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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 ligase is a characteristic Nrf2 target gene, which establishes 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 giant knotweed and 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 100% 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+    3,376    5,569 2,758 221,866 34,169 267,738
Results are expressed in micro mole TE/g

The total Ultimate Protector+ ORAC5.0 value per serving of 6 small vegetarian capsules (containing 3.55 g) is over 950,00 Micro mole TE.

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

 SCIENTIFIC ARTICLES

 

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USING HPDI FOUNDATIONAL SUPPLEMENTS

Fred Liers PhD foundational supplements nutritionHPDI foundational supplements are designed to provide a complete range of essential nutrients that complement a healthy diet and lifestyle. They help ensure sufficient levels of nutrients required for good health.

We define foundational supplements as basic or “core” supplements that should be part of everyone’s daily regimen. They are the foundation of a complete nutritional supplement program.

HPDI has a three-tiered system of nutritional supplements: 1) Foundational Supplements, 2) Enhancement Formulas, and 3) Specific-Condition Formulas. All three tiers comprise a complete nutritional supplement program.

When properly combined, these three tiers of nutritional supplements help create optimal health. This month, I explain how to use HPDI foundational supplements, the base or bottom tier of the system (see cone diagram below).

The HPDI supplement system can be visualized as a cone having a base of Foundational Supplements ascending toward an apex of Enhancement Formulas and Specific Condition Formulas.

foundational supplements HPDI system

The HPDI Supplement System includes six types of Foundational Supplements forming its base.

USING HPDI FOUNDATIONAL SUPPLEMENTS

My intent is to guide consumers and health care professionals to decide the foundational supplements that are best for their purposes, and that provide the most effective results.

For anyone new to HPDI’s Foundational Supplements system, we recommend six basic types of supplements. The six categories are: 1) multivitamin formulas, 2) vitamin C / antioxidant formulas, 3) essential fats, 4) high-RNA foods (Rejuvenate! superfoods), 5) gut health formulas, and 6) hydrogen formulas.

We established the original three types of foundational supplements about 1988. We have always suggested that clients and health professionals take and/or recommend multivitamins, vitamin C and antioxidants, and essential fats.

About 10 years ago, we added high-RNA foods (like Rejuvenate! superfoods) as a fourth type of foundational supplement because research indicates dietary nucleic acids are essential nutrients—see our blog articles on nucleic acids, Benjamin S. Frank, MD, PhD, and about Rejuvenate! superfoods (Original, Plus, and Berries & Herbs).

Two categories of foundational supplements are new: gut health formulas and hydrogen formulas. Hank wrote an article (Amending the HPDI Foundational Program) about these changes in April. We added these two categories after much consideration regarding their benefits, and have written extensively about them in this blog (see resources section below).

The entire HPDI supplement system is depicted (above) as a cone. The six types of foundational supplements form the base of the cone. Enhancement Formulas and Specific-Condition formulas sit above toward the apex.

ultimate protector foundational supplements

Ultimate Protector Nrf2 formula is a foundational supplement in the vitamin C / antioxidant category.

HOW I USE HPDI FOUNDATIONAL SUPPLEMENTS

I use all six types of HPDI foundational supplements. I take the following supplements (below) and present them here as an example of how they can be integrated into a complete supplement regimen. Foundational Supplements I take:

1. Multivitamin: Hank & Brian’s Mighty Multi-Vite! (4 per day in divided doses)

2. Vitamin C / antioxidants: PRO-C (6-8 per day) and Ultimate Protector Nrf2 activator (8-12 per day)

3. Essential Fats: Essential Fats Plus E (4 per day)

4. Rejuvenate!™ superfood: All three Rejuvenate! superfoods (2-8 scoops per day)

5. Gut Health: RESTORE For Gut Health (1-2 ounces per day) and Terraflora™ synbiotic (with soil-based organisms) (1-3 per week)

6. Hydrogen: Megahydrate (2-6 per day)

Taking one supplement from each of the six foundational supplement categories builds, supports, and maintains optimal health.

We at HPDI recommend everyone take one of each type of foundational supplement. That is, we suggest an individual select for personal use a multivitamin, vitamin C/antioxidant formula, essential fats formula, Rejuvenate!™ superfood (or other high-RNA superfood), hydrogen product, and at least one gut health product (depending on their gut-health needs).

Similarly we suggest health care professionals recommend for their clients one of each of the six types of foundational supplements.

The other two categories in the HPDI nutritional supplement system are Enhancement Formulas and Specific-Condition Formulas (see cone diagram). These are not foundational supplements. However, I include the supplements I take in these categories for the sake of completeness, as well as to show how Enhancement and Specific-Condition Formulas integrate with Foundational Supplements to form a complete supplement program providing a wide-range of essential nutrients required for health.

Enhancement Formulas I take include: B-Complex-50 (B complex), Myo-Mag (magnesium/malic acid), Ubiquinol-50, Bone Guardian, and Vitamin D3 Plus.

Specific Condition Formulas I take include: Joint Health Formula, Allergy Support Formula, Eye & Vision Formula, Intestinal Rejuvenation Formula, and Warrior Mist (pain topical), and Warrior Sleep (sleep topical).

While I take supplements from all three categories (Foundationals, Enhancements, and Specific-Condition) in the HPDI supplement system, I always prioritize foundational supplements—I take them first—because they are base on which my personal supplement program rests.

Foundational supplements should be the base on which your supplement program—or those of your clients—rests, as well.

We have seen the results of taking a complete set of foundational supplements. They work because the nutrients they provide are needed by everyone.

HPDI foundational supplements multivitamin

Muti Two Caps is a high-potency multi with coenzyme forms for optimal utilization in the body.

FOUNDATIONAL SUPPLEMENTS: RESULTS

Individuals who take all types of foundational supplements do best in terms of optimizing health. The reason is that all six types provide nutrients required for good health.

I can attest that HPDI Foundational Supplements are effective for improving or maintaining good health. In addition, I have witnessed numerous instances where individuals benefit most greatly when taking all four–and now all six–types of foundational supplements.

Each of the six categories of foundational supplement provide unique benefits. Yet, each performs functions required by the human body for good health. That is one reason when they are combined they exert synergistic effects for health going far beyond the benefits of using, one, two, or three of the types of foundational supplements.

WHEN FOUNDATIONAL SUPPLEMENTS ARE NOT PRIORITIZED

I talk to people who may or may not take a multivitamin. And they may or may not take vitamin C. Yet, they may take calcium for their bones, glucosamine for their joints, and lutein for their eyes. Or they may take a low-potency, off-the-shelf multivitamin providing merely the RDA for all nutrients.

There is nothing wrong with individuals taking supplements they regard as important or useful. But that cannot guarantee that a wide range—and sufficient levels—of nutrients necessary for health are available to the body on a regular basis.

In fact, I regard the supplement intake programs of most persons to be “hit-or-miss.” They may consume nutrients important for a few functions in the body, yet fail to obtain other essential nutrients required for the nutrients they take to work most effectively. We have written extensively on this topic on our website and in blog articles (see below).

Not taking regularly a complete set of foundational supplements likely means key nutrients (and key levels of nutrients) go missing. Over time, this means fewer and lower levels of nutrients available to support the body’s needs for them at levels known to sustain the good health.

The best way to ensure a sufficient range of nutrients at plentiful levels is to take foundational supplements. After a baseline of nutrients is established by taking foundational supplements, additional supplements can be added, as necessary.

rejuvenate superfood foundational supplements

High-RNA foods like Rejuvenate! PLUS superfood provide dietary nucleic acids important for health.

A COMPLETE SYSTEM OF SUPPLEMENTS, INCLUDING FOUNDATIONALS

After obtaining sufficient levels of basic nutrients required for health, then a person can add (or you can recommend) specific nutrients or formulas that target certain problems or issues. This is the basis for HPDI development of Enhancement Formulas and Specific-Condition Formulas.

Nutritional supplements in the categories of Enhancement Formulas and Specific-Condition Formulas therefore “stack” on top of HPDI’s Foundational Supplements (see cone diagram above). In this way, a complete nutritional supplement program begins with the most essential nutrients and continues with customizations based on the unique needs of an individual.

ENHANCEMENT FORMULAS

Enhancement Formulas in the HPDI system are supplements we regard as falling into the next tier in terms of importance, at least for most people. They do not necessarily provide essential nutrients, and yet many people (including myself) benefit significantly from them.

Enhancement Formulas include: magnesium formulas (topical and capsule), Vitamin D3 Plus, Nascent Iodine, Vitamin B12 (methylcobalamin), mushroom-based products (like Immune-Assist™), Prolyt (proteolytic enzymes), Digase (plant-based enzymes), and Warrior Mist (topical pain reliever), and many other formulas.

