosteen extract in obtained from the skin and whole fruit for which numerous biological activities have been reported including: antimutagenic, antibacterial, hypocholesterolemic, antioxidant, and protective against tumorigenesis.

Mangosteen contains nutrients with antioxidant capacity, such as vitamin C and folate. Plus, it provides xanthones — a unique type of plant compound known to have strong antioxidant properties. In several test-tube and animal studies, the antioxidant activity of xanthones has resulted in anti-inflammatory, anticancer, anti-aging, heart protective, and antidiabetic effects.

Additionally, some research suggests that certain plant compounds in mangosteen may have antibacterial properties — which could benefit your immune health by combating potentially harmful bacteria. In a 30-day study in 59 people, those taking a mangosteen-containing supplement experienced reduced markers of inflammation and significantly greater increases in healthy immune cell numbers compared to those taking a placebo.

Metabolite Composition of Mangosteen

Xanthone is one of the compound classes that are prevalent in mangosteen. These metabolites have been extracted and characterized in various studies as reviewed by several publications. So far, there are more than 68 xanthones isolated from the mangosteen fruit with the majority of them are a- and c-mangostin. The molecular structure of these compounds have been elucidated and more recently, novel xanthones have been discovered such as 1,3,6-trihydroxy-2-(3-methylbut-2-enyl)-8-(3-formyloxy-3-methylbutyl)–xanthone, 7-O-demethyl mangostin, garmoxanthone, as well as mangostanaxanthone III, IV, and VII. These xanthones were also implicated in various pharmaceutical properties but more studies are needed to verify their effectiveness in human applications.It is interesting that using subcritical water extraction to extract xanthones from mangosteen fruit, eliminated the need for the chemical solvents.

A study showed that the aqueous micellar biphasic system they developed could also efficiently extract xanthones from mangosteen pericarp. This suggests that xanthones could be viable for human application but bioavailability studies need to be performed in the future to ascertain their delivery and efficacy. Interestingly, solubilizing a-mangostin in soybean oil (containing traces of linoleate, linolenic acid, palmitate, oleic acid, and stearate) improved the xanthone bioavailability in rats, such that the compound was found in brain, pancreas, and liver organs after 1 h treatment. This signifies the potential of using oil-based formulation for increasing the bioavailability of xanthones.

Other than xanthones, mangosteen pericarp is also known to contain one of the highest procyanidin content, compared to other fruit such as cranberry, Fuji apple, jujube, and litchi. These procyanidins including monomer (47.7%), dimer (24.1%), and trimer (26%) may also contribute to the antioxidant capability of mangosteen extract as shown in 1,1-diphenyl-2-picrylhydrazyl (DPPH) and Ferric Reducing Antioxidant Power (FRAP) assays. Other phenolics such as benzoic acid derivatives (vanilic acid and protocatechuic acid), flavonoids (rutin, quercetin, cactechin, epicatechin) and anthocyanins (cyanidin 3-sophoroside) were also highly present in mangosteen pericarp.

Furthermore, mangosteen compounds have also been profiled using metabolomics approach. Using GC-MS analysis, a study reported that mangosteen pericarp contains mainly sugars (nearly 50% of total metabolites) followed by traces of other metabolite classes such as sugar acids, alcohols, organic acids, and aromatic compounds. This study also found several phenolics such as benzoic acid, tyrosol, and protocatechuic acid which are known to possess anti-oxidative and anti-inflammatory activities.

SCIENTIFIC STUDIES ON THE ANTIOXIDANT EFFECTS OF MANGOSTEEN

Below, I provide relevant scientific studies on the antioxidant effects and potential health benefits of mangosteen.

Recent updates on metabolite composition and medicinal benefits of mangosteen plant

Wan Mohd Aizat, Ili Nadhirah Jamil, Faridda Hannim Ahmad-Hashim and Normah Mohd Noor
Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia (UKM), Bangi, Selangor, Malaysia

From: https://peerj.com/articles/6324.pdf

ABSTRACT

Background: Mangosteen (Garcinia mangostana L.) fruit has a unique sweet-sour taste and is rich in beneficial compounds such as xanthones. Mangosteen originally been used in various folk medicines to treat diarrhea, wounds, and fever. More recently, it had been used as a major component in health supplement products for weight loss and for promoting general health. This is perhaps due to its known medicinal benefits, including as anti-oxidant and anti-inflammation. Interestingly, publications related to mangosteen have surged in recent years, suggesting its popularity and usefulness in research laboratories. However, there are still no updated reviews (up to 2018) in this booming research area, particularly on its metabolite composition and medicinal benefits.

Method: In this review, we have covered recent articles within the years of 2016 to 2018 which focus on several aspects including the latest findings on the compound composition of mangosteen fruit as well as its medicinal usages.
Result: Mangosteen has been vastly used in medicinal areas including in anti-cancer, anti-microbial, and anti-diabetes treatments. Furthermore, we have also described the benefits of mangosteen extract in protecting various human organs such as liver, skin, joint, eye, neuron, bowel, and cardiovascular tissues against disorders and diseases.

Conclusion: All in all, this review describes the numerous manipulations of mangosteen extracted compounds in medicinal areas and highlights the current trend of its research. This will be important for future directed research and may allow researchers to tackle the next big challenge in mangosteen study: drug development and human applications.

α-Mangostin induces apoptosis in human chondrosarcoma cells through downregulation of ERK/JNK and Akt signaling pathway.

