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KIDS VITAMINS – NO KIDDING!

Fred Liers PhD kids mighty multi multivitamin chewableLooking for a high-quality, natural KIDS MULTIVITAMIN? Me, too. Do you look in vitamin stores, natural foods stores, and online marketplaces—in vain? I have.

A couple years ago, HPDI’s formulator, my father Hank Liers, PhD decided to reformulate our already excellent kids multivitamin—the Kids Mighty-Multi!—to make it better. His intentions were good: the world’s best designer of adult multivitamins would improve the best children’s vitamin.

My quandary? While Dr. Hank was busy at work reformulating our kids multi, the existing—and uber-excellent—original Kids Mighty-Multi! went out-of-stock, and never came back. Suddenly, my seven-year-old son’s “go-to” multivitamin was gone…indefinitely!

I took action—kids vitamins became my obsession—because I wanted the best multivitamin for my child. I searched everywhere for high-quality kids vitamins. Leaving no stone unturned, we tried them all—including organic, whole food, gluten-free, vegan-friendly brands with glossy labels. Did we find good ones? Not really.

What DID we find? Well, not much—and a lot. That is, not much in the way of high potency, high-purity, or advanced forms, like coenzyme vitamins. And a lot of false promises and junk ingredients. Like sugar and corn syrup and GMO ingredients—even from “reputable” brands.

Not to mention artificial sweeteners, colorings, flavorings, as well as toxic preservatives and fillers, which are the de facto standard in conventional products. Natural products are better—not always by as much as you’d expect.

chewable kids mighty-Multi! multivitamin

Looking for a good children’s multivitamin? Look no further than chewable Kids Mighty-Multi!

MY MULTIVITAMIN WISHLIST

Now in label-induced miasmic SHOCK…I proposed a reversal of terms. I simply wanted a lot of good things—like complete, balanced nutrients—and not much in the way of toxic additives.

Reeling, I scrawled a brief manifesto or “wishlist” for my ideal kids multivitamin:

“Great taste, high-purity, balanced nutrients at optimal levels, chewable; sugar free, non-GMO. No artificial ingredients, especially toxic sweeteners like aspartame or sucralose. No harmful additives or preservatives like sodium benzoate, BHT, or propylene glycol (no antifreeze please!); a few good-for-you functional ingredients.”

Was I asking *too* much? No way. Yet, I was giving up on finding a suitable kids multivitamin. My son instead began taking an HPDI adult multivitamin (Multi Two Caps) we scaled to his sixty five-pound weight. The taste wasn’t great—so we opened capsules directly into his juices and smoothies—because he’s not ready to swallow capsules or tablets whole. At best…a partial solution.

KIDS MIGHTY-MULTI! BACK — BETTER THAN EVER!

Then. It. Happened. Lighting struck—HPDI’s Kids Mighty-Multi! is BACK! Turns out my dad finished reformulating the world’s best kids multivitamin. He broke the news with a smile. Stunned and unbelieving…I took a breath. My heart skipped a beat. Then I grabbed a bottle!

Who knew it would take two years?—and now, who cares!? This month, HPDI proudly introduces a *new* Kids Mighty Multi!. Worth the wait? Yes. Because the new version is better than ever.

I’ve thrown away my wishlist. My search is over. Yours may be, too. Because no kids multivitamin comes *close* to Kids Mighty-Multi!. See the comparison chart and nutrient table (below).

A SERIOUS VITAMIN FOR KIDS – FINALLY!

What makes the new Kids Mighty-Multi! so good, and so much better? Let me count the ways. Here is a summary of benefits before I dive into discussing them in greater detail.

• Kids and adults love the taste!

• Full-spectrum of balanced, essential nutrients needed for creating, supporting, and maintaining excellent health for your child. Includes natural coenzyme form vitamins and Krebs’ cycle bionutrients that work with young bodies to provide energy for metabolic processes, healing, and optimal health.

• Bioavailable vitamin and mineral carriers the body recognizes and can assimilate rapidly. Plus, multiple carriers of individual nutrients ensure assimilation. Chewable form speeds uptake in the body.

Variety of well-known herbal ingredients, including quercetin, grape extract, turmeric, broccoli powder, and octacosanol

Complete, balanced supply of carotenoids, including beta-carotene, lycopene, and lutein

Functional ingredients built into every aspect of the formula, including the taste-enhancing package, herbal ingredients, and cofactors. Functional ingredients serve multiple purposes in supporting health.

• Flavored using only healthy, natural sweeteners and taste enhancers, including mannitol, fructooligosaccharides (FOS) (from chicory root), organic beet root powder, natural fruit flavor, xylitol, and stevia leaf extract. Taste enhancers exhibiting additional positive benefits (i.e., prebiotic effects, cavity prevention, and antioxidant action).

• NO refined sugars, no corn syrup, and…NO GMOs!

• NO artificial colorings or flavorings, artificial sweeteners (like aspartame, saccharin, or sucralose), or hydrogenated vegetable oils

• Excludes common food source allergens like wheat, corn, soy, and dairy

• Excludes unnecessary excipients, including fillers, binders, and additives

• Foundational formula ideal for providing basic nutrients for health. A high-quality multivitamin is the first step toward a complete nutritional supplement regimen. Formulated to work well with other HPDI foundational formulas, such as vitamin C / antioxidant formulas (like PRO-C™) and essential fatty acids (like Essential Fats plus E).

Kids Multivitamin comparison chart

TASTE-ENHANCING COMPLEX: FUNCTIONAL INGREDIENTS

Kids Mighty-Multi! tastes GREAT! Kids and adults LOVE the taste. From the perspective of your child’s taste buds, that’s *all* that matters.

But I want to talk a bit about the importance of healthy sweeteners…and how the best sweeteners perform double duty as health promoters.

WHY does Kids Mighty-Multi! taste so good? (Did I mention it contains NO refined sugars—or any artificial sweeteners or flavorings?)

Because Dr. Liers created a natural taste-enhancing complex. This taste-enhancing package includes xylitol, mannitol, FOS (fructooligosaccharides), beet root juice powder, natural fruit flavors, and stevia leaf extract.