SPECIFIC-CONDITION FORMULAS

In the HPDI system, individuals can add (in a modular way) various formulas and single nutrients designed to support a particular set of needs or a target a specific condition.

We offer a complete range of supplements (almost 100) including a range of supplements formulated to address specific conditions. These include Joint Health Formula, Eye & Vision Formula, Blood Sugar Support, Allergy Support Plus, Prosta Plus, and many other formulas.

ONE SYSTEM. THREE TIERS. HPDI SUPPLEMENTS.

HPDI Foundational Supplements collectively form the base tier of a complete nutritional supplement system comprised of three tiers: 1) Foundational Supplements (six types), 2) Enhancement Formulas (or simply “Enhancements”), and 3) Specific-Condition Formulas.

Foundational Supplements are necessary because they provide nutrients foundational to health. Taking them daily or recommending your clients take them daily can help mean big differences in health, nutrition, and quality of life.

We at HPDI design our nutritional supplements to be the most effective dietary supplements available. HPDI products are known for: 1) Advanced Formulation (including use of superior forms of nutrients), 2) Ultra-High Purity, 3) Avoidance of Harmful Ingredients, and 4) being made with Good Manufacturing Practices (GMP). For more details, please see The HPDI Difference and our Statement on Additives (Excipients).

At least 40 of HPDI’s products are formulated by Dr. Hank Liers. They fall in all categories in HPDI’s supplement system. They can be found under “Dr. Hank Liers original formulas.”

omega plus foundational supplement

Omega Plus provides exceptionally well-balanced omega-3 and omega-6 fatty acids.

FOUNDATIONAL SUPPLEMENTS: FREQUENTLY ASKED QUESTIONS (FAQ)

We frequently get questions from HPDI clients and resellers regarding foundational supplements. These questions include:

“Why did you add gut health and hydrogen products to your foundational supplements program?”
We found it necessary to add categories for gut health and hydrogen because they provide nutrients that are support the body and help ensure the foundational supplement system supports health most effectively. You can read more in previous blog articles (see below).

“Which is the better multivitamin: Multi Two or Mighty Multi-Vite!™?”
It depends on whether you need more B vitamins or antioxidants. Multi Two provides more B vitamins and Mighty Multi-Vite™ provides more antioxidants and cofactors. I take a separate HPDI B-Complex-50 formula, so I take Mighty Multi-Vite!™ as my primary multivitamin.

“What are the differences between Rejuvenate!™ Original, PLUS, and Berries & Herbs superfoods?”
They each provide about 340 mg of dietary nucleic acids. Original is the “greenest” with a large percentage of dietary nucleic acids coming from chlorella and spirunlina. PLUS is our most popular and 30% is identical to Original with more protein and a built-in multivitamin complex. Berries & Herbs contains no greens, yet more nucleic acids (390 mg), protein, and a built-in multivitamin. See our Rejuvenate! comparison page for more information.

“Should I take a vitamin C formula with antioxidants like PRO-C or one with Nrf2 activators like Ultimate Protector?”
Both provide vitamin C and Nrf2 activators, but Ultimate Protector provides more types of Nrf2 activators. Ultimate Protector capsules are smaller than PRO-C capsules, so a daily dose may require taking more capsules.

“How important are hydrogen supplements?”
Very important for energy production, recovery, antioxidant functions, and gut health. Hydrogen supplements like Active H2 and Megahydrate ensure high levels of hydrogen are available in the body.

What are your best products for supporting gut health?
It depends on your needs: cleansing (Intestinal Rejuvenation Formula), probiotic/microbiome support (Terraflora™), or tightening tight junctions in the gut (RESTORE)? We offer products for all these purposes.

These are just a few questions frequently asked about HPDI foundational supplements. If you need more information about products, please contact the HPDI office (800-228-4265) or email support@healthproductsdistributors.com.

You can also contact Fred Liers, PhD (520-400-0155) or Hank Liers, PhD (formulator) with questions you may have regarding products, ingredients, or formulation.

SOURCES AND RESOURCES

Foundational Supplements

HPDI Full Product Overview

The Need for Foundational Supplements (.pdf)

The HPDI Difference (4 Pillars of Formulation)

HPDI BLOG ARTICLES

Amending the HPDI Foundational Supplements Program

Foundational Supplements Remain Fundamental

Vitamin C / Antioxidants

PRO-C and Ultimate Protector Comparison

Questions and Answers about Ultimate Protector

The Amazing Healing Potential of Natural Nrf2 Activators

Ultimate Protector™: First Impressions

Ultimate Protector™ Brunswick Labs ORAC5.0™ Test Results

Preventing Free-Radical Damage Using Ultimate Protector™

Description and Comparison of ORAC Tests for Well Known Plant Ingredients and Ultimate Protector™

Ultimate Protector and the Role of Foundational Supplements for Health

Natural Phytochemical Nrf2 Activators for Chemoprevention

New Directions for Preventing Free Radical Damage

Review of Scientific Research on Oligomeric Proanthocyanidins (OPC)” by Dr. Hank Liers

“Vitamin C – An Amazing Nutrient” by Dr. Hank Liers

Rejuvenate! Superfoods

Rejuvenate! Berries & Herbs: Ingredients for Optimal Nutrition

9 Things to Know About Rejuvenate!™ Superfoods

High-RNA Rejuvenate!™ Superfood

Get Results with Rejuvenate! Superfoods

Dietary RNA for Athletic Performance

DIETARY NUCLEIC ACIDS – DR. BENJAMIN S. FRANK, PART 1

DIETARY NUCLEIC ACIDS – DR. BENJAMIN S. FRANK, PART 2

Super-Tasty Morning Nutritional Drinks

Hydrogen

The Science Behind Megahydrate

Hydrogen for Optimal Health

Wonders of Molecular Hydrogen

Gut Health

Gut Health – Effects of Glyphosate and Antibiotics

Gut Health – Intestinal Rejuvenation Formula

PRODUCTS

Vitamin formulas, including multivitamins

Mighty Multi-Vite!

Multi Two Caps

Rejuvenate!™ Berries & Herbs

Rejuvenate!™ PLUS

Rejuvenate!™ (Original)

Rejuvenate! Superfoods: Product Comparison

Ultimate Protector™ Nrf2 Activator (vitamin C/antioxidant)

PRO-C (Vitamin C/Antioxidant formula)

Intestinal Rejuvenation Formula (gut health)

Restore For Gut Health (lignite formula)

Active H2 (hydrogen)

Megahydrate (hydrogen)

Terraflora™ (synbiotic)

HPDI FOUNDATIONAL SUPPLEMENTS

2

PRO-C AND ULTIMATE PROTECTOR – COMPARISON OF ANTIOXIDANT FORMULAS

Dr. Hank Liers, PhD antioxidant formulasI have written extensively regarding the benefits HPDI’s PRO-C™ and Ultimate Protector™ antioxidant formulas. Based upon my experience with these formulas they are among the most effective antioxidant formulas available.

Both antioxidant formulas are included in HPDI’s system of foundational supplements and work most effectively when used with multivitamins, essential fats, and superfoods.

Yet, both formulas also are excellent standalone products that can rapidly provide the body with extremely high protection against free radicals.
Ultimate Protector antioxidant formulas

We are often asked “which of these two antioxidant formulas should I take?” My answer usually is to take both formulas. I personally take both of them on a daily basis.

Below I will briefly show the reason my answer is to take both formulas. I include information showing the relationship, in terms of ingredients of the two formulas (per serving of three (3) capsules daily of PRO-C and six (6) capsules daily of Ultimate Protector).

Ultimate Protector

INGREDIENTS OF ANTIOXIDANT FORMULAS

PRO-C™ (per serving of three “00” veggie caps)

• Buffered non-GMO Vitamin C (1,500 mg)  buffered with Ca/Mg/Zn
• Grape Extract (seed, skin, and pulp) (90 mg)
• Green Tea Extract 95% polyphenols 40% min. EGCG (90 mg)
• Glutathione – reduced (60 mg)
• N-Acetyl-l-Cysteine (NAC) (45 mg)
• R-Lipoic Acid (15 mg)
• Coenzyme B2/R5P (3 mg)
• Coenzyme B6/P5P (3 mg)
• Selenium from l-selenomethionine (30 mcg)
• Calcium (70 mg)
• Magnesium (70 mg)
• Zinc (6 mg)

ULTIMATE PROTECTOR™ (per serving of six “0” veggie caps)

• Vitamin C as non-GMO Ascorbic acid (1500 mg)
• Anthocomplete™ (135 mg)  Wild Blueberry, Wild Bilberry, Acai, Black Currant Extract, Sweet Cherry, Raspberry, Elderberry, Blackberry, Aronia, Black Soybean Hull Extract, and Blue Corn
• CoffeeBerry®Forte (135 mg)
• Vitaberry® Plus (90 mg) freeze-dried Grape Seed, Wild Blueberry, Wild Bilberry, Cranberry, Tart Cherry, Prune, Raspberry Seed, Strawberry, Trans-Resveratrol, and Quercetin
• VitaVeggie® (90 mg)  Broccoli, Broccoli Sprouts, Tomato, Kale, Carrot, Brussels Sprouts, Onion, and Spinach
• Curcumin 95%  (90 mg)
• Trans-Resveratrol 98% (90 mg)
• Malic Acid (500 mg)
• Calcium (60 mg)
• Magnesium (60 mg)
• BioPerine® (7.5 mg)

The products together contain nine (9) unique PRO-C™ ingredients, eight (8) unique Ultimate Protector™ ingredients, and three (3) overlapping ingredients.