2011 May 25;59(10):5746-54. doi: 10.1021/jf200620n. Epub 2011 Apr 11.
Krajarng A1, Nakamura Y, Suksamrarn S, Watanapokasin R.
From: https://www.ncbi.nlm.nih.gov/pubmed/21446759

Abstract

Chondrosarcoma is a malignant primary bone tumor that is resistant to chemotherapy and radiation therapy. α-Mangostin, a component of Garcinia mangostana Linn, is a xanthone derivative shown to have antioxidant and antitumor properties. This study is the first to investigate anticancer effects of α-mangostin in the human chondrosarcoma cell line SW1353. We showed that α-mangostin inhibited cell proliferation of SW1353 cells in a time- and dose-dependent manner by using the trypan blue exclusion method. Hoechst 33342 nuclear staining and nucleosomal DNA-gel electrophoresis revealed that α-mangostin could induce nuclear condensation and fragmentation, typically seen in apoptosis. Flow cytometry using Annexin V/PI double staining assessed apoptosis, necrosis and viability. α-Mangostin activated caspase-3, -8, -9 expression, decreased Bcl-2 and increased Bax. This promotes mitochondrial dysfunction, leading to the release of cytochrome c from the mitochondria to the cytoplasm. In addition, total and phosphorylated ERK and JNK were downregulated in α-mangostin-treated SW1353 cells but no changes in p38. α-Mangostin also decreased phosphorylated Akt without altering total Akt. These results suggest that α-mangostin inhinbited cell proliferation and induced apoptosis through downregulation of ERK, JNK and Akt signaling pathway in human chondrosarcoma SW1353 cells.

Characterized mechanism of alpha-mangostin-induced cell death: caspase-independent apoptosis with release of endonuclease-G from mitochondria and increased miR-143 expression in human colorectal cancer DLD-1 cells.

2007 Aug 15;15(16):5620-8. Epub 2007 May 18.
Nakagawa Y, Iinuma M, Naoe T, Nozawa Y, Akao Y.

From: https://www.ncbi.nlm.nih.gov/pubmed/17553685

Abstract

alpha-Mangostin, a xanthone from the pericarps of mangosteen (Garcinia mangostana Linn.), was evaluated for in vitro cytotoxicity against human colon cancer DLD-1 cells. The number of viable cells was consistently decreased by the treatment with alpha-mangostin at more than 20 microM. The cytotoxic effect of 20 microM alpha-mangostin was found to be mainly due to apoptosis, as indicated by morphological findings. Western blotting, the results of an apoptosis inhibition assay using caspase inhibitors, and the examination of caspase activity did not demonstrate the activation of any of the caspases tested. However, endonuclease-G released from mitochondria with the decreased mitochondrial membrane potential was shown. The levels of phospho-Erk1/2 were increased in the early phase until 1h after the start of treatment and thereafter decreased, and increased again in the late phase. On the other hand, the level of phospho-Akt was sharply reduced with the process of apoptosis after 6h of treatment. Interestingly, the level of microRNA-143, which negatively regulates Erk5 at translation, gradually increased until 24h following the start of treatment. We also examined the synergistic growth suppression in DLD-1 cells by the combined treatment of the cells with alpha-mangostin and 5-FU which is one of the most effective chemotherapeutic agents for colorectal adenocarcinoma. The co-treatment with alpha-mangostin and 5-FU, both at 2.5 microM, augmented growth inhibition compared with the treatment with 5 microM of alpha-mangostin or 5 microM 5-FU alone. These findings indicate unique mechanisms of alpha-mangostin-induced apoptosis and its action as an effective chemosensitizer.

SUMMARY

Mangosteen is an important fruit full of polyphenols, anthocyanins, antioxidants, xanthones, and Nrf2 activators that help to make Ultimate Protector+ such an outstanding nutritional supplement.

Mangosteen
MANGOSTEEN, Garcinia mangostana—Painted by Dr. M.J. Dijkman

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PRO-C ANTIOXIDANT FORMULA UPDATE + VIDEO

Dr. Hank Liers, PhD pro-c™ pro-c super antioxidant formulaFred Liers PhD pro-c antioxidant vitamin c nrf2 formulaLooking for an advanced antioxidant formula? Already using or recommending vitamin C? Curious about cellular Nrf2 activation? Look no further than PRO-C™.

PRO-C™ is among the most effective antioxidant formulas available. It is an HPDI foundational supplement that works most effectively when used with multivitamins, essential fats, and superfoods. However, it is also an excellent standalone formula that can rapidly provide the body with extremely high protection from free radicals.

We ourselves have taken PRO-C daily for many years with excellent results. Our personal experience together with detailed feedback from health professionals and end-users affirms the effectiveness of PRO-C as a super-antioxidant–vitamin C-Nrf2 activator formula.

PRO-C provides 500 mg of buffered vitamin C per capsule (buffered with calcium, magnesium, and zinc) along with grape extract (seed, skin, pulp) and green tea extract (95% polyphenols). In addition, we include a special combination of the “network antioxidants” l-glutathione (reduced), n-acetyl-l-cysteine (NAC), r-lipoic acid, and selenium. Vitamin B2 and Vitamin B6 in coenzyme forms support the enzymatic effectiveness of the “network antioxidants”. The formula works so well because this combination of ingredients leverages the antioxidant power of vitamin C, grape extract, green tea extract, and the other nutrients to act synergistically in order to maximize effectiveness.

FORMULATION HISTORY AND THE SCIENCE BEHIND PRO-C™

What you may not know is the history of the development PRO-C and the scientific knowledge on which Dr. Hank Liers based his formulation of it.