Dr. Hank selected healthy, functional ingredients—as much as possible—in order to enhance the taste. That means these taste enhancers are not only NOT unhealthy like the refined sugars, corn syrups, and artificial sweeteners I found in so many other kids vitamins. But they are GOOD for you!

Functional sweeteners and taste-enhancing ingredients in Kids Mighty-Multi! include:

Xylitol – Proven sweetener that is a polyol (sugar alcohol) known to fight cavities, improve bone health, and more! (see: http://xylitol.org/about-xylitol/)

Mannitol – Natural polyol sweetener with added benefits as an antioxidant. Mannitol surprisingly has a very powerful effect on the hydroxyl free-radical. (see: https://www.ncbi.nlm.nih.gov/pubmed/9090754). Mannitol serves double duty as a healthy sweetener and important hydroxyl radical free-radical trapper.

• Fructooligosaccharides (FOS) (from chicory root) – Naturally sweet with no or low glycemic index. It is also a prebiotic that supports the growth of beneficial bacteria.

• Beet Root Powder (organic) – Naturally sweetens and colors Kids Mighty-Multi!. Beet is a functional ingredient providing methyl donors and easily assimilable iron. Moreover, Dr. Benjamin S. Frank found beets contain an amino acid the body uses to create its own dietary nucleic acids and a nutrient important to brain function (No-Aging Diet, 81).

• Berry & Fruit Extracts / Flavors – Mixed berry, strawberry, raspberry, and pomegranate. These berry extracts provide extremely good, fruity taste—bursting with berry flavors!

• Stevia Extract – Natural sweetens with little or no glycemic value. Kids Mighty-Multi! contains a newer, improved stevia extract which is de-bittered

• Malic Acid – Provides a naturally tart taste, supports the utilization of magnesium, and feeds into the Krebs’ cycle that makes cellular energy (ATP)

Why is choosing “good-for-you” functional sweeteners and taste enhancers important?

Because despite what adults might wish, sweeteners still comprise the largest percentage of kids multivitamins by weight. That means your child will be ingesting significant amounts (of whatever these sweeteners are) relative to the size of their multivitamin.

Who wants the bulk of their child’s multivitamin intake comprised of sugars, corn syrup, sucralose, or worse (think aspartame)? This is the reason natural sweeteners providing functional benefits make all the difference for health.

COMPLETENESS MATTERS – A LOT!

Kids Mighty-Multi! is nothing if not complete. As formulated by Dr. Hank Liers, it provides therapeutic levels of all essential vitamins, minerals, cofactors, and much more.

If you read labels (like I do), you’ll see most kids vitamins are “hit-or-miss.” They provide certain nutrients, but often completely miss others—usually with no rhyme or reason. (What was its formulator thinking?)

Missing important nutrients is bad for consumers—like you and your child—because all nutrients require other nutrients to “do a body good.” It’s called synergy, and it’s the way our cells are designed to work.

That means if you obtain sufficient amounts of a specific nutrient, but not enough of another, you may be unable to effectively utilize the nutrient you have—because utilization requires the nutrient you *don’t* have. Catch-22, huh? I’ll talk more about this later.

Do your child—and yourself—a favor: choose a complete multivitamin like Kids Mighty-Multi!.

kids mighty multi multivitamin

Kids Mighty-Multi! is nothing if not COMPLETE. (Tablets in photo appear larger than actual size.)

ADVANCED FORMS OF NUTRIENTS…LIKE YOU’VE NEVER SEEN

Then, there are advanced forms of nutrients, like coenzyme B vitamins. Most kids vitamins (and adult multivitamins) offer you the B complex vitamins as synthetic forms. How can you tell? Well, coenzyme vitamin B1 in Kids Mighty-Multi! is from Thiamin Diphosphate and is very different from synthetic “thiamine HCl.” Vitamin B2 is from Riboflavin-5′-Phosphate is not synthetic “riboflavin.” The vitamin B6 is from Pyridoxal-5′-Phosphate is not “pyridoxine HCl.” And so on.

What about vitamin B12 as toxic “cyanocobalamin”? Never. Kids Mighty-Multi! provides coenzyme B12 as methylcobalamin. Other brands sometimes use this form, but then provide synthetic forms for other B vitamins. That makes sense—NOT.

Sure, coenzyme B vitamins cost more to source. But the truth is, your body requires far less coenzyme form vitamins because they are the natural forms found in foods—you easily assimilate and utilize them. Kids Mighty-Multi! doesn’t need large amounts of coenzyme vitamins to give you big benefits.

Meanwhile, synthetic forms are not as easily assimilated—most go through a complex enzymatic breakdown before the body can use them. In some cases (for example if your child lacks certain enzymes due to genetics), syntethic forms cannot be broken down—or used—at all!

Case in point: Folate. Most kids vitamins give you “folic acid,” which is synthetic vitamin B1. A large percentage of the population (including me) lacks the gene providing the enzyme required to process folic acid. If folic acid builds up in cells (because it can’t be broken down), then it can be toxic. Solution: we use coenzyme folate—or 5-MTHF (5-methyl tetrahydrofolate) in Kids Mighty-Multi!. Problem solved.

Recall I said Kids Mighty-Multi! is complete?—and the importance of completeness in a multivitamin? Well, for example, if your kids’ multivitamin only provides synthetic vitamin B6 (as Pyridoxine HCl), it won’t be convertable into its biologically active (coenzyme) form without coenzyme vitamin B1 (Riboflavin-5′-Phosphate).

Did you catch that? To convert Pyridoxine HCl (synthetic vitamin B6) to its usable coenzyme form Pyridoxal-5′-Phosphate, you need coenzyme Riboflavin (Riboflavin-5′-Phosphate). You need a coenzyme form of one B vitamin in order to convert another B vitamin to its coenzyme form!

If you have only synthetic forms of these B vitamins, your body must go through multiple conversion processes in order to first convert synthetic Riboflavin into coenzyme Riboflavin so that you can convert synthetic vitamin B6 (Pyridoxine HCl) into its coenzyme B6 form (Pyridoxal-5′-Phosphate).

Yes, you can *survive* on synthetic forms of B vitamins. But why make your body work so hard? Why survive when you can *thrive* (with coenzyme vitamins)?