DISCUSSION OF ANTIOXIDANT FORMULAS

PRO-C™

When PRO-C™ was first released in 1997 there were few publications available regarding Nrf2 ingredients and their benefits. The product design was based on the work of Dr. Lester Packer and his work done on the “Antioxidant Network” showing how nutrients such as Vitamin E, Vitamin C, Glutathione, and Lipoic acid work in a redox network to regenerate key nutrients in the body (see Figure 1. below)

doctor lester packer antioxidant formulas

                                                Figure 1. – Dr. Packer’s Antioxidant Network

At that time the powerful antioxidant formulas of Grape Seed Extract and Green Tea Extract were well known, but their powerful Nrf2 effects were not discovered until later. These ingredients are able to trap free radicals and conserve the body’s store of network antioxidants.

Also, the Nrf2 effects of NAC and Lipoic acid were not known at the time, but their powerful effects on the body were known to support the production of glutathione. Additionally, the super powerful glutathione (reduced) was included with supporting coenzymes B2 (from riboflavin 5′-phosphate) and B6 (from pyridoxal 5′-phosphate) that allow the enzymes glutathione reductase and transferase to function at a higher level.

ULTIMATE PROTECTOR™

From the beginning of the design process, Ultimate Protector™ (UP) was focused on creating a highly effective Nrf2 activator formula with outstanding antioxidant effects. Our understanding was that a very broad spectrum of plant polyphenols including flavonoids, anthocyandins, oligoproanthocyanidins (OPCs), etc. would deliver the best results.

We selected Futureceuticals Anthocomplete™, CoffeeBerry® Forte, Vitaberry® Plus, and VitaVeggie® in order to accomplish this and added Curcumin 95%, and Trans-Resveratrol 98% because of the powerful scientific findings regarding Nrf2 activation for these two ingredients. We found out later in testing that this combination of ingredients produces very high ORAC5.0 values (486,000 units/serving of six capsules) and works effectively against all of the primary types of free radicals in the body.

WHY TAKE BOTH PRO-C™ AND
ULTIMATE PROTECTOR™ ANTIOXIDANT FORMULAS?

Ultimate Protector versus PRO-C antioxidant formulas

Venn diagram showing unique and overlapping ingredients in PRO-C and Ultimate Protector.

There are 29 unique Nrf2 activator ingredients in Ultimate Protector (UP) and four (4) non-overlapping Nrf2 activator ingredients in PRO-C. Thus by taking both formulas you are able to receive 33 identifiable Nrf2 activator ingredients (870 mg). The amount of unique Nrf2 ingredients is probably significantly more than this because most of the identifiable ingredients contain a range of plant polyphenols.

Other unique ingredients of each formula include glutathione – reduced (60 mg), malic acid (500 mcg), zinc (6 mg), selenium (30 mcg), B2 (3 mg) and B6 (3 mg) from coenzyme forms, and Bioperine (7.5 mg) (for enhanced absorption of nutrients). These are important ingredients to have the formulas work more effectively together.

The overlapping ingredients in the formula include Vitamin C (3 gm – 1.5 gm from each formula), calcium (130 mg – 70 mg from PRO-C & 60 mg from UP), magnesium (130 mg – 70 mg from PRO-C & 60 mg from UP), and a little grape seed extract (~10 mg). We view this to be very positive especially because we believe that most people should take in at least 3 grams daily of Vitamin C. Equal amounts of calcium and magnesium balance each other in the body and have many important functions such as being part of critical enzymes.

SOURCES & RESOURCES

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

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

HPDI BLOG ARTICLES

CONTACT US:

You can reach HPDI by calling 1-800-228-4265, email support(at)IntegratedHealth.com, or visit the retail website: IntegratedHealth.com

Health care professionals and resellers can apply for wholesale account, which includes access to the HPDI reseller website: HealthProductsDistributors.com. Email: Support(at)HealthProductsDistributors.com.

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ULTIMATE PROTECTOR INGREDIENTS – BLACK CURRANT EXTRACT

Dr. Hank Liers, PhD biography HPDI integratedhealth formulator scientist physicist black currant extractUltimate Protector contains black currant extract, as well as components from 29 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 will explore the ingredient black currant extract, which is a component of Anthocomplete™ from Futureceuticals.

ANTHOCOMPLETE™

AnthoComplete™ (N669) is a specially designed blend of anthocyanins derived from wild bilberry and wild blueberry, açaí, black currant extract, sweet cherry, raspberry, elderberry, blackberry, aronia, black soybean hull extract, and blue corn. Anthocyanins are powerful plant polyphenols associated with a variety of areas of human health, including healthy aging, healthy glucose metabolism, cardiovascular health, and inflammation management.

Carefully designed to maximize the amount of beneficial anthocyanins that can be available in a single source, AnthoComplete™ is a proprietary formula suitable for a wide range of applications.

With its diverse blend, AnthoComplete™ contains a minimum level of 10% anthocyanins, 3,000 ORAC μmole TE/g (typical), and 15% total phenolics (typical).

Owing to the high levels of anthocyanins and vitamin C, two types of important antioxidants, black currants have been shown by scientific research to have many benefits in promoting health and wellness. Vitamin C is an essential nutrient required for the body’s normal functions and the antioxidant polyphenols in black currants (particularly anthocyanins) may help in maintaining cardiovascular health, aging and brain health, urinary tract health, and healthy vision.

Black Currant

Black Currant Berries

HEALTH BENEFITS OF BLACK CURRANT EXTRACT

Black currants (Ribes nigrum) have been used in a wide variety of foods for many years. They contain a relatively large vitamin C content, more than almost any other commonly consumed fruit. Ongoing research is further showing the benefits of black currants based largely on the polyphenolic content of the fruit and its related products.

Black currants have antioxidant value (oxygen radical absorbance capacity – ORAC) of 7950 Trolex Equivalents per 100 g, which is one of the highest value for fruits after chokeberries, elderberry, and cranberries.

The intensely dark color of blackcurrants is due to its high content of anthocyanin — primarily 3-glucosides and 3-rutinosides of cyanidin and delphinidin. It has been found that these components exhibit powerful hydroxyl radical scavenging abilities and protect endothelial cells in model systems.

In addition, the anthocyanins have been shown to positively influence the α-glucosidase phase of starch digestion providing a reduction of sugar release during starch food digestion.

Also, black currants are a good source of glycosylated flavonols such as quercetin, myrecetin and kaempferol. Scientific studies at the fundamental cellular level have indicated that these compounds can interact with the bodies own innate Antioxidant Response Elements (ARE), such as the transcription factor Nrf2, and more specifically stimulate expression of the detoxification enzymes such as NAD(P)H:quinone oxidoreductase, glutathione S-transferase, and uridine diphosphate-glucuronosyltransferase isoenzymes.

SCIENTIFIC STUDIES ON THE ANTIOXIDANT EFFECTS OF BLACK CURRANTS

Below, we provide a few relevant scientific studies on the antioxidant effects and potential health benefits of black currant extracts.

Biological activity of blackcurrant extracts (Ribes nigrum L.) in relation to erythrocyte membranes.
From: http://www.ncbi.nlm.nih.gov/pubmed/24527456

Abstract

Compounds contained in fruits and leaves of blackcurrant (Ribes nigrum L.) are known as agents acting preventively and therapeutically on the organism. The HPLC analysis showed they are rich in polyphenol anthocyanins in fruits and flavonoids in leaves, that have antioxidant activity and are beneficial for health. The aim of the research was to determine the effect of blackcurrant fruit and leaf extracts on the physical properties of the erythrocyte membranes and assess their antioxidant properties. The effect of the extracts on osmotic resistance, shape of erythrocytes and hemolytic and antioxidant activity of the extracts were examined with spectrophotometric methods. The FTIR investigation showed that extracts modify the erythrocyte membrane and protect it against free radicals induced by UV radiation. The results show that the extracts do not induce hemolysis and even protect erythrocytes against the harmful action of UVC radiation, while slightly strengthening the membrane and inducing echinocytes. The compounds contained in the extracts do not penetrate into the hydrophobic region, but bind to the membrane surface inducing small changes in the packing arrangement of the polar head groups of membrane lipids. The extracts have a high antioxidant activity. Their presence on the surface of the erythrocyte membrane entails protection against free radicals.