Dr. Hank formulated his first product in 1989. It was a potent antioxidant formula he called PYC-C™ (sounds like “pixie”). PYC-C consisted of a combination of buffered Vitamin C (including magnesium, calcium, and zinc ascorbates) and pycnogenols from pine bark.

Much of the scientific research data Dr. Hank collected during the development of PYC-C regarding oligomeric proanthocyanidins (OPC) he later incorporated into an article (currently published on this blog) titled “Review of Scientific Research on Oligomeric Proanthocyanidins (OPC)” (rev. 2017)

By 1997 Dr. Hank had gathered a great deal of new scientific information regarding green tea catechins and the nutrients termed “network antioxidants” by Dr. Lester Packer, director of Packer Lab at University of California, Berkeley. Beyond this information, Dr. Hank studied additional research regarding how various nutrients worked together synergistically. At that point, he was ready to formulate the new, improved PRO-C™ super antioxidant formula.

PRO-C combines the ingredients of PYC-C (now known as OPC-C™) and uses grape pulp, skin, and seed extract with green tea extract (with high polyphenols >95% and EpiGalloCatechinGalate (EGCG) >45%), n-acetyl-l-cysteine (NAC), reduced glutathione (GSH), R-lipoic acid, selenium, and coenzyme Vitamins B2 and B6.

PRO-C super antioxidant formula 180 cap 90 cap

HPDI launched PRO-C™ in late 1997. It rapidly became one of our best-selling products. Our customers raved about how effective it was for them if they felt like they were “coming down with something” (like a cold, flu, virus, infection, etc.). Greater skin elasticity greatly helped pregnant women avoid stretch marks and episiotomies. Today, we highly recommend its use together with our other Foundational Supplements to ensure optimal health and anti-aging effects.

THE PRO-C™ SUPER ANTIOXIDANT FORMULA

PRO-C™ super antioxidant formula is extremely synergistic, especially in so far as it increases the body’s ability to quench free radicals in its aqueous (i.e., water-based) compartments. Because antioxidants may become free radicals themselves after they have done their job, the body has developed an elaborate system for recovery of oxidized antioxidants.

 

Dr. Lester Packer was the primary researcher investigating the synergistic character of antioxidants. He made this statement in his interview with Dr. Richard Passwater after publication of Packer’s The Antioxidant Miracle (1999):

[The major theme of] The Antioxidant Miracle is that antioxidants work in a coordinated manner. They interact with one another, and this interaction, which we like to call the antioxidant network, is very important to the overall antioxidant defense that we possess. The key members of the antioxidant network are vitamin E and vitamin C, but there are other participants in this network. These are thiol antioxidants, antioxidants that contain sulfur groups in the body. Glutathione perhaps is the best known of these, but there are other sulfur-containing antioxidants that also are very important.”

Dr. Packer continues:

“This whole antioxidant network works like an orchestra depending on individuals who have, of course, different complements of antioxidants depending upon their nutritional regimens and the individuality of their own body metabolisms. The idea behind having a network of antioxidants is that if one antioxidant happens to be deficient the others can compensate and still keep the antioxidant defense system strong.”

The following diagram shows some of the relationships in the antioxidant network and how they support each other.

Lester Packer antioxidant network diagram Figure 1 – Dr. Packer’s Antioxidant Network

We see, for example, reduced glutathione (GSH) has the ability to reduce oxidized Vitamin C back to its unoxidized state. Vitamin C reduces oxidized Vitamin E back to its unoxidized state, and both reduces glutathione and spares it for other important functions, including detoxification and immune enhancement.

Many polyphenols (e.g., oligomeric proanthocyanidins (OPCs), anthocyanidins and catechins) found in red grape and green tea extracts spare Vitamin C and glutathione in the body, as well as operate as powerful antioxidants, anti-inflammatories, and connective tissue strengtheners.

grapes grape extract antioxidant

Grapes provide antioxidant nutrients such as polyphenols, OPCs, anthocyans, and resveratrol.

R-Lipoic Acid (see abstracts below) operates as an antioxidant both in its oxidized and reduced states, reduces the oxidized forms of both Vitamin E and Vitamin C, and and has been shown to enhance glutathione levels. Because several of these substances are able to protect Vitamin E contained in cell membranes, this combination also has a significant beneficial effect on the fat soluble antioxidant status of the body!

The nutrients in PRO-C have been carefully selected and balanced to provide optimal effects, especially as related to free radical protection, detoxification, immune system enhancement, connective tissue strengthening, and reduction of inflammation. PRO-C therefore provides outstanding nutritional support in a wide variety of conditions of poor health, as well as acts to support and maintain a state of health and well-being.

It the last several years the research results on Nrf2 activators have become well known and products developed that take advantage of these nutrients. For details see our blog article Natural Phytochemical Nrf2 Activators for Chemoprevention. Researchers have been studying specifically how enzyme-activating substances such as OPCs and anthocyans activate a transcription factor known as Nrf2 that causes the body to endogenously produce higher levels of a wide variety of protective enzymes including superoxide dismutase (SOD), catalase, and glutathione peroxidase.

Although we did not know about Nrf2 activators in 1997 when we formulated PRO-C, we have subsequently learned that four of the ingredients in the formula have powerful Nrf2 activity. These include grape seed extract, green tea extract, NAC, and r-lipoic acid. With this knowledge, we now understand that PRO-C provides both powerful external antioxidants (with extremely high ORAC5.0 values) that support redox cycles within the body, but also provides ingredients that allow the body to endogenously produce powerful protective enzymes for even greater free-radical protection and health.