Why other kids vitamins don’t include coenzyme forms is BEYOND ME. If other brands go with conventional (and sometimes toxic) synthetic forms, so be it. Run, and go with Kids Mighty-Multi!.

Other advanced forms include vitamin D as D3 (cholecalciferol), vitamin K as K1 and K2 (Menaquinone-7), and minerals using Krebs’ cycle carriers (like citrates, malates, fumarates, succinates, and aspartates) that are best recognized and utilized in the body because they plug into the body’s energy (ATP) production system.

KIDS MIGHTY-MULTI!™ NUTRIENT TABLE

NUTRIENT

AMOUNT

% Daily Value

Vitamin A
(as beta-carotene from Dunaliella salinas)
470 IU 10
Vitamin C
(from potassium, magnesium, and calcium ascorbates)
16 mg 27
Vitamin D3 (as cholecalciferol) 50 IU 13
Vitamin E (from d-alpha tocopheryl succinate and 5 mg natural mixed tocopherols) 13 IU 42
Vitamin K (10 mcg as phylloquinone (K1) and 5 mcg as MK-7 (K2)) 15 mcg 18
Vitamin B1 (from thiamin diphosphate) 1.6 mg 107
Vitamin B2 (from riboflavin-5′-phosphate) 1.6 mg 94
Vitamin B3 (80% from niacinamide and 20% from niacin) 12 mg 60
Pantothenic Acid (from calcium pantothenate) 5 mg 50
Vitamin B6 (from pyridoxal-5′-phosphate) 2.5 mg 125
Vitamin B12 (as methylcobalamin) 15 mcg 250
Folate (from 5-MTHF – Quatrefolic®†) 50 mcg 13
Biotin (pure crystalline) 30 mcg 10
Magnesium (from malate) 6 mg 1.5
Calcium (from Krebs cycle bionutrients) 6 mg 0.6
Potassium (from citrate) 4.7 mg <1
Zinc (from citrate) 1.25 mg 8.3
Iron (from fumarate) 0.3 mg 1.7
Manganese (from citrate) 0.3 mg 15
Copper (from aspartate) 0.125 mg 6.3
Chromium (from polynicotinate) 13 mcg 11
Molybdenum (from citrate) 6 mcg 8
Selenium (from l-selenomethionine) 5 mcg 7
Choline (from bitartrate) 6 mg *
Inositol (pure crystalline) 15 mg *
N-Acetyl-L-Cysteine (NAC) 5 mg *
L-Taurine 5 mg *
Betaine HCl 3 mg *
Quercetin (as dihydrate) 3 mg *
Turmeric (from Curcuma longa) (root) 3 mg *
Broccoli Sprouts Powder 2 mg *
Grape Extract (Vitis vinifera) (from seed, skin, and stem) 1 mg *
Lycopene (tomato extract) (fruit) 200 mcg *
Boron (from glycinate and aspartate) 125 mcg *
Lutein (from Calendula officinalis) (flower) 70 mcg *
Octacosanol (from policosanol) 15 mcg *
Vanadium (from BGOV – bis glycinato oxo vanadium) 6 mcg *

* No established Daily Value
† Quatrefolic® is a registered trademark of Gnosis SPD

SCALABLE DOSING – CALLING ALL KIDS – AND ADULTS!

Maybe the best feature of Kids Mighty-Multi! is scalable dosing. Scalability makes it suitable for children and youth of all sizes—and adults, too!

Glancing at Kids Mighty-Multi!‘s label, you might assume it’s as low potency as the most kids’ vitamins available in stores. Not so fast.

Because Dr. Hank designed this multivitamin for everyone, including adults. How do I know? Because he told me: he takes these chewables himself!

How does it work? You simply take two (2) tablets per 20 pounds of body weight—up to six tablets—for kids. But since most older kids and adults weigh more than 60 pounds, you can take 8–10+ tablets and approximate the nutrition you would get from your regular adult vitamin. How cool is that!

Scalable dosing works well for people who don’t like swallowing capsules or tablets, or who prefer a good-tasting chewable. And who doesn’t, sometimes? It is especially useful for traveling because the entire family can use it.

In my case, I usually take four capsules per day of Hank & Brian’s Mighty Multi-Vite! , which my favorite adult multivitamin, and the inspiration for creating the Kids Mighty-Multi!. Yet, there are many days when I thrill to the taste of the new chewable kids multivitamin—knowing I get a significant amount of nutritional value. That means a lot. A lot of goodness. And not much to worry about.

Chewable Kids Mighty-Multi! multivitamin

Dr. Hank Liers pulled out the stops in formulating Kids Mighty-Multi!

CHOOSE KIDS MIGHTY-MULTI!

You’ve got choices. You can go online or to your local natural market, pharmacy, or big box store and fill up on whatever kids vitamins you find. Take your chances. Or you can try Kids Mighty-Multi! to discover how good a children’s multivitamin can (and should) be—a truly superior formula.

Choose our awesome kids multivitamin. Dr. Hank did his job. We’re 110% confident it meets—or exceeds—the needs and expectations of your child, and likely you, too. And definitely those of your clients, if you’re a health professional.

Of course, you’ve got a brain. But this choice is a “no-brainer.” Go for Kids Mighty Multi!. Your kids will never go back to their old multivitamin. And they’ll be healthier for it.

 

SOURCES & RESOURCES

Products

Kids Mighty-Multi! Multivitamin

HPDI Multivitamins

References

Coenzyme Vitamins (HPDI)

Fructooligosaccharides Abstracts (HPDI)

Statement on Additives (Excipients) (HPDI)

The HPDI Difference: Four Pillars of Excellence

Percent Daily Values (DV) Calculation Table (FDA)

Xylitol.org

Dr. Frank’s No-Aging Diet
by Benjamin S. Frank, MD, PhD

Studies

Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro.” Res Commun Mol Pathol Pharmacol. 95(2):179-89.
(Study includes mannitol benefits)

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WONDERS OF MOLECULAR HYDROGEN

Fred Liers PhD molecular hydrogen H2I drink hydrogen-infused water. You should, too. Why? Because the age of hydrogen is here. Molecular hydrogen, that is. We now know that molecular hydrogen has therapeutic potential for nearly every organ in the human body, as well as for 150 different human disease models! And it’s extremely safe.