 

Anthocyanin-rich black currant extract suppresses the growth of human hepatocellular carcinoma cells.

Abstract

Dietary antioxidants, such as anthocyanins, are helpful in the prevention and control of various diseases by counteracting the imbalance of oxidative and antioxidative factors in the living systems. Black currant (Ribes nigrum L., Grossulariaceae) is known to contain high amounts of anthocyanins (250 mg/100 g fresh fruit). Black currant fruits have been used in Asian and European traditional medicine for the treatment of a variety of diseases. Black currant extract has recently been found to be the second most effective amongst nine different berry extracts studied for their free radical scavenging activity. Constituents present in black currant juice have been found to exert a number of health-promoting effects, including immunomodulatory, antimicrobial and antiinflammatory actions, inhibition of low-density lipoprotein, and reduction of cardiovascular diseases. Although antioxidant and antiinflammatory effects of black currant juice could be of value in preventing and treating oxidative stress- and inflammation-driven cancers, no experimental evidence is available to now. The objective of the present study was to evaluate the potential antiproliferative effects of black currant fruit skin extract against HepG2 human liver cancer cells. The aqueous extract yielded an anthocyanin-rich fraction with cyanidin-3-O-rutinoside as one of the major anthocyanins. This fraction exhibited a potent cytotoxic effect on HepG2 cells and this effect was more pronounced than that of delphinidin and cyanidin, two major aglycones of anthocyanins present in black currant. Our results indicate, for the first time, that black currant skin containing an anthocyanin-rich fraction inhibits the proliferation of liver cancer cells, possibly due to additive as well as synergistic effects. This product could be useful in the prevention and treatment of human hepatocellular carcinoma.

 

Black currant anthocyanins abrogate oxidative stress through Nrf2-mediated antioxidant mechanisms in a rat model of hepatocellular carcinoma.

Abstract

Hepatocellular carcinoma (HCC), considered to be one of the most lethal cancers with almost > 1 million deaths reported annually worldwide, remains a devastating disease with no known effective cure. Hence, chemopreventive strategies come into play, offering an effective and safe mode of treatment, ideal to ward off potential cancer risks and mortality. A major predisposing condition, pertinent to the development and progression of HCC is oxidative stress. We previously reported a striking chemopreventive effect of anthocyanin-rich black currant skin extract (BCSE) against diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats. The current study aims to elucidate the underlying antioxidant mechanisms of black currant anthocyanins implicated in the previously observed chemopreventive effects against experimental hepatocarcinogenesis. Dietary BCSE (100 and 500 mg/kg) administered four weeks before and 18 weeks after DENA challenge decreased abnormal lipid peroxidation, protein oxidation, and expression of inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in a dose-responsive fashion. Mechanistic studies revealed that BCSE upregulated the gene expression of a number of hepatic antioxidant and carcinogen detoxifying enzymes, such as NAD(P)H:quinone oxidoreductase, glutathione S-transferase, and uridine diphosphate-glucuronosyltransferase isoenzymes, in DENA-initiated animals. Protein and mRNA expressions of nuclear factor E2-related factor 2 (Nrf2) were substantially elevated with BCSE treatment, providing a direct evidence of a coordinated activation of the Nrf2-regulated antioxidant pathway, which led to the upregulation of a variety of housekeeping genes. The results of our study provide substantial evidence that black currant bioactive anthocyanins exert chemopreventive actions against DENA-inflicted hepatocarcinogenesis by attenuating oxidative stress through activation of Nrf2 signaling pathway.

 

Black currant phytoconstituents exert chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis by suppression of the inflammatory response.

From: http://www.ncbi.nlm.nih.gov/pubmed/22213170

Abstract

Black currant fruits containing high amounts of anthocyanins are known to possess potent antioxidant and anti-inflammatory properties. We have previously reported that anthocyanin-rich black currant skin extract (BCSE) inhibits diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats although the underlying mechanisms are not fully understood. Our present study investigates the anti-inflammatory mechanisms of BCSE during DENA rat liver carcinogenesis. Dietary BCSE (100 or 500 mg/kg) treatment for 22 wk afforded a striking inhibition of DENA-induced hepatic gamma-glutamyl transpeptidase-positive preneoplastic foci in a dose-responsive fashion. There was a significant increase in hepatic expression of heat shock proteins (HSP70 and HSP90), cyclooxygenase-2, and nuclear factor-κB (NF-κB) in DENA-exposed rat livers. Dietary BCSE dose-dependently abrogated all these elevated inflammatory markers. The possible cardiotoxicity of BCSE was assessed by monitoring cardiac functions using transthoracic echocardiography. BCSE-mediated anti-inflammatory effects during rat liver carcinogenesis have been achieved without any cardiotoxicity. Our results provide convincing evidence, for the very first time, that suppression of the inflammatory cascade through modulation of the NF-κB signaling pathway could be implicated, at least in part, in the chemopreventive effects of black currant bioactive phytoconstituents against experimental hepatocarcinogenesis. These results coupled with an excellent safety profile of BCSE support the development of black currant phytochemicals for the chemoprevention of inflammation-driven hepatocellular cancer.

 

Anthocyanin-rich black currant (Ribes nigrum L.) extract affords chemoprevention against diethylnitrosamine-induced hepatocellular carcinogenesis in rats.

Abstract

Anthocyanins are known to possess potent anticarcinogenic properties against several cancers thus demonstrating potential for cancer prevention. Black currant (Ribes nigrum L., Grossulariaceae) fruits have a high anthocyanin content. This “superfruit” is known to possess various pharmacological effects including alleviation of chronic oxidative stress and inflammation. In contrast to a large volume of literature on the health benefits of black currant, limited evidence on antitumor effects of black currant exists with virtually no data on the prevention of experimental carcinogenesis. In the current study, we have investigated the chemopreventive effects of an anthocyanin-rich black currant skin extract (BCSE) utilizing our well-characterized model of rat liver carcinogenesis. Initiation of hepatocarcinogenesis was done by intraperitoneal injection of diethylnitrosamine (DENA) followed by promotion with phenobarbital. The rats were exposed to dietary BCSE for 4 weeks prior to initiation, and the treatment was continued for 22 consecutive weeks. BCSE dose-dependently decreased the incidence, total number, multiplicity, size and volume of preneoplastic hepatic nodules. The antihepatocarcinogenic effect of BCSE was confirmed by histopathological examination of liver sections. Immunohistochemical analysis of proliferating cell nuclear antigen and DNA fragmentation revealed BCSE-mediated inhibition of abnormal cell proliferation and induction of apoptosis in DENA-induced rat liver tumorigenesis respectively. Mechanistic studies revealed that BCSE-mediated proapototic signal during experimental hepatocarcinogenesis may be propagated via the up-regulation of Bax and down-regulation of Bcl-2 expression at the translational level. These results along with a safety profile of BCSE encourage the development of black currant bioactive constituents as chemopreventive agents for human liver cancer.

 

Purified Anthocyanins from Bilberry and Black Currant Attenuate Hepatic Mitochondrial Dysfunction and Steatohepatitis in Mice with Methionine and Choline Deficiency

Abstract

Abstract Image

The berries of bilberry and black currant are a rich source of anthocyanins, which are thought to have favorable effects on nonalcoholic steatohepatitis (NASH). This study was designed to examine whether purified anthocyanins from bilberry and black currant are able to limit the disorders related to NASH induced by a methionine-choline-deficient (MCD) diet in mice. The results showed that treatment with anthocyanins not only alleviated inflammation, oxidative stress, steatosis, and even fibrosis but also improved depletion of mitochondrial content and damage of mitochondrial biogenesis and electron transfer chain developed concomitantly in the liver of mice fed the MCD diet. Furthermore, anthocyanins treatment promoted activation of AMP-activated protein kinase (AMPK) and expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α). These data provide evidence that anthocyanins possess significant protective effects against NASH and mitochondrial defects in response to a MCD diet, with a mechanism maybe through affecting the AMPK/PGC-1α signaling pathways.

SUMMARY

Black currants are an important fruit full of polyphenols, anthocyanins, antioxidants, and Nrf2 activators that help to make Ultimate Protector such an outstanding nutritional supplement.