PRO-C™ ANTIOXIDANT FORMULA INGREDIENTS

PRO-C contains buffered vitamin C (in the form of powdered calcium, magnesium, and zinc ascorbates), high-potency grape extract (from grape pulp, skins, and seeds), green tea extract (with>95% polyphenols and >45% EGCG), reduced glutathione, N-Acetyl-L-Cysteine (NAC), R-lipoic acid, coenzyme forms of vitamin B2 (R5P) and vitamin B6 (P5P), and selenium.

Below we will discuss each ingredient and show some of the research that confirms its effectiveness.

VITAMIN C

Vitamin C typically is called l-ascorbic acid or ascorbate and is an essential nutrient for humans and other animal species. The term “vitamin C” refers to a number of vitamins that have vitamin C activity in animals, including ascorbic acid and its salts (e.g., magnesium ascorbate, calcium ascorbate, sodium ascorbate, etc.), and some oxidized forms such as dehydroascorbate and semidehydroascorbate.

Vitamin C is known to perform many critical functions within the body involving detoxification, tissue building, immune enhancement, pain control, and controlling or killing pathogenic organisms. It is also known to be helpful for wound and bone healing, healthy skin and eyes, fighting infections, stress control, toxic exposure, and repairing damaged tissue of all types. For much more information on the many benefits of Vitamin C see our blog article Vitamin C – An Amazing Nutrient.

Below are two abstracts that show some of the beneficial effects of Vitamin C when used with other network antioxidants:

ABSTRACT 1:
Exhaustive physical exercise causes oxidation of glutathione status in blood: prevention by antioxidant administration.
Sastre J, Asensi M, Gasco E, Pallardo FV, Ferrero JA, Furukawa T, Vina J
In: Am J Physiol (1992 Nov) 263(5 Pt 2):R992-5

We have studied the effect of exhaustive concentric physical exercise on glutathione redox status and the possible relationship between blood glutathione oxidation and blood lactate and pyruvate levels. Levels of oxidized glutathione (GSSG) in blood increase after exhaustive concentric physical exercise in trained humans. GSSG levels were 72% higher immediately after exercise than at rest. They returned to normal values 1 h after exercise. Blood reduced glutathione (GSH) levels did not change significantly after the exercise. We have found a linear relationship between GSSG-to-GSH and lactate-to-pyruvate ratios in human blood before, during, and after exhaustive exercise. In rats, physical exercise also caused an increase in blood GSSG levels that were 200% higher after physical exercise than at rest. GSH levels did not change significantly. Thus, both in rats and humans, exhaustive physical exercise causes a change in glutathione redox status in blood. We have also found that antioxidant administration, i.e., oral vitamin C, N-acetyl-L- cysteine, or glutathione, is effective in preventing oxidation of the blood glutathione pool after physical exercise in rats.

ABSTRACT 2:
The effect of glutathione and vitamins A, C, and E on acute skin flap survival.

Hayden RE, Paniello RC, Yeung CS, Bello SL, Dawson SM
In: Laryngoscope (1987 Oct) 97(10):1176-9

Vitamins A, C, and E act as antioxidants and as free radical scavengers in biological systems. Glutathione is involved in several reactions in vitamin metabolism and also plays an important role in cell membrane protection against lipid peroxidation by free radicals. We sought to use these natural defense mechanisms against oxygen free radicals formed during reperfusion of ischemic skin flaps. An acute axial random skin flap model was utilized in the rat. Vitamins or glutathione were administered by oral gastric tube or intravenously in the perioperative period, and survival of the flap was measured at 1 week. Glutathione, beta-carotene, ascorbic acid and alpha-D- tocopherol showed mean flap survival of 84% to 89%, each of which was significantly improved over saline controls (67% p less than .0005). The mechanisms and biochemistry of these vitamins, and their interactions with other vitamins and with glutathione, are discussed, along with clinical implications of free radical scavenging and skin flap survival.

GRAPE EXTRACT

Grape extract (seeds, skin, pulp) contain highly bioavailable bioflavonoid complexes that in research studies have been shown to have powerful antioxidant capability. The Oligomeric Proanthocyanidins (OPCs) in grape seed extract are able to strengthen collagen fibers in aging or damaged connective tissue and can act as a preventative against connective tissue degradation.

Some research indicates that anthocyans, which are found in extracts of grape skin and stems (but not in grape seed extract), can reduce oxidized glutathione while at the same time become reduced themselves. In addition, extracts of grape skin and stems (but not those of grape seed extract) contain a material called trans-resveratrol that has been shown to have chemopreventive effects.

Below we have provided some of the abstracts that are included in our broad list of relevant abstracts for PRO-C.

ABSTRACT 3:
Protective effects of grape seed proanthocyanidins and selected antioxidants against TPA-induced hepatic and brain lipid peroxidation and DNA fragmentation, and peritoneal macrophage activation in mice.
Bagchi D, Garg A, Krohn RL, Bagchi M, Bagchi DJ, Balmoori J, Stohs SJ
In: Gen Pharmacol (1998 May) 30(5):771-6