MOLECULAR HYDROGEN: BACKGROUND

Molecular hydrogen, also known as “diatomic hydrogen,” is a colorless, tasteless, and odorless gas.

Elemental hydrogen (H) is the most abundant element in the universe constituting 75% of its mass. Yet, it is absent on earth in its monoatomic form, being present in water, and inorganic and organic compounds. Molecular hydrogen is found in the earth’s atmosphere at less than one part per million.

molecular hydrogen H2 water

Hydrogen-infused water is a simple means to consume molecular hydrogen.

The science regarding benefits to health of molecular hydrogen (H2) has advanced rapidly in recent years thanks to the pioneering efforts of research scientists around the globe.

Now hydrogen science is moving quickly beyond theory to practical applications. Moreover, new products exist allowing medical professionals and consumers to leverage the health benefits of hydrogen.

For decades, diatomic molecular hydrogen was generally considered an “inert” gas. That is perhaps the primary reason that molecular hydrogen has been recognized as a therapeutic molecule only recently.

Indeed, science has known about the health benefits of molecular hydrogen as early as 1798. Yet, as noted, for most of modern history the belief persisted that hydrogen was inert in the body. It was only in the late 20th century (ca. 1975) that it gained the attention of medical researchers, and only in the past 10 years has evidence for the health effects of molecular hydrogen gained critical mass in the scientific literature.

There are now more than 500 peer-reviewed articles demonstrating the therapeutic potential of hydrogen for nearly every organ in the human body, as well as in 150 different human disease models, according to the Molecular Hydrogen Foundation.

HEALTH BENEFITS OF MOLECULAR HYDROGEN (H2)

• Molecular hydrogen reduces oxidative stress as a selective antioxidant and by maintaining homeostatic levels of glutathione, superoxide dismutase, catalase,  and other free-radical scavenging nutrients.

• The antioxidant capacities of molecular hydrogen are such that it is beneficial for persistent and acute oxidative stress.

• Acute oxidative stress arises from a multitude of causes, including inflammation, cardiac or cerebral infarction, organ transplantation, heavy exercise, cessation of operative bleeding, and many other causes.

• Persistent oxidative stress relates to reactive oxygen species (ROS) generated in the body throughout life. For example, during exercise, exposure to pollutants and toxins or UV light, as well as physical and psychological stresses, and the aging process itself. As aerobic organisms, we generate ROS when breathing consumes oxygen.

• Molecular hydrogen is effective against hydroxyl radicals (OH). The hydroxyl radical is the radical species that causes much of the oxidative damage in the body. While vitamin C, glutathione, and certain plant-based antioxidants are somewhat effective against this radical, there is no Nrf2-induced enzyme that effectively quenches the hydroxl radical.

• This positions molecular hydrogen as a uniquely effective antioxidant against the hydroxyl radical. Notably, when molecular hydrogen quenches the hydroxyl radical, it produces water, which is non-toxic in the body.

• Beyond this, molecular hydrogen, like other gaseous signaling molecules such as NO, CO, H2S, appears to exhibit cell signal-modulating activity that confers it with anti-inflammatory, anti-obesity, anti-allergy, and many other benefits.

MOLECULAR HYDROGEN MEDICINE

The scientific literature discusses the use of molecular hydrogen for many clinical applications, including the following:

• METABOLIC SYNDROME including diabetes, hyperlipidemia, arteriosclerosis, hypertension, and obesity

• ISCHEMIA / REPERFUSION injuries including cerebral and myocardial infarctions, organ transplants, post-cardiac arrest

• NEUROPROTECTION including applications for dementia, Parkinson’s disease, depression, and anesthesia

• INFLAMMATION including applications for polymicrobial sepsis, rheumatoid arthritis, wound healing, and bowel diseases

• MITOCHONDRIAL DISEASES

• HEMODIALYSIS / VENTILATION

• AGING including cognitive decline

• EXERCISE including applications for fatigue, lactic acid, recovery, and oxidative stress related to heavy exercise

SIDE EFFECTS OF CANCER THERAPIES including radiotherapy and chemotherapy

• MANY OTHER BENEFITS

athlete molecular hydrogen performance race

Athletes benefit from molecular hydrogen. You can, too.

HOW MOLECULAR HYDROGEN WORKS

According to the Molecular Hydrogen Foundation, there are three ways molecular hydrogen exerts positive health effects.

1.  Molecular hydrogen easily diffuses into subcellular compartments where it scavenges cytotoxic oxygen radicals, thereby protecting DNA, RNA, and proteins against oxidative stress.

2.  Molecular hydrogen triggers activation or upregulation of additional antioxidant enzymes (e.g., glutathione, superoxide dismutase, catalase, and others) and/or cytoprotective proteins of the body.

3.  Molecular hydrogen may be a novel signaling molecule that alters cell signaling, cell metabolism, and gene expression. This may explain its apparent anti-inflammatory, anti-allergic, and anti-apoptotic (or anti-cell death) effects.

MOLECULAR HYDROGEN IS SAFE

Molecular hydrogen exhibits great safety, and it is regarded as safe for use in the body. It is shown no toxicity even in high concentrations.

Safety standards are already established for high concentrations of molecular hydrogen for inhalation because high-pressure H2 gas is used in deep-water diving gas mixtures to prevent decompression sickness.

Notably, H2 gas combusts only at temperatures higher than 527 °C, and it explodes by chain reaction with oxygen (O2) only in the range of Hconcentration (4–75%, vol/vol).

Molecular hydrogen can be used for medical applications safely by several ingestion methods including inhalation of 1–4% hydrogen gas, which exhibits great effectiveness.

All these factors mean that molecular hydrogen is safe, easy-to-use, and effective for therapeutic purposes.

molecular hydrogen H2 water

Hydrogen-infused water is safe, easy-to-consume, and cost effective.

USING MOLECULAR HYDROGEN

Methods for consuming molecular hydrogen include inhalation, oral ingestion of hydrogen-infused water, injection of hydrogen saline, and direct diffusion (eye drops, baths, cosmetics, etc.).