 

 

Contact Us:

You can reach HPDI by calling 1-800-228-4265, email support(at)IntegratedHealth.com, or visit the retail website: www.IntegratedHealth.com

Health care professionals and retailers can apply for wholesale account, which includes access to the HPDI reseller website: www.HealthProductsDistributors.com

0

ULTIMATE PROTECTOR INGREDIENTS – WILD BILBERRY AND WILD BLUEBERRY

Dr. Hank Liers, PhD biography about us HPDI integratedhealth formulator founder CEO scientist physicist wild bilberry and wild blueberry

Ultimate Protector contains wild bilberry and wild blueberry, as well as components from 29 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 will explore the ingredients wild bilberry and wild blueberry, which are components of Anthocomplete™ and VitaBerry Plus® from Futureceuticals.

ANTHOCOMPLETE™

AnthoComplete™ (N669) is a specially designed blend of anthocyanins derived from wild bilberry and wild blueberry, acai, black currant extract, sweet cherry, raspberry, elderberry, blackberry, aronia, black soybean hull extract, and blue corn. Anthocyanins are powerful plant polyphenols associated with a variety of areas of human health, including healthy aging, healthy glucose metabolism, cardiovascular health, and inflammation management.

Carefully designed to maximize the amount of beneficial anthocyanins that can be available in a single source, AnthoComplete is a proprietary formula suitable for a wide-range of applications.

With its diverse blend, AnthoComplete contains a minimum level of 10% anthocyanins, 3,000 ORAC μmole TE/g (typical), and 15% total phenolics (typical).

Bilberry / Blueberry wild bilberry and wild bluebery

VITABERRY PLUS®

VitaBerry® (N1023) is the trade name for a line of high ORAC blends of fruit powders and fruit extracts, exclusively available through FutureCeuticals.

VitaBerry® is a proprietary formula that combines wild bilberry and wild blueberry, cranberry, raspberry, strawberry, prune, cherry, and grape whole powders and extracts into lines of custom blends. High in fruit polyphenols, anthocyanins, proanthocyanins, ellagic acid, chlorogenic acid, resveratrol, and quinic acid, VitaBerry offers 6,000 ORAC units in a single gram.

VitaBerry® Plus (N81.3) combines the standard blend of VitaBerry® with resveratrol and quercetin to deliver a minimum of 12,000 ORAC units per gram.

HEALTH BENEFITS OF WILD BILBERRY AND WILD BLUEBERRY

Bilberry is any of several Eurasian  species of low-growing shrubs in the genus Vaccinium, bearing edible, nearly black berries. The species most often referred to is Vaccinium myrtillus L., but there are several other closely related species. Bilberries are distinct from blueberries but closely related. Whereas the bilberry is native to Europe, the blueberry is native to North America.

The bilberry fruit is smaller than that of the blueberry, but with a fuller taste. Bilberries are darker in color, and usually appear near black with a slight shade of purple. While blueberry fruit pulp is light green in color, bilberry is red or purple, heavily staining the fingers, lips, and tongue of consumers eating the raw fruit. The color comes from diverse anthocyanins.

So-called wild (lowbush) blueberries, smaller than cultivated highbush ones, are prized for their intense color. “Wild” has been adopted as a marketing term for harvests of managed native stands of lowbush blueberries. The bushes are not planted or genetically manipulated, but they are pruned or burned every two years, and pests are “managed”. The content of polyphenols and anthocyanins in lowbush (wild) blueberries (V. angustifolium) exceeds values found in highbush cultivars.

wild bilberry and wild blueberry

Wild bilberry and wild blueberry (above) 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

Scientific Studies on the Antioxidant Effects of Wild Bilberry and Wild Blueberry

Databases of scientific studies (like the National Institutes of Health (NIH) PubMed database) contain thousands of up-to-date studies and abstracts about various Vaccinium species, including wild bilberry and wild blueberry (V. myrtillis and V. angustfolium, respectively).

We provide a few relevant scientific studies on the antioxidant effects of wild bilberry and wild blueberry.

In vitro anticancer activity of fruit extracts from Vaccinium species.

From: http://www.ncbi.nlm.nih.gov/pubmed/8693031

Abstract

Fruit extracts of four Vaccinium species (lowbush blueberry, bilberry, cranberry, and lingonberry) were screened for anticarcinogenic compounds by a combination of fractionation and in vitro testing of their ability to induce the Phase II xenobiotic detoxification enzyme quinone reductase (QR) and to inhibit the induction of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis, by the tumor promoter phorbol 12-myristate 13-acetate (TPA). The crude extracts, anthocyanin and proanthocyanidin fractions were not highly active in QR induction whereas the ethyl acetate extracts were active QR inducers. The concentrations required to double QR activity (designated CDqr) for the ethyl acetate extracts of lowbush blueberry, cranberry, lingonberry, and bilberry were 4.2, 3.7, 1.3, and 1.0 microgram tannic acid equivalents (TAE), respectively, Further fractionation of the bilberry ethyl acetate extract revealed that the majority of inducer potency was contained in a hexane/chloroform subfraction (CDqr = 0.07 microgram TAE). In contrast to their effects on QR, crude extracts of lowbush blueberry, cranberry, and lingonberry were active inhibitors of ODC activity. The concentrations of these crude extracts needed to inhibit ODC activity by 50% (designated IC50) were 8.0, 7.0, and 9.0 micrograms TAE, respectively. The greatest activity in these extracts appeared to be contained in the polymeric proanthocyanidin fractions of the lowbush blueberry, cranberry, and lingonberry fruits (IC50 = 3.0, 6.0, and 5.0 micrograms TAE, respectively). The anthocyanidin and ethyl acetate extracts of the four Vaccinium species were either inactive or relatively weak inhibitors of ODC activity. Thus, components of the hexane/chloroform fraction of bilberry and of the proanthocyanidin fraction of lowbush blueberry, cranberry, and lingonberry exhibit potential anticarcinogenic activity as evaluated by in vitro screening tests.

 

Bilberry (Vaccinium myrtillus) anthocyanins modulate heme oxygenase-1 and glutathione S-transferase-pi expression in ARPE-19 cells.

From: http://www.ncbi.nlm.nih.gov/pubmed/17460300

Abstract

PURPOSE: To determine whether anthocyanin-enriched bilberry extracts modulate pre- or posttranslational levels of oxidative stress defense enzymes heme-oxygenase (HO)-1 and glutathione S-transferase-pi (GST-pi) in cultured human retinal pigment epithelial (RPE) cells.

METHODS: Confluent ARPE-19 cells were preincubated with anthocyanin and nonanthocyanin phenolic fractions of a 25% enriched extract of bilberry (10(-6)-1.0 mg/mL) and, after phenolic removal, cells were oxidatively challenged with H(2)O(2). The concentration of intracellular glutathione was measured by HPLC and free radical production determined by the dichlorofluorescin diacetate assay. HO-1 and GST-pi protein and mRNA levels were determined by Western blot and RT-PCR, respectively.

RESULTS: Preincubation with bilberry extract ameliorated the intracellular increase of H(2)O(2)-induced free radicals in RPE, though H(2)O(2) cytotoxicity was not affected. By 4 hours, the extract had upregulated HO-1 and GST-pi protein by 2.8- and 2.5-fold, respectively, and mRNA by 5.5- and 7.1-fold, respectively, in a dose-dependent manner. Anthocyanin and nonanthocyanin phenolic fractions contributed similarly to mRNA upregulation.

CONCLUSIONS: Anthocyanins and other phenolics from bilberry upregulate the oxidative stress defense enzymes HO-1 and GST-pi in RPE, suggesting that they stimulate signal transduction pathways influencing genes controlled by the antioxidant response element.

 

Berry anthocyanins suppress the expression and secretion of proinflammatory mediators in macrophages by inhibiting nuclear translocation of NF-κB independent of NRF2-mediated mechanism.

From: http://www.ncbi.nlm.nih.gov/pubmed/24565673

Abstract

The objectives of this study were to compare the anti-inflammatory effects of anthocyanins from blueberry (BBA), blackberry (BKA), and blackcurrant (BCA) and to determine the relationship between their antioxidant capacity and anti-inflammatory effect in macrophages. Major anthocyanins in BBA, BKA and BCA were malvidin-3-glucoside (16%), cyanidin-3-glucoside (98%) and delphinidin-3-rutinoside (44%), respectively. BKA showed higher total antioxidant capacity than BBA and BCA. RAW 264.7 macrophages were incubated with 0-20 μg/ml of BBA, BKA and BCA, and subsequently activated by lipopolysaccharide (LPS) to measure proinflammatory cytokine production. Interleukin 1β (IL-1β) messenger RNA (mRNA) levels were significantly decreased by all berry anthocyanins at 10 μg/ml or higher. Tumor necrosis factor α (TNFα) mRNA levels and secretion were also significantly decreased in LPS-treated macrophages. The levels of the repression were comparable for all berry anthocyanins. LPS-induced nuclear factor κB (NF-κB) p65 translocation to the nucleus was markedly attenuated by all of the berry anthocyanins. In bone marrow-derived macrophages (BMMs) from nuclear factor E2-related factor 2 wild-type (Nrf2(+/+)) mice, BBA, BKA and BCA significantly decreased cellular reactive oxygen species (ROS) levels with a concomitant decrease in IL-1β mRNA levels upon LPS stimulation. However, in the BMM from Nrf2(-/-) mice, the anthocyanin fractions were able to significantly decrease IL-1β mRNA despite the fact that ROS levels were not significantly affected. In conclusion, BBA, BKA and BCA exert their anti-inflammatory effects in macrophages, at least in part, by inhibiting nuclear translocation of NF-κB independent of the NRF2-mediated pathways.