1. The comparative protective abilities of a grape seed proanthocyanidin extract (GSPE) (25-100 mg/kg), vitamin C (100 mg/kg), vitamin E succinate (VES) (100 mg/kg) and beta-carotene (50 mg/kg) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced lipid peroxidation and DNA fragmentation in the hepatic and brain tissues, as well as production of reactive oxygen species by peritoneal macrophages, were assessed. 2. Treatment of mice with GSPE (100 mg/kg), vitamin C, VES and beta-carotene decreased TPA-induced production of reactive oxygen species, as evidenced by decreases in the chemiluminescence response in peritoneal macrophages by approximately 70%, 18%, 47% and 16%, respectively, and cytochrome c reduction by approximately 65%, 15%, 37% and 19%, respectively, compared with controls. 3. GSPE, vitamin C, VES and beta-carotene decreased TPA-induced DNA fragmentation by approximately 47%, 10%, 30% and 11%, respectively, in the hepatic tissues, and 50%, 14%, 31% and 11%, respectively, in the brain tissues, at the doses that were used. Similar results were observed with respect to lipid peroxidation in hepatic mitochondria and microsomes and in brain homogenates. 4. GSPE exhibited a dose-dependent inhibition of TPA- induced lipid peroxidation and DNA fragmentation in liver and brain, as well as a dose-dependent inhibition of TPA-induced reactive oxygen species production in peritoneal macrophages. 5. GSPE and other antioxidants provided significant protection against TPA-induced oxidative damage, with GSPE providing better protection than did other antioxidants at the doses that were employed.

ABSTRACT 4:
Clinical and capillaroscopic evaluation of chronic uncomplicated venous insufficiency with procyanidins extracted from vitis vinifera
Costantini A, De Bernardi T, Gotti A
In: Minerva Cardioangiol (1999 Jan-Feb) 47(1-2):39-46

BACKGROUND: The pharmacological treatment of non-complicated chronic venous insufficiency is a current and well-debated topic. The introduction of new products with action on the venous system, improved knowledge on the physiopathology of venous insufficiency and the possibility provided by new analytical instruments, have given new impulse to the consolidation of the clinical value of phlebotonics in this indication. METHODS: In light of this, 24 patients with non-complicated chronic venous insufficiency were treated with oral administration of Oligomeric Proanthocyanidins (Pycnogenols-OPC) 100 mg/day. To evaluate the therapeutic efficacy of the treatment, an instrumental evaluation by optical probe capillaroscope was employed in addition to the traditional subjective clinical parameters: swelling, itching, heaviness and pain. The videocapillaroscope examination was performed at the lower third of the leg and the first toe. Edema in the capillaroscopic field, the number of observable capillaries and the capillary dilatation were the parameter chosen to evaluate the efficacy of treatment. All patients completed the study with no reports of adverse events during the period of observation. RESULTS: The results obtained show a positive clinical response (improved or absent symptoms) in over 80% of patients, with significant improvement of symptoms already evident after the first 10 days of treatment. The mechanism of action of the OPCs explains the rapid reduction of the swelling of the lower limbs and correlated with this are the other evaluable symptoms: heaviness and itching. Particularly striking results were observed for itching and pain which completely disappeared during the course of therapy in 80% and 53% of the patients respectively. Noteworthy is the good correlation between the clinical and instrumental data, with improvement in a total of 70% of patients. CONCLUSIONS: The results obtained in the course of this clinical experience, with evident improvement already during the first weeks of treatment, the absence of adverse events added to the benefit of a once-a-day administration, justify the use of OPC in the treatment of non-complicated chronic venous insufficiency.

ABSTRACT 5:
Polymeric procyanidin fraction from defatted grape seeds protects HepG2 cells against oxidative stress by inducing phase II enzymes via Nrf2 activation.
Younghwa Kim, Youngmin Choi, Hyeonmi Ham, Heon-Sang Jeong, Junsoo Lee
Kim, Y., Choi, Y., Ham, H. et al. Food Sci Biotechnol (2013) 22: 485. https://doi.org/10.1007/s10068-013-0105-x

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that regulates antioxidant response element (ARE)-driven phase II detoxification enzymes. In this study, induction of phase II enzymes via Nrf2/ARE activation in the cytoprotective effect of crude polyphenol extract (CPE), oligomeric procyanidin fraction (OPF), and polymeric procyanidin fraction (PPF) from defatted grape seeds in HepG2 cells was evaluated. Among these treatments, the treatment with PPF significantly increased Nrf2 protein expression in the nuclear fraction. Treating the samples increased heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) protein expression in a dose-dependent manner, and PPF significantly increased the levels of phase II enzymes. Cellular generation of reactive oxygen species (ROS) were effectively reduced by PPF. These results suggest that pretreatment with PPF shows a cytoprotective effect by inhibiting ROS production and inducing HO-1 and NQO1 expression via Nrf2 activation in HepG2 cells.

GREEN TEA EXTRACT

Green tea extract is obtained from the unfermented leaves of Camellia sinensis for which numerous biological activities have been reported including: antimutagenic, antibacterial, hypocholesterolemic, antioxidant, and protective against tumorigenesis. Below we have selected a few of the many abstracts we have on file showing the benefit of green tea extract.

Green tea antioxidant polyphenols catechins

Green tea leaves are high in antioxidant polyphenols and catechins.

ABSTRACT 6:
Enhancement of antioxidant and phase II enzymes by oral feeding of green tea polyphenols in drinking water to SKH-1 hairless mice: possible role in cancer chemoprevention.
Khan SG, Katiyar SK, Agarwal R, Mukhtar H
In: Cancer Res (1992 Jul 15) 52(14):4050-2

Following 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 (0.2%, w/v) to mice for 30 days significantly increased the activities of glutathione peroxidase, catalase, and quinone reductase in small bowel, liver, and lungs, and glutathione S-transferase in small bowel and liver. GTP feeding to mice also resulted in considerable enhancement of glutathione reductase activity in liver. In general, the increase in antioxidant and phase II enzyme activities was more pronounced in lung and small bowel as compared to liver and skin. The significance of these results can be implicated in relation to the cancer chemopreventive effects of GTP against the induction of tumors in various target organs.