An advantage of inhaled H2 gas is that is acts rapidly. In this respect, may be suitable for defense against acute oxidative stress.

It has been shown that inhalation of 3–4% hydrogen (H2) gas reaches a plateau at approximately 10–20 μM in the arterial and venous blood in about 20 minutes. This is shown not to affect any physiological parameters (e.g., blood pressure), suggesting no adverse effects.

According to the Molecular Hydrogen Foundation, the consensus is that drinking H2-rich water is the easiest, and often the most effective, method for obtaining molecular hydrogen although it does not provide as many hydrogen molecules to the body as other methods.

Some studies show consuming H2-infused water to be more effective than inhalation or increasing intestinal H2 production via lactulose administration.

Another advantage of drinking hydrogen infused water is that it allows gastric induction of ghrelin, which is mediated via activation of beta 1 adrenergic receptors.

Above all, drinking hydrogen-infused water is easy to do, and convenient as you can drink it at home or while traveling.

HYDROGEN-INFUSED WATER

Inhalation of molecular hydrogen gas may be impractical for continuous H2 consumption in daily life. In contrast, solubilized H2 (hydrogen-infused water) is a portable, easily administered, and safe means to ingest H2.

H2 can be dissolved in water up to 0.8 mM (1.6 mg/L) under atmospheric pressure at room temperature without changing pH.

Hwater can be made by several methods: infusing H2 gas into water under pressure, electrolyzing water to producing H2, and reacting magnesium metal or its hydride with water.

Notably, H2 penetrates glass or plastic walls of vessels in a short time, yet aluminum containers retain hydrogen gas for a long time.

Water ionizers produce hydrogen gas via electrolysis. This method produces hydrogen concentrations from less than 0.05 ppm to more than 2.5 ppm. Typically 0.1 to 0.7 ppm hydrogen is produced, yet most companies manufacturing water ionizers neither know the concentration produced nor understand the significance of hydrogen for health.

In this regard, depending upon the production method much of the water containing molecular hydrogen exhibits a negative oxygen reduction potential (ORP). Yet, ORP is only a general indication of hydrogen production and is not a measurement of its concentration.

A second method of producing hydrogen-rich water by electrolysis is by infusion. In this method, hydrogen is directly infused into filtered water within a machine.

Another convenient method to generate molecular hydrogen is to add alkali-earth metals to water. Magnesium metal in commonly used for this purpose. This method allows for the production of high concentrations of molecular hydrogen that are generally near saturation (1.6 ppm), and therefore less water needs to be consumed by individuals drinking it.

Magnesium sticks and tablets/capsules are available (some of which are placed in water and others that can be consumed directly) that rapidly produce 2–4 ppm molecular hydrogen concentration. Like electrolysis, adding metals to water also increased the pH of water because they reduce the concentration of H+ ions.

Other methods exist that can produce supersaturated concentrations of molecular hydrogen with or without alteration of water pH. Advantages of these methods include having to drink a fraction of the amount of water in order to obtain an equal amount of molecular hydrogen.

Drinking water containing molecular hydrogen is probably the easiest and most cost-effective means for most persons to obtain hydrogen.

man drinks water infused with molecular hydrogen

Hydrogen-infused water can be consumed using tablets, prepared H2 beverages, or ionized water.

MOLECULAR HYDROGEN FROM YOUR MICROBIOME

Certain types bacteria in the intestinal tract produce hydrogen gas from non-digestible fibers, which may explain how fiber-rich diets reduce inflammation, and exert cardiovascular and other health benefits.

Diets low in dietary fiber from fruits and vegetables, or a decrease in microbiome diversity could potentially reduce production of molecular hydrogen. This could exert adverse effects on health.

The presence (or absence) of a diverse and robust microbiome may be one of the most significant factors in terms of how much hydrogen can be generated in the body. Most people today do not create the levels of molecular hydrogen in their digestive tracts that humans in earlier time periods generated largely because due to modern diets and less than optimal microbiome health.

Factors that influence or reduce microbiome health and diversity include antibiotic use, imbalanced diet, lack of certain fiber-rich vegetables in the diet, and consumption of herbicides, pesticides, and GMOs (that include glyphosate) that harm microbial populations and cause “leaky gut”.

As knowledge increases regarding ways we can support a healthy microbiome, the biological significance of hydrogen historically produced in our digestive tracts will be better understood.

BENEFIT TODAY FROM MOLECULAR HYDROGEN

The clinical applications of molecular hydrogen are impressive. One of the great advantages of molecular hydrogen infused water is that  it is easy to consume it, or make it in your own home or wherever you happen to be.

HPDI now sells a tablet hydrogen product from Purative known as Active H2.

Active H2 is a unique, patent-pending combination of all-natural minerals used to generate molecular hydrogen and electron-rich potential (-ORP). This distinguishes it from existing hydrogen formulas and electrolysis (water ionizers).

Active H2 is easy to use.  Simply place one tablet of in a 1/2 liter (16 oz) container of pure water (filled to the top) and close tightly. Wait at least 5–10 minutes for it to completely disintegrate (fizz), and then drink.

A one pint glass mason jar works well as a container for this purpose. However, you can use up to one liter (about 32 ounces) of water in a container, so a quart mason jar also works well. Consume the hydrogen-infused water ideally at least 30 minutes before food.

Active H2 formula consists of a proprietary blend of pure magnesium, malic acid, fumaric acid, and maltose that synergistically act to generate molecular hydrogen and electron-rich potential (-ORP).

Active H2 is the only all-natural add-in tablet providing molecular hydrogen in the amount of greater than 1.8 ppm, That is, one tablet typically generates molecular hydrogen in the concentration of about 2 ppm.

There are other molecular hydrogen products, including tablets, sticks, and pre-infused bottled products like H2Bev. H2Bev provides about 1.2–1.5 ppm of molecular hydrogen and comes in a 12 oz coated aluminum container for excellent H2 retention.

MOLECULAR HYDROGEN SUMMARY

Molecular hydrogen sits in the unique position of providing significant, wide-ranging benefits for health with an unmatched ease-of-use, and at relatively low cost for what it delivers.