 

Purified Anthocyanins from Bilberry and Black Currant Attenuate Hepatic Mitochondrial Dysfunction and Steatohepatitis in Mice with Methionine and Choline Deficiency

From: http://pubs.acs.org/doi/abs/10.1021/jf504926n

Abstract

The berries of bilberry and black currant are rich source of anthocyanins, which are thought to have favorable effects on non-alcoholic steatohepatitis (NASH). This study was designed to examine whether purified anthocyanins from bilberry and black currant are able to limit the disorders related to NASH induced by a methionine-choline-deficient (MCD) diet in mice. The results showed that treatment with anthocyanins not only alleviated inflammation, oxidative stress, steatosis and even fibrosis, but also improved the depletion of mitochondrial content and damage of mitochondrial biogenesis and electron transfer chain developed concomitantly in the liver of mice fed the MCD diet. Furthermore, anthocyanins treatment promoted activation of AMP-activated protein kinase (AMPK) and expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α). These data provide evidence that anthocyanins possess significant protective effects against NASH and mitochondrial defects in response to a MCD diet, with mechanism maybe through affecting the AMPK/PGC-1α signaling pathways.

 

Effect of blueberry on hepatic and immunological functions in mice.

From: http://www.ncbi.nlm.nih.gov/pubmed/20382588

Abstract

Background: Conventional drugs used in the treatment and prevention of liver diseases often have side effects, therefore research into natural substances are of significance. This study examined the effects of blueberry on liver protection and cellular immune functions.

METHODS: To determine the effects of blueberry on liver protective function, male mice were orally administered blueberry (0.6 g/10 g) or normal saline for 21 days. Hepatic RNA was extracted by Trizol reagent, and the expression of Nrf2, HO-1, and Nqo1 was determined by real-time RT-PCR. Superoxide dismutase (SOD) and malondialdehyde (MDA) in liver homogenate were determined, and liver index was measured. To assess the effects of blueberry on cellular immune function, male mice received blueberry (0.4, 0.6, or 0.8 g/10 g) for 35 days, and the percentages of CD3+, CD4+, and CD8+ T lymphocyte subgroups in peripheral blood were detected by flow cytometry, the index of the thymus and spleen was measured, and lymphocyte proliferation in the spleen was determined by MTT assay.

RESULTS: Blueberry treatment significantly increased the expression of Nrf2, HO-1, and Nqo1, the important antioxidant components in the liver. Hepatic SOD in the blueberry group was higher and MDA was lower than that in the control group (P<0.05). Blueberry also increased the index of the spleen and enhanced the proliferation of lymphocytes of the spleen (P<0.05). The percentages of the CD3+ and CD4+ T lymphocyte subsets and the CD4+/CD8+ ratio were also increased by blueberry (P<0.05).

CONCLUSIONS: Blueberry induces expression of Nrf2, HO-1, and Nqo1, which can protect hepatocytes from oxidative stress. In addition, blueberry can modulate T-cell function in mice.

 

Anthocyanins: Janus Nutraceuticals Displaying Chemotherapeutic and Neuroprotective Properties

From: http://link.springer.com/chapter/10.1007/978-94-007-4575-9_21

Abstract

Anthocyanins are natural polyphenolic compounds widely distributed as pigments in many fruits and vegetables. In addition to displaying antioxidant properties, these nutraceuticals exhibit anti-inflammatory, anti-proliferative, and pro-apoptotic activities suggesting their potential as novel chemotherapeutic agents. Through cell cycle down-regulation, and context-specific pro-oxidant activity, anthocyanins induce cytotoxicity in cancer cells in vitro and in vivo. Specifically, via regulation of the Bcl-2 protein family and induction of caspase-dependent or caspase-independent apoptotic pathways, anthocyanins inhibit the growth of cancers by inducing cell death. Moreover, by modulating the activities of specific kinases and proteases, including (but not limited to) cyclin-dependent kinases, mitogen-activated protein kinases, matrix metalloproteases, and urokinase-type plasminogen activators, anthocyanins induce apoptosis, inhibit motility, and suppress invasion of cancer cells. In marked contrast to their effects in cancer cells, we have found that anthocyanins display significant anti-apoptotic activity in neurons. Antioxidant properties of these nutraceuticals, particularly at the level of the mitochondria, appear to underlie their neuroprotective effects. The opposing effects of anthocyanins on cancer cells and neurons suggest that these nutraceuticals are promising candidates for development as either chemotherapeutic agents or novel neuroprotective compounds for the treatment of cancers or neurodegenerative diseases, respectively.

Recent Research on Polyphenolics in Vision and Eye Health

From: http://pubs.acs.org/doi/abs/10.1021/jf903038r#end-1

Abstract

A long-standing yet controversial bioactivity attributed to polyphenols is their beneficial effects in vision. Although anecdotal case reports and in vitro research studies provide evidence for the visual benefits of anthocyanin-rich berries, rigorous clinical evidence of their benefits is still lacking. Recent in vitro studies demonstrate that anthocyanins and other flavonoids interact directly with rhodopsin and modulate visual pigment function. Additional in vitro studies show flavonoids protect a variety of retinal cell types from oxidative stress-induced cell death, a neuroprotective property of significance because the retina has the highest metabolic rate of any tissue and is particularly vulnerable to oxidative injury. However, more information is needed on the bioactivity of in vivo conjugates and the accumulation of flavonoids in ocular tissues. The direct and indirect costs of age-related vision impairment provide a powerful incentive to explore the potential for improved vision health through the intake of dietary polyphenolics.

 

Bilberry Extracts Induce Gene Expression Through the Electrophile Response Element

From: http://www.tandfonline.com/doi/abs/10.1207/s15327914nc5401_11#.VLK6LVqBO24

Abstract

A number of genes important for detoxification and antioxidant defense induced by mild stress generated by, for example, physical activity/exercise, caloric restriction, or alcohol may provide health benefits by causing the organism to mount such a defense response. More recently, induction of these defenses has also been attributed to phytochemicals or secondary metabolites from dietary plants. Many polyphenols, which constitute a large fraction of these phytochemicals, increase cellular levels of antioxidants, such as glutathione and other components of the detoxification systems, via the transactivation of genes containing electrophile response elements (EpREs) within their promoters. One such gene, γ-glutamylcysteine synthetase, has previously been shown to be positively regulated by quercetin, a flavonoid found in high concentrations in onions, apples, and bilberries through EpRE transactivation. As a further step, we have investigated whether bilberries and quercetin have the ability to induce transcription of Fos-related antigen 1 (Fra-1), which contains two EpREs in its promoter. Fra-1 is a member of the activator protein 1 (AP-1) family of transcription factors and, due to the lack of transactivation domain Fra-1, can suppress activation of AP-1. We present results demonstrating that extracts from bilberries, and the flavonoid quercetin, abundant in bilberries, induce the fra-1 promoter and the cellular content of Fra-1 mRNA. We further provide evidence that this induction is mediated through EpREs.