ABSTRACT 7:
INHIBITORY EFFECT OF SIX GREEN TEA CATECHINS AND CAFFEINE ON THE GROWTH OF FOUR SELECTED HUMAN TUMOR CELL LINES.
In: Anticancer Drugs (1996 Jun) 7(4):461-8
Institutional address: Department of Pharmacology and Toxicology College of Pharmacy University of Arizona Tucson 85721 USA.

Green tea is an aqueous infusion of dried unfermented leaves of Camellia sinensis (family Theaceae) from which numerous biological activities have been reported including antimutagenic, antibacterial, hypocholesterolemic, antioxidant, antitumor and cancer preventive activities. From the aqueous-alcoholic extract of green tea leaves, six compounds (+)-gallocatechin (GC), (-)-epicatechin (EC), (-)- epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)- epigallocatechin gallate (EGCG) and caffeine, were isolated and purified. Together with (+)-catechin, these compounds were tested against each of four human tumor cells lines (MCF-7 breast carcinoma, HT-29 colon carcinoma, A-427 lung carcinoma and UACC-375 melanoma). The three most potent green tea components against all four tumor cell lines were EGCG, GC and EGC. EGCG was the most potent of the seven green tea components against three out of the four cell lines (i.e. MCF-7 breast cancer, HT-29 colon cancer and UACC-375 melanoma). On the basis of these extensive in vitro studies, it would be of considerable interest to evaluate all three of these components in comparative preclinical in vivo animal tumor model systems before final decisions are made concerning which of these potential chemopreventive drugs should be taken into broad clinical trials.

GLUTATHIONE AND N-ACETYL-L-CYSTEINE (NAC)

Glutathione and NAC (a major precursor of glutathione) both provide important protection against toxins and free radicals, and can strengthen the immune system. Glutathione is considered to be one of the most important protective substances in the human body with almost 60% of liver detoxification accounted for by this key substance. In addition, glutathione is one of the most potent anti-viral substances known.

Some research has indicated that glutathione may not be able to enter easily into certain types of cells, but NAC is able to enter these cells and be converted into glutathione once inside the cell. Thus, the combination of glutathione and NAC appear to be more potent than either alone.

Below we provide some of the key abstracts we have on file regarding NAC and glutathione.

ABSTRACT 8
GSH rescue by N-acetylcysteine.
Ruffmann R Wendel A
In: Klin Wochenschr (1991 Nov 15) 69(18):857-62

Reduced glutathione (GSH) is the main intracellular low molecular weight thiol. GSH acts as a nucleophilic scavenger and as an enzyme-catalyzed antioxidant in the event of electrophilic/oxidative tissue injury. Therefore, GSH has a major role as a protector of biological structures and functions. GSH depletion has been recognized as a hazardous condition during paracetamol intoxication. Conversely, GSH rescue, meaning recovery of the protective potential of GSH by early administration of N-acetylcysteine (NAC), has been found to be life-saving. Lack of GSH and electrophilic/oxidative injury have been identified among the causes of the adult respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and the acquired immunodeficiency syndrome (AIDS). Experimental and early clinical data (in ARDS) point to the role of NAC in the treatment of these conditions. Recently, orally given NAC has been shown to enhance the levels of GSH in the liver, in plasma, and notably in the bronchoalveolar lavage fluid. Rescue of GSH through NAC needs to be appreciated as an independent treatment modality for an array of different disease, all of which have one feature in common: pathogenetically relevant loss of GSH.

ABSTRACT 9
Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine.
Bridgeman MM Marsden M MacNee W Flenley DC Ryle AP
In: Thorax (1991 Jan) 46(1):39-42

N-acetylcysteine (600 mg/day) was given to patients by mouth for five days before bronchoscopy and bronchoalveolar lavage to determine whether N-acetylcysteine could increase the concentrations of the antioxidant reduced glutathione in plasma and bronchoalveolar lavage fluid. Bronchoalveolar lavage was performed 1-3 hours (group 2, n = 9) and 16-20 hours (group 3, n = 10) after the last dose of N-acetylcysteine and the values were compared with those in a control group receiving no N-acetylcysteine (group 1, n = 8). N-Acetylcysteine was not detected in plasma or lavage fluid. Plasma concentrations of cysteine, the main metabolite of N-acetylcysteine and a precursor of reduced glutathione, were greater in the groups receiving treatment (groups 2 and 3) than in group 1. Cysteine concentrations in lavage fluid were similar in the three groups. Concentrations of reduced glutathione were greater in both plasma and lavage fluid in group 2 than in group 1. These data suggest that N-acetylcysteine given by mouth is rapidly deacetylated to cysteine, with resulting increases in the concentrations of cysteine in plasma and of reduced glutathione in plasma and the airways, which thus temporarily increase the antioxidant capacity of the lung.

R-LIPOIC ACID / ALPHA-LIPOIC ACID

R-Lipoic Acid is normally made at low levels in the human body, where it functions primarily as an important metabolic nutrient in the conversion of pyruvic acid into acetyl coenzyme A. As such, it plays a crucial role in the metabolism of both fats and carbohydrates into energy. In addition, r-lipoic acid functions as an extremely powerful antioxidant capable of trapping many different types of free radicals in the body.

Because it is both water and fat soluble, lipoic acid is able to operate in a broader range of body tissues than most other antioxidants. Its small size allows lipoic acid to enter areas of the body not easily accessible to many other substances; this allows lipoic acid, for example, to enter the cell nucleus and prevent free-radical damage to DNA.