We highly recommend the use of molecular hydrogen for its health benefits and for therapeutic applications. This includes the consumption of hydrogen-infused water whether from prepared H2 beverages, water ionizers, or highly effective Active H2 tablets.

Below we include important scientific abstracts you may find helpful in understanding the benefits and applications of molecular hydrogen.

 

SCIENTIFIC STUDIES ON MOLECULAR HYDROGEN

Beneficial biological effects and the underlying mechanisms of molecular hydrogen – comprehensive review of 321 original articles

From: http://www.ncbi.nlm.nih.gov/pubmed/26483953

Abstract
Therapeutic effects of molecular hydrogen for a wide range of disease models and human diseases have been investigated since 2007. A total of 321 original articles have been published from 2007 to June 2015. Most studies have been conducted in Japan, China, and the USA. About three-quarters of the articles show the effects in mice and rats. The number of clinical trials is increasing every year. In most diseases, the effect of hydrogen has been reported with hydrogen water or hydrogen gas, which was followed by confirmation of the effect with hydrogen-rich saline. Hydrogen water is mostly given ad libitum. Hydrogen gas of less than 4% is given by inhalation. The effects have been reported in essentially all organs covering 31 disease categories that can be subdivided into 166 disease models, human diseases, treatment-associated pathologies, and pathophysiological conditions of plants with a predominance of oxidative stress-mediated diseases and inflammatory diseases. Specific extinctions of hydroxyl radical and peroxynitrite were initially presented, but the radical-scavenging effect of hydrogen cannot be held solely accountable for its drastic effects. We and others have shown that the effects can be mediated by modulating activities and expressions of various molecules such as Lyn, ERK, p38, JNK, ASK1, Akt, GTP-Rac1, iNOS, Nox1, NF-κB p65, IκBα, STAT3, NFATc1, c-Fos, and ghrelin. Master regulator(s) that drive these modifications, however, remain to be elucidated and are currently being extensively investigated.

Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine

From: http://www.ncbi.nlm.nih.gov/pubmed/24769081

Abstract
Molecular hydrogen (H2) has been accepted to be an inert and nonfunctional molecule in our body. We have turned this concept by demonstrating that H2 reacts with strong oxidants such as hydroxyl radical in cells, and proposed its potential for preventive and therapeutic applications. H2 has a number of advantages exhibiting extensive effects: H2 rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect signaling reactive oxygen species; therefore, there should be no or little adverse effects of H2. There are several methods to ingest or consume H2; inhaling H2 gas, drinking H2-dissolved water (H2-water), injecting H2-dissolved saline (H2-saline), taking an H2 bath, or dropping H2-saline into the eyes. The numerous publications on its biological and medical benefits revealed that H2 reduces oxidative stress not only by direct reactions with strong oxidants, but also indirectly by regulating various gene expressions. Moreover, by regulating the gene expressions, H2 functions as an anti-inflammatory and anti-apoptotic, and stimulates energy metabolism. In addition to growing evidence obtained by model animal experiments, extensive clinical examinations were performed or are under investigation. Since most drugs specifically act to their targets, H2 seems to differ from conventional pharmaceutical drugs. Owing to its great efficacy and lack of adverse effects, H2 has promising potential for clinical use against many diseases.

Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury.

From: http://www.ncbi.nlm.nih.gov/pubmed/25251220

Abstract
Traumatic brain injury (TBI) in its various forms has emerged as a major problem for modern society. Acute TBI can transform into a chronic condition and be a risk factor for neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, probably through induction of oxidative stress and neuroinflammation. Here, we examined the ability of the antioxidant molecular hydrogen given in drinking water (molecular hydrogen water; mHW) to alter the acute changes induced by controlled cortical impact (CCI), a commonly used experimental model of TBI. We found that mHW reversed CCI-induced edema by about half, completely blocked pathological tau expression, accentuated an early increase seen in several cytokines but attenuated that increase by day 7, reversed changes seen in the protein levels of aquaporin-4, HIF-1, MMP-2, and MMP-9, but not for amyloid beta peptide 1-40 or 1-42. Treatment with mHW also reversed the increase seen 4 h after CCI in gene expression related to oxidation/carbohydrate metabolism, cytokine release, leukocyte or cell migration, cytokine transport, ATP and nucleotide binding. Finally, we found that mHW preserved or increased ATP levels and propose a new mechanism for mHW, that of ATP production through the Jagendorf reaction. These results show that molecular hydrogen given in drinking water reverses many of the sequelae of CCI and suggests that it could be an easily administered, highly effective treatment for TBI.

The evolution of molecular hydrogen: a noteworthy potential therapy with clinical significance

From: http://www.ncbi.nlm.nih.gov/pubmed/23680032

Abstract
Studies on molecular hydrogen have evolved tremendously from its humble beginnings and have continued to change throughout the years. Hydrogen is extremely unique since it has the capability to act at the cellular level. Hydrogen is qualified to cross the blood brain barrier, to enter the mitochondria, and even has the ability to translocate to the nucleus under certain conditions. Once in these ideal locations of the cell, previous studies have shown that hydrogen exerts antioxidant, anti-apoptotic, anti-inflammatory, and cytoprotective properties that are beneficial to the cell. Hydrogen is most commonly applied as a gas, water, saline, and can be applied in a variety of other mediums. There are also few side effects involving hydrogen, thus making hydrogen a perfect medical gas candidate for the convention of novel therapeutic strategies against cardiovascular, cerebrovascular, cancer, metabolic, and respiratory diseases and disorders. Although hydrogen appears to be faultless at times, there still are several deficiencies or snares that need to be investigated by future studies. This review article seeks to delve and comprehensively analyze the research and experiments that alludes to molecular hydrogen being a novel therapeutic treatment that medicine desperately needs.

Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases

From: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377272/

Abstract
Effects of molecular hydrogen on various diseases have been documented for 63 disease models and human diseases in the past four and a half years. Most studies have been performed on rodents including two models of Parkinson’s disease and three models of Alzheimer’s disease. Prominent effects are observed especially in oxidative stress-mediated diseases including neonatal cerebral hypoxia; Parkinson’s disease; ischemia/reperfusion of spinal cord, heart, lung, liver, kidney, and intestine; transplantation of lung, heart, kidney, and intestine. Six human diseases have been studied to date: diabetes mellitus type 2, metabolic syndrome, hemodialysis, inflammatory and mitochondrial myopathies, brain stem infarction, and radiation-induced adverse effects. Two enigmas, however, remain to be solved. First, no dose-response effect is observed. Rodents and humans are able to take a small amount of hydrogen by drinking hydrogen-rich water, but marked effects are observed. Second, intestinal bacteria in humans and rodents produce a large amount of hydrogen, but an addition of a small amount of hydrogen exhibits marked effects. Further studies are required to elucidate molecular bases of prominent hydrogen effects and to determine the optimal frequency, amount, and method of hydrogen administration for each human disease.

Molecular hydrogen is a novel antioxidant to efficiently reduce oxidative stress with potential for the improvement of mitochondrial diseases

From: http://www.ncbi.nlm.nih.gov/pubmed/21621588

Abstract

BACKGROUND:
Mitochondria are the major source of oxidative stress. Acute oxidative stress causes serious damage to tissues, and persistent oxidative stress is one of the causes of many common diseases, cancer and the aging process; however, there has been little success in developing an effective antioxidant with no side effect. We have reported that molecular hydrogen has potential as an effective antioxidant for medical applications [Ohsawa et al., Nat. Med. 13 (2007) 688-694].

SCOPE OF REVIEW:
We review the recent progress toward therapeutic and preventive applications of hydrogen. Since we published the first paper in Nature Medicine, effects of hydrogen have been reported in more than 38 diseases, physiological states and clinical tests in leading biological/medical journals. Based on this cumulative knowledge, the beneficial biological effects of hydrogen have been confirmed. There are several ways to intake or consume hydrogen, including inhaling hydrogen gas, drinking hydrogen-dissolved water, taking a hydrogen bath, injecting hydrogen-dissolved saline, dropping hydrogen-dissolved saline into the eyes, and increasing the production of intestinal hydrogen by bacteria. Hydrogen has many advantages for therapeutic and preventive applications, and shows not only anti-oxidative stress effects, but also has various anti-inflammatory and anti-allergic effects. Preliminary clinical trials show that drinking hydrogen-dissolved water seems to improve the pathology of mitochondrial disorders.

MAJOR CONCLUSIONS:
Hydrogen has biological benefits toward preventive and therapeutic applications; however, the molecular mechanisms underlying the marked effects of small amounts of hydrogen remain elusive.

GENERAL SIGNIFICANCE:
Hydrogen is a novel antioxidant with great potential for actual medical applications. This article is part of a Special Issue entitled Biochemistry of Mitochondria.

Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications

From: http://www.ncbi.nlm.nih.gov/pubmed/21736547

Abstract
Persistent oxidative stress is one of the major causes of most lifestyle-related diseases, cancer and the aging process. Acute oxidative stress directly causes serious damage to tissues. Despite the clinical importance of oxidative damage, antioxidants have been of limited therapeutic success. We have proposed that molecular hydrogen (H(2)) has potential as a “novel” antioxidant in preventive and therapeutic applications [Ohsawa et al., Nat Med. 2007: 13; 688-94]. H(2) has a number of advantages as a potential antioxidant: H(2) rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect reactive oxygen species (ROS) that function in cell signaling, thereby, there should be little adverse effects of consuming H(2). There are several methods to ingest or consume H(2), including inhaling hydrogen gas, drinking H(2)-dissolved water (hydrogen water), taking a hydrogen bath, injecting H(2)- dissolved saline (hydrogen saline), dropping hydrogen saline onto the eye, and increasing the production of intestinal H(2) by bacteria. Since the publication of the first H(2) paper in Nature Medicine in 2007, the biological effects of H(2) have been confirmed by the publication of more than 38 diseases, physiological states and clinical tests in leading biological/medical journals, and several groups have started clinical examinations. Moreover, H(2) shows not only effects against oxidative stress, but also various anti-inflammatory and antiallergic effects. H(2) regulates various gene expressions and protein-phosphorylations, though the molecular mechanisms underlying the marked effects of very small amounts of H(2) remain elusive.

Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals

From: http://www.ncbi.nlm.nih.gov/pubmed/17486089

Abstract
Acute oxidative stress induced by ischemia-reperfusion or inflammation causes serious damage to tissues, and persistent oxidative stress is accepted as one of the causes of many common diseases including cancer. We show here that hydrogen (H(2)) has potential as an antioxidant in preventive and therapeutic applications. We induced acute oxidative stress in cultured cells by three independent methods. H(2) selectively reduced the hydroxyl radical, the most cytotoxic of reactive oxygen species (ROS), and effectively protected cells; however, H(2) did not react with other ROS, which possess physiological roles. We used an acute rat model in which oxidative stress damage was induced in the brain by focal ischemia and reperfusion. The inhalation of H(2) gas markedly suppressed brain injury by buffering the effects of oxidative stress. Thus H(2) can be used as an effective antioxidant therapy; owing to its ability to rapidly diffuse across membranes, it can reach and react with cytotoxic ROS and thus protect against oxidative damage.

ADDITIONAL RESOURCES

MOLECULAR HYDROGEN (H2) AT FOREFRONT OF HEALTH RESEARCH
by Hank Liers, PhD (from the HPDI blog)

ACTIVE H2 (tablet product)

Molecular Hydrogen Foundation (MHF)

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 – GRAPE SEED EXTRACT

Dr. Hank Liers, PhDUltimate Protector contains grape seed extract and associated oligomeric proanthocyanidins (OPCs), 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 grape seed extract which is a component of VitaBerry®Plus from Futureceuticals.

During the last 24 years I have designed more than 20 products incorporating OPCs from whole grape and grape seed extracts. Some of these products include: Antioxidant FormulaDiabetes Support FormulaEye & Vision FormulaJoint Health FormulaChewable Kid’s Mighty-MultiHank & Brian’s Mighty Multi-vite!Mini MultiMulti TwoOPC-CPRO-CProlytRejuvenate! ProRejuvenate! Berries & Herbs, and Rejuvenate! Strawberry-Peach Protein Plus.