 

Bilberry (Vaccinium myrtillus)

From: http://www.sigmaaldrich.com/life-science/nutrition-research/learning-center/plant-profiler/vaccinium-myrtillus.html

Synonyms / Common Names / Related Terms
Airelle, anthocyanins, Bickbeere (German), bilberry leaf, black whortle, Blaubeere (Dutch), blaubessen, bleaberry, blueberry, blueberry leaf, bogberry, bog bilberry, burren myrtle, cranberry, dwarf bilberry, dyeberry, Ericaceae (family), European blueberry, Heidelbeere (Dutch), Heidelbeereblatter, heidelberry, huckleberry, hurtleberry, lingonberry, lowbush blueberry, Mirtillo nero (Italian), Myrtilli folium, Myrtilli fructus, Myrtilus niger Gilib., Optiberry, resveratrol, sambubiosides, trackleberry, Vaccinium angulosum Dulac, Vaccinium montanum Salibs., Vaccinium myrtillus anthocyanoside extract, VMA extract, VME, whortleberry, wineberry
Mechanism of Action

Pharmacology:

  • Constituents: Bilberry contains several compounds that have demonstrated biological activity. The main chemicals contained in bilberry extract have been shown to be: anthocyanins30,31, flavonoids, hydroquinone, oleanolic acid, neomyrtillin, sodium, tannins, and ursolic acid17,20,32,33,34. Bilberry also contains resveratrol.28,29 The anthocyanosides, tannins, and flavonoids have been of particular scientific interest. Flavonoids have been shown in vitro to possess a number of biological properties, including inhibition of prostacyclin synthesis, reduction of capillary permeability and fragility, free radical scavenging, inhibition of a wide range of enzymes, impairment of coagulation and platelet aggregation, and anticarcinogenicity.33,5
  • Mechanism of action: Anthocyanins and other phenolics from bilberry upregulate the oxidative stress defense enzymes heme-oxygenase-1 and glutathione S-transferase-pin cultured human retinal pigment epithelial cells, suggesting that they stimulate signal transduction pathways, influencing genes controlled by the antioxidant response element.30
  • Antibacterial effects: In an in vitro study using Staphylococcus aureus, Staphylococcus aureus Oxford, Enterococcus faecalisBacillus subtilis, and Escherichia coli, an aqueous extract of bilberry leaves had a MIC of 12.7-17.8mg/mL and an aqueous extract of bilberry fruit had a MIC of 15.4-30.7mg/mL.24
  • Anticarcinogenic effects: In an in vitro study, anthocyanin-rich extracts from bilberry (Vaccinium myrtillus L.) inhibited the growth of a colon cancer cell line.6
  • Bomser et al. screened fruit extracts of bilberry for potential anticarcinogenic compounds by a combination of fractionation and in vitro testing of their ability to induce the Phase 2 xenobiotic detoxification enzyme quinone reductase (QR) and to inhibit the induction of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis, by the tumor promoter phorbol 12-myristate 13-acetate (TPA).5 The crude extracts, anthocyanin, and proanthocyanidin fractions were not found to be highly active in Phase 2 xenobiotic detoxification enzyme quinone reductase (QR) induction, whereas the ethyl acetate extracts were active QR inducers. The concentrations required to double QR activity (designated CDqr) for the ethyl acetate extracts of bilberry were 1.0mcg tannic acid equivalents (TAE). Further fractionation of the bilberry ethyl acetate extract revealed that the majority of inducer potency was contained in a hexane/chloroform subfraction (CDqr = 0.07mcg TAE). The anthocyanidin and ethyl acetate extracts of bilberry were either inactive or relatively weak inhibitors of ornithine decarboxylase (ODC) activity. The authors concluded that components of the hexane/chloroform fraction of bilberry exhibit potential anticarcinogenic activity, as evaluated by in vitro screening tests.
  • Antihyperglycemic effects: In normal and depancreatized dogs, oral administration of bilberry leaves reduced hyperglycemia, even when the glucose was injected intravenously concurrently.15,16
  • Antioxidant effects: Bilberry contains anthocyanosides that are flavonoid derivatives of anthocyanins (the blue, red, or violet pigments found in many berry varieties), which are closely related in structure and activity to flavonoids17 and possess free radical scavenging/antioxidant properties. Antioxidant properties have been attributed to bilberry based on in vitro studies.1,2,34
  • Antiplatelet activity: In a clinical study of 30 subjects with normal platelet aggregation, 480mg of Myrtocyan® (Vaccinium myrtillus anthocyanins) daily, 3g of ascorbic acid daily, or both treatments all reduced platelet aggregation after 30 and 60 days.11 Bilberry anthocyanins reduced platelet aggregation more than ascorbic acid alone, but bilberry anthocyanins and ascorbic acid together were the most effective. Also, in in vitro studies, anthocyanins extracted from bilberry have inhibited platelet aggregation.13,14,10,12
  • Flavonoids have been shown in vitro to inhibit prostacyclin synthesis. In one animal model, Vaccinium myrtillus anthocyanosides were studied for their effects on prostacyclin-like activity in rat arterial issue.7
  • Antiproliferative effects: According to one laboratory study, anthocyanins were the predominant phenolic compounds in bilberry extracts.31 Compared to other plants with anthocyanins, such as black currant or lingonberry, cell growth inhibition was greater for bilberry than other plants studied. The pro-apoptosis marker, Bax, was increased 1.3-fold in bilberry-treated cells, whereas the pro-survival marker, Bcl-2, was detected only in control cells. The results demonstrated that bilberry and other berry extracts containing anthocyanins inhibited cancer cell proliferation, mainly via the p21WAF1 pathway.
  • Antiulcer effects: In an animal study, large doses of cyanidin chloride from bilberry significantly increased gastric mucosal release of prostaglandin E2.19 In animal models of gastric ulcers, cyanidin chloride showed antiulcer activity.26,8
  • Astringent effects: Bilberry contains tannins that have been used medicinally as astringents and to treat diarrhea.
  • Connective tissue stabilizing effects: An in vitro study has suggested that anthocyanosides appear to stabilize connective tissue by enhancing collagen synthesis, inhibiting collagen degradation, and enhancing collagen cross linking.35 In contrast, Boniface et al. found a significant decrease in connective tissue synthesis (collagen and glycoproteins) in gingival tissue samples of 12 adult diabetics treated with 600mg of anthocyanosides daily for two months.36
  • Hepatoprotective activity: In an animal study, anthocyans exerted a protective effect on liver cells.27
  • Hyperglycemic effects: In an oral glucose tolerance test in healthy rats, an alcoholic extract of Vaccinium myrtillus leaves increased serum glucose levels compared to controls.25
  • Hypotensive effects: Bilberry has been theorized to potentially drop blood pressure, based on pre-clinical evidence of vascular smooth muscle-relaxing properties.21,22,23
  • Anthocyanoside extracts have been shown to have smooth muscle-relaxing activity, which may account for their purported effects in one series of women with dysmenorrhea.18 Bioflavonoids and extracts of anthocyanosides (such as those present in bilberry) have been shown to relax vascular smooth muscles in experimental models, possibly via stimulation of prostaglandins.21,22,23
  • Intracellular signaling effects: Anthocyanosides have been shown to inhibit cAMP phosphodiesterase, which is involved in intracellular signal transduction pathways.8
  • Ocular effects: Anthocyanosides have been shown to exert direct effects on the retina, including the alteration of local enzymatic reactions and enhancement of the recovery of rhodopsin.9 The multi-ingredient product Mirtogenol (Pycnogenol® – French maritime pine bark extract and Mirtoselect® – standardized bilberry extract) has been reported to lower intraocular pressure and improve ocular blood flow.37
  • Smooth muscle relaxant effects: Anthocyanoside extracts have been shown to have smooth muscle-relaxing activity, which may account for their purported effects in one series of women with dysmenorrhea.18 Bioflavonoids and extracts of anthocyanosides (such as those present in bilberry) have been shown to relax vascular smooth muscles in experimental models, possibly via stimulation of prostaglandins.21,22,23
  • Vasoprotective effects: Flavonoids have been shown in vitro to reduce capillary permeability and fragility. Anthocyanosides have been studied for their potential protective effect in disorders due to abnormal capillary fragility.33

Pharmacodynamics/Kinetics:

  • There are limited data regarding the pharmacodynamics and kinetics of Vaccinium myrtillus (bilberry) anthocyanosides (VMA). In one animal study, bilberry anthocyanosides were rapidly distributed after intra-peritoneal injection and intravenous administration.38 In another animal study, bilberry anthocyanosides were found to be eliminated via the bile and urine with a modest level of liver extraction.32
  • Bioavailability in animals is low. Following oral doses in rats, plasma levels of VMA reached a peak at 15 minutes and declined rapidly within two hours, and the absolute bioavailability was 1.2% of the administered dose.38 The gastrointestinal absorption of VMA was 5% of the administered dose. Another study found a differential affinity of VMA for certain tissues (especially skin and kidney).20 This suggests that different tissues may have more persistent local concentrations.
References:

  1. Martin-Aragon S, Basabe B, Benedi JM, and et all. In vitro and in vivo antioxidant properties of Vaccinium myrtillus. Pharmaceutical Biology 1999;37(2):109-113.
  2. Prior R, Cao G, Martin A, and et all. Antioxidant capacity as influence by total phenolic and anthocyanin content, maturity, and variety of Vaccinium species. J Agricult Food Chem 1998;46:2686-2693.
  3. Martin-Aragon S, Basabe B, Benedi J, and et all. Antioxidant action of Vaccinium myrtillus L. Phytotherapy 1998;46:S104-S106.
  4. Laplaud, P. M., Lelubre, A., and Chapman, M. J. Antioxidant action of Vaccinium myrtillus extract on human low density lipoproteins in vitro: initial observations. Fundam Clin Pharmacol 1997;11(1):35-40. 9182074
  5. Bomser, J., Madhavi, D. L., Singletary, K., and Smith, M. A. In vitro anticancer activity of fruit extracts from Vaccinium species. Planta Med 1996;62(3):212-216.
  6. Zhao, C., Giusti, M. M., Malik, M., Moyer, M. P., and Magnuson, B. A. Effects of commercial anthocyanin-rich extracts on colonic cancer and nontumorigenic colonic cell growth. J Agric Food Chem  10-6-2004;52(20):6122-6128. 15453676
  7. Morazzoni P and Magistretti MJ. Effects of Vaccinium myrtillus anthocyanosides on prostacyclin-like activity in rat arterial issue. Fitoterapia 1986;57:11-14.
  8. Magistretti, M. J., Conti, M., and Cristoni, A. Antiulcer activity of an anthocyanidin from Vaccinium myrtillus. Arzneimittelforschung  1988;38(5):686-690. 3415709
  9. Cluzel, C., Bastide, P., Wegman, R., and Tronche, P. [Enzymatic activities of retina and anthocyanoside extracts of Vaccinium myrtillus (lactate dehydrogenase, alpha-hydroxybutyrate dehydrogenase, 6-phosphogluconate dehydrogenase, glucose-6-phosphate dehydrogenase, alpha-glycerophosphate dehydrogenase, 5-nucleotidase, phosphoglucose isomerase)]. Biochem Pharmacol 1970;19(7):2295-2302. 4329039
  10. Morazzoni P and Bombardelli E. Vaccinium myrtillus L. Fitoterapia 1996;66:3-29.
  11. Pulliero G, Montin S, Bettini V, and et al. Ex vivo study of the inhibitory effects of Vaccinium myrtillus anthocyanosides on human platelet aggregation. Fitoterapia 1989;60:69-75.
  12. Bottecchia D. Preliminary report on the inhibitory effect of vaccinium myrtillus anthocyanosides on platelet aggregation and clot retraction. Fitoterapia 1987;48:3-8.
  13. Zaragoza, F., Iglesias, I., and Benedi, J. [Comparative study of the anti-aggregation effects of anthocyanosides and other agents]. Arch Farmacol Toxicol 1985;11(3):183-188. 4096552
  14. Fdez, M., Zaragoza, F., and Alvarez, P. In vitro platelet aggregation effects of anthocyanosides of vaccinium myrtilus L. Anales de la Real Academia de Farmacia 1983;49:79-90.
  15. Bever B. Plants with oral hypoglycemic action. Q J Crude Drugs Res 1979;17:139-196.
  16. Allen, F. M. Blueberry leaf extract: Physiologic and clinical properties in relation to carbohydrate metabolism. 89:1577-81, 1927. JAMA 1927;89:1577-1581.
  17. Havsteen, B. Flavonoids, a class of natural products of high pharmacological potency. Biochem Pharmacol 4-1-1983;32(7):1141-1148. 6342623
  18. Colombo D and Vescovini R. Controlled clinical trial of anthocyanosides from Vaccinium myrtillus in primary dysmenorrhea. G Ital Obstet Ginecol 1985;7:1033-1038.
  19. Mertz-Nielsen, A., Munck, L. K., Bukhave, K., and Rask-Madsen, J. A natural flavonoid, IdB 1027, increases gastric luminal release of prostaglandin E2 in healthy subjects. Ital J Gastroenterol  1990;22(5):288-290. 2134327
  20. Lietti, A., Cristoni, A., and Picci, M. Studies on Vaccinium myrtillus anthocyanosides. I. Vasoprotective and antiinflammatory activity. Arzneimittelforschung 1976;26(5):829-832. 9100
  21. Colantuoni, A., Bertuglia, S., Magistretti, M. J., and Donato, L. Effects of Vaccinium Myrtillus anthocyanosides on arterial vasomotion. Arzneimittelforschung  1991;41(9):905-909. 1796918
  22. Bettini V. Effects of Vaccinium myrtillus anthocyanosides on vascular smooth muscle. Fitoterapia 1984;55(5):265-272.
  23. Bettini V, Mayellaro F, Ton P, and et al. Interactions between Vaccinium myrtillusanthocyanosides and serotonin on splenic artery smooth muscle. Fitoterapia 1984;55(4):201-208.
  24. Brantner, A. and Grein, E. Antibacterial activity of plant extracts used externally in traditional medicine. J Ethnopharmacol 1994;44(1):35-40. 7990502
  25. Neef H, Declercq P, and Laekeman G. Hypoglycaemic activity of selected European plants. Phytotherapy Research 1995;9:45-48.
  26. Cristoni, A. and Magistretti, M. J. Antiulcer and healing activity of Vaccinium myrtillus anthocyanosides. Farmaco [Prat] 1987;42(2):29-43. 3582621
  27. Mitcheva, M., Astroug, H., Drenska, D., Popov, A., and Kassarova, M. Biochemical and morphological studies on the effects of anthocyans and vitamin E on carbon tetrachloride induced liver injury. Cell Microbiol 1993;39(4):443-448. 8329983
  28. Lyons, M. M., Yu, C., Toma, R. B., Cho, S. Y., Reiboldt, W., Lee, J., and van Breemen, R. B. Resveratrol in raw and baked blueberries and bilberries. J Agric Food Chem  9-24-2003;51(20):5867-5870. 13129286
  29. Rimando, A. M., Kalt, W., Magee, J. B., Dewey, J., and Ballington, J. R. Resveratrol, pterostilbene, and piceatannol in vaccinium berries. J Agric Food Chem 7-28-2004;52(15):4713-4719. 15264904
  30. Milbury, P. E., Graf, B., Curran-Celentano, J. M., and Blumberg, J. B. Bilberry (Vaccinium myrtillus) anthocyanins modulate heme oxygenase-1 and glutathione S-transferase-pi expression in ARPE-19 cells. Invest Ophthalmol Vis Sci 2007;48(5):2343-2349. 17460300
  31. Wu, Q. K., Koponen, J. M., Mykkanen, H. M., and Torronen, A. R. Berry phenolic extracts modulate the expression of p21(WAF1) and Bax but not Bcl-2 in HT-29 colon cancer cells. J Agric Food Chem 2-21-2007;55(4):1156-1163. 17243699
  32. Lietti, A. and Forni, G. Studies on Vaccinium myrtillus anthocyanosides. II. Aspects of anthocyanins pharmacokinetics in the rat. Arzneimittelforschung  1976;26(5):832-835. 989354
  33. Mian E. Anthocyanosides and microvessel walls: new findings on the mechanism of action of their protective effect in syndromes due to abnormal capillary fragility. Minerva Med 1977;68(52):3565-3581.
  34. Marcollet M, Bastide P, and Tronche P. Effet angio-protecteur des anthocyanosides de Vaccinium myrtillus odjective vis a vis de la liberation de la lactate deshydrogenase (LDH) et de ses isoenzymes cardiaques chez le rat soumis a une epreuve de nage. C R Soc Biol  1970;163:1786.
  35. Jonadet, M., Meunier, M. T., Bastide, J., and Bastide, P. [Anthocyanosides extracted from Vitis vinifera, Vaccinium myrtillus and Pinus maritimus. I. Elastase-inhibiting activities in vitro. II. Compared angioprotective activities in vivo]. J Pharm Belg 1983;38(1):41-46. 6553084
  36. Boniface, R. and Robert, A. M. [Effect of anthocyanins on human connective tissue metabolism in the human]. Klin Monatsbl Augenheilkd  1996;209(6):368-372. 9091714
  37. Steigerwalt, R. D., Gianni, B., Paolo, M., Bombardelli, E., Burki, C., and Schonlau, F. Effects of Mirtogenol on ocular blood flow and intraocular hypertension in asymptomatic subjects. Mol Vis  2008;14:1288-1292. 18618008
  38. Morazzoni, P., Livio, S., Scilingo, A., and Malandrino, S. Vaccinium myrtillus anthocyanosides pharmacokinetics in rats. Arzneimittelforschung  1991;41(2):128-131. 2043174

SUMMARY

Wild bilberries and wild blueberries are important fruits full of polyphenols, anthocyanins, antioxidants, and Nrf2 activators that help to make Ultimate Protector such an outstanding nutritional supplement.

 

up-4 elderberry wild bilberry and wild blueberry

Ultimate Protector provides wild bilberry and wild blueberry, and 27 other Nrf2 activator-containing plant-based ingredients.

ADDITIONAL RESOURCES