Because it is such a powerful antioxidant and can easily function as such in both a reduced and oxidized state, lipoic acid is able to protect other important antioxidants such as glutathione, Vitamin E, and Vitamin C. R-lipoic acid is also able to chelate heavy metals such as lead, cadmium, mercury, free iron, and free copper out of the body.

Below we provide relevant scientific abstracts from our database regarding R-Lipoic acid.

ABSTRACT 10:
Alpha-Lipoic acid as a biological antioxidant.
Packer L Witt EH Tritschler HJ
In: Free Radic Biol Med (1995 Aug) 19(2):227-50

alpha-Lipoic acid, which plays an essential role in mitochondrial dehydrogenase reactions, has recently gained considerable attention as an antioxidant. Lipoate, or its reduced form, dihydrolipoate, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its antioxidant activities, dihydrolipoate may exert prooxidant actions through reduction of iron. alpha-Lipoic acid administration has been shown to be beneficial in a number of oxidative stress models such as ischemia-reperfusion injury, diabetes (both alpha-lipoic acid and dihydrolipoic acid exhibit hydrophobic binding to proteins such as albumin, which can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration, and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor. We review the properties of lipoate in terms of (1) reactions with reactive oxygen species; (2) interactions with other antioxidants; (3) beneficial effects in oxidative stress models or clinical conditions.

ABSTRACT 11:
Regeneration of glutathione by α-lipoic acid via Nrf2/ARE signaling pathway alleviates cadmium-induced HepG2 cell toxicity.
Zhang J, Zhou X, Wu W, Wang J, Xie H, Wu Z.
In: Environ Toxicol Pharmacol. 2017 Apr;51:30-37. doi: 10.1016/j.etap.2017.02.022. Epub 2017 Feb 27.

Alpha-lipoic acid (α-LA) is an important antioxidant that is capable of regenerating other antioxidants, such as glutathione (GSH). However, the underlying molecular mechanism by which α-LA regenerates GSH remains poorly understood. The current study aimed to investigate whether α-LA regenerates GSH by activation of Nrf2 to alleviate cadmium-induced cytotoxicity in HepG2 cells. In the present study, we found that cadmium induced cell death by depletion of GSH through inactivation of Nrf2. Addition of α-LA to cadmium-treated cells reactivated Nrf2 and regenerated GSH through elevating the Nrf2-downstream genes γ-glutamate-cysteine ligase (γ-GCL) and GR, both of which are key enzymes for GSH synthesis. However, blocking Nrf2 with brusatol in the cells co-treated with α-LA and cadmium reduced the mRNA and the protein levels of γ-GCL and GR, thus suppressed GSH regeneration by α-LA. Our results indicated that α-LA activated Nrf2 signaling pathway, which upregulated the transcription of the enzymes for GSH synthesis and therefore GSH contents to alleviate cadmium-induced cytotoxicity in HepG2 cells.

SELENIUM

Selenium has been shown by clinical research to be a key mineral in the body’s defenses against free radicals and has been shown to be a major factor in reducing the symptoms of HIV infections and in the prevention of tumors. Selenium is used in conjunction with glutathione to form the powerful enzyme glutathione peroxidase that is responsible for detoxification of peroxides formed during the process of aerobic metabolism in humans and other animals.

ABSTRACT 12
Serum selenium concentrations in rheumatoid arthritis.
In: Ann Rheum Dis (1991 Jun) 50(6):376-8

O’Dell JR, Lemley-Gillespie S, Palmer WR, Weaver AL, Moore GF, Klassen LW

Selenium is a trace element and an essential part of the enzyme glutathione peroxidase, which protects cells from oxidative damage. Selenium has been shown to have antiproliferative, anti-inflammatory, antiviral, and immune altering effects. Serum selenium concentrations in 101 patients with seropositive rheumatoid arthritis were found to be significantly lower than those in 29 normal, healthy controls (mean (SD) 148 (42) v 160 (25) micrograms/l) and also lower than those in eight patients with fibrositis (148 (42) v 166 (25) micrograms/l). It is speculated that serum selenium concentrations may modulate the effect of viral or other infections in subjects with the appropriate genetic background and in this way enhance the development or progression of rheumatoid arthritis.

ABSTRACT 13
Studies on selenium in top athletes.
Dragan I, Ploesteanu E, Cristea E, Mohora M, Dinu V, Troescu VS
In: Physiologie (1988 Oct-Dec) 25(4):187-90

The authors performed a controlled trial in 18 top athletes (9 weight lifters and 9 rowers, girls) in order to make evident some chronic and acute effects (antioxidant) of selenium. Nonprotein–SH (essential glutathione), lipid peroxides (MDA-malondialdehyde), glucose-6-phosphate dehydrogenases (G-6-PDH) and fructose-1,6- diphosphate aldolase in serum, have been recorded initially on basal conditions, after 3 weeks of treatment (100 micrograms/day selenium or placebo) and again after 3 weeks of treatment, also on basal conditions, when crossing over the groups (between a free interval of 10 days). In another trial we registered these parameters on basal conditions and after two hours of hard training accompanied by a per oral administration of 150 micrograms selenium (respectively placebo). The results show significant changes under selenium treatment of the peroxides, G-6-PDH and light changes, not significant of the nonprotein–SH, changes which could suggest an antioxidant effect of this element.

VITAMINS B2 and B6 IN COENZYME FORMS

Vitamin B2 as coenzyme riboflavin-5-phosphate is a key vitamin that supports the regeneration of glutathione (via glutathione reductase). Vitamin B6 as coenzyme pyridoxal-5-phosphate is a key vitamin that supports the ability of glutathione to combine with toxic substances (via glutathione transferase) in the process of eliminating them from the body. They are especially effective in their coenzyme forms which allows them to be directly utilized by the body starting in the intestinal tract.

MAGNESIUM, CALCIUM, AND ZINC

Magnesium, zinc, and calcium synergistically work with (and enhance the effects of) the other ingredients in PRO-C. Minerals are especially needed as active components of enzymes that drive metabolic activity. For example, magnesium is required in the functioning of more than 325 types of enzymes.

PRO-C™ SUPER ANTIOXIDANT FORMULA BENEFITS

HIGHLY EFFECTIVE VITAMIN C FORMULA PLUS ANTIOXIDANTS. A complete vitamin C formula, a powerful antioxidant Formula, and Nrf2 activator combined in a single advanced supplement!

POWERFUL, SYNERGISTIC FREE-RADICAL QUENCHING FORMULA. PRO-C™ components work together to quench free radicals in your body. Vitamin C enables grape seed extract to function more effectively, and conversely grape seed extract potentiates vitamin C. Green tea extract boosts ORAC (Oxygen Radical Absorbance Capacity) value.

PROVIDES SIGNIFICANT AMOUNTS OF POWERFUL NRF2 ACTIVATORS (from Grape Extract, Green Tea Extract, NAC, and R-Lipoic Acid) that stimulate the production of the body’s own protective antioxidants including superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase.

SUPERIOR, BUFFERED (NON-ACIDIC) FORM OF VITAMIN C. Mineral Ascorbates never acidify your body, keeping you pH balanced. Staying alkaline is an important element in maintaining a healthy body.

RAPID ASSIMILATION. Capsule form ensures rapid uptake and assimilation in the body. You may also empty capsule contents into water, food, or directly Into mouth, if desired. Good, mildly tart taste!

COMPOSITION OF PRO-C™ SUPER ANTIOXIDANT FORMULA

One (1) vegetarian capsule of PRO-C provides the following percentages of the Daily Value:

NUTRIENT AMOUNT % Daily Value
Vitamin C (from mineral ascorbates) 500 mg 833%
BioVin® Grape Extract 30 mg *
Green Tea Extract 30 mg *
Calcium (from calcium ascorbate) 23 mg 2.3%
Magnesium (from magnesium ascorbate) 23 mg 5.7%
L-Glutathione (reduced) 20 mg *
N-Acetyl-L-Cysteine (NAC) 15 mg *
R-Lipoic Acid 5 mg *
Zinc (from zinc ascorbate) 2 mg 13%
Vitamin B2 (from riboflavin-5′-phosphate) 1 mg 118%
Vitamin B6 (from pyridoxal-5′-phosphate) 1 mg 50%
Selenium (from l-selenomethionine) 10 mcg *

* No established Daily Value

DIRECTIONS: As a dietary supplement take 1–3 capsules or more daily in divided doses (i.e., spread out over the day), or as recommended by a health care professional. It initially may be useful to take up to 6 capsules per day in divided doses for one week. The contents of the capsule may be emptied into juice or food, as needed.

INGREDIENTS: PRO-C™ SUPER ANTIOXIDANT FORMULA contains only the highest-quality USP grade magnesium ascorbate, USP grade calcium ascorbate, BioVin® grape extract (greater than 75% polyphenols, 93% OPC, greater than 3.5% anthocyanidins from grape pulp, skins, and seeds, and a small amount of trans resveratrol), green tea extract (95% min. polyphenols and 45% min. EGCG), l-glutathione (reduced), USP grade n-acetyl-l-cysteine, USP grade zinc ascorbate, r-(+)-lipoic acid, riboflavin-5′-phosphate, pyridoxal-5′-phosphate, l-selenomethionine, the smallest amounts of microcrystalline cellulose and silica in a vegetarian capsule.

PRO-C™ does not contain wheat, rye, oats, corn antigen, barley, gluten, soy, egg, dairy, yeast, sugar, sulfates, phosphates (other than coenzyme forms), fats, chlorides, GMOs, wax, preservatives, colorings, or artificial flavorings.

Click here to order PRO-C™.

SOURCES & RESOURCES

BOOKS

The Antioxidant Miracle. Lester Packer, PhD, and Carol Coleman. New York: John Wiley and Sons, 1999.

How to Live Longer and Feel Better. Dr. Linus Pauling. Corvallis, OR: Oregon State University Press, 2006.

ARTICLES

Review of Scientific Research on Oligomeric Proanthocyanidins (OPC)” (rev. 2017) by Hank Liers, PhD

“Vitamin C – An Amazing Nutrient” by Hank Liers, PhD

PRO-C™ and Ultimate Protector™ – Comparison by Hank Liers, PhD

“Antioxidant Cocktail Update: Part 1: The Take Home Message is to Use Antioxidant Supplements”
(An interview of Dr. Lester Packer by Richard A. Passwater, PhD, Whole Foods Magazine 1999)

ABSTRACTS

PRO-C™ / Vitamin C Abstracts

Catechin Abstracts

N-Acetyl-L-Cysteine (NAC) Abstracts

Lipoic Acid Abstracts

WEBSITES

Orthomolecular.org
(Therapeutic Nutrition Based Upon Biochemical Individuality)

PRODUCTS

PRO-C™Super Antioxidant Formula

Ultimate Protector™Nrf2 Activator Formula

OPC-C™

HPDI Vitamin C Products