In 1993 I prepared an extensive review of OPCs including the sources of grape seed extract and pine bark extract. In this review article entitled Review of Scientific Research on Oligomeric Proanthcyanidins (OPC), I pointed out that grape seed extract consists of approximately 92% polyphenols, 32% monomers (flavan-3-ol), and 68% OPCs. OPCs consist of  catechins (referring to both catechins and epicatechins) that have the peculiar property of forming polymers with themselves. When the number of connected catechins is 10 or less they are called oligomers and thus the term used is “oligomeric proanthocyanidins.” When the number of connected catechins is more than 10 the term condensed tannins is generally used. The term proanthocyanidins comes about because when these materials are subjected to 10% hydrochloric acid and heated to boiling (this is what is termed the Bate-Smith test), they yield an anthocyanidin, with its intense red coloration, and a catechin.

Grape Seeds

It has only been more recent that ORAC5.0 testing has shown that grape seed extract is one of the most powerful antioxidants known and provides excellent protection against all five of the free radical types tested for in the ORAC5.0 tests. The table shown below taken from my blog article entitled THE AMAZING HEALING POTENTIAL OF NATURAL NRF2 ACTIVATORS provides test data to support this statement.

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

TABLE 2: ORAC5.0™ COMPARATIVE RESULTS

Ingredient Peroxyl Radical Hydroxyl Radical Peroxy-nitrite Radical Super-
oxide Radical
Singlet O2 Radical Total ORAC5.0
Curcumin 98% 5,750 8,920 906 597 66,290 82,500
Bilberry 25% 7,000 25,000 1,000 16,000 5,000 54,000
Cocoa 10,000 28,000 1,000 11,000 2,000 52,000
Grape Seed Extract 17,000 47,000 1,000 25,000 4,000 94,000
Green Tea Extract 11,000 41,000 2,000 56,000 3,000 113,000
Coffee Berry Extract 5,000 29,000 1,000 1,000 2,000 38,000
Mangosteen 4,000 8,000 1,000 18,000 4,000 35,000
Pine Bark 7,000 23,000 1,000 17,000 2,000 50,000
Resveratrol 12,000 50,000 1,000 8,000 22,000 93,000
ULTIMATE PROTECTOR 6,300 5,900 2,500 106,000 52,000 173,000
Results are expressed in micro mole TE/g
From ORAC DATABASE (INCLUDING ORAC5.0 TEST RESULTS)

 

Below we provide information from several research articles that highlight some of the potential health effects of grape seed extract.

 

Procyanidins from Wild Grape (Vitis amurensis) Seeds Regulate ARE-Mediated Enzyme Expression via Nrf2 Coupled with p38 and PI3K/Akt Pathway in HepG2 Cells

From: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269721/

Abstract

Procyanidins, polymers of flavan-3-ol units, have been reported to exhibit many beneficial health effects such as antioxidant and anti-carcinogenic effects. In this study, we investigated the cancer chemopreventive properties of procyanidins from wild grape (Vitis amurensis) seeds in particular their roles in inducing phase II detoxifying/antioxidant enzymes as well as in modulating the upstream kinases. Ethanolic extract of V. amurensis seeds was fractionated with a series of organic solvents and finally separated into six fractions, F1–F6. Chemical properties of the procyanidins were analyzed by vanillin assay, BuOH-HCl test, and depolymerization with phloroglucinol followed by LC/MS analysis. The F5 had the highest procyanidin content among all the fractions and strongly induced the reporter activity of antioxidant response element as well as the protein expression of nuclear factor E2-related factor (Nrf2) in HepG2 human hepatocarcinoma cells. The procyanidin-rich F5 also strongly induced the expression of the phase II detoxifying and antioxidant enzymes such as NAD(P)H:quinone oxidoreductase1 and hemeoxygenase1. Phosphorylations of the upstream kinases such as MAPKs and PI3K/Akt were significantly increased by treatment with procyanidin fraction. In addition, the procyanidin-mediated Nrf2 expression was partly attenuated by PI3K inhibitor LY294002, and almost completely by p38 inhibitor SB202190, but neither by JNK inhibitor SP600125 nor by MEK1/2 inhibitor U0126. Taken together, the procyanidins from wild grape seeds could be used as a potential natural chemopreventive agent through Nrf2/ARE-mediated phase II detoxifying/antioxidant enzymes induction via p38 and PI3K/Akt pathway.

Keywords: wild grape seed, Vitis amurensis, procyanidin, chemoprevention, MAPKs, Nrf2, phase II detoxifying enzyme, antioxidant enzyme

 

Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release.

From: http://www.ncbi.nlm.nih.gov/pubmed/12419835

Carcinogenesis. 2002 Nov;23(11):1869-76, Agarwal C1, Singh RPAgarwal R.

Abstract

Grape seed extract (GSE), rich in the bioflavonoids commonly known as procyanidins, is one of the most commonly consumed dietary supplements in the United States because of its several health benefits. Epidemiological studies show that many prostate cancer (PCA) patients use herbal extracts as dietary supplements in addition to their prescription drugs. Accordingly, in recent years, we have focused our attention on assessing the efficacy of GSE against PCA. Our studies showed that GSE inhibits growth and induces apoptotic death of human PCA cells in culture and in nude mice. Here, we performed detailed studies to define the molecular mechanism of GSE-induced apoptosis in advanced human PCA DU145 cells. GSE treatment of cells at various doses (50-200 micro g/ml) for 12-72 h resulted in a moderate to strong apoptotic death in a dose- and time-dependent manner. In the studies assessing the apoptotic-signaling pathway induced by GSE, we observed an increase in cleaved fragments of caspases 3, 7 and 9 as well as PARP in GSE-treated cells after 48 and 72 h of treatment. Pre-treatment of cells with general caspases inhibitor, z-Val-Ala-Asp(OMe)-FMK or caspase 3-like proteases inhibitor [z-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-FMK], almost completely (approximately 90%) inhibited the GSE-induced apoptotic cell death. In a later case, GSE-induced caspase-3 activity was completely inhibited. Selective caspase 9 inhibitor [z-Leu-Glu(OMe)-His-Asp(OMe)-FMK] showed only partial inhibition of GSE-induced apoptosis whereas GSE-induced protease activity of caspase 9 was completely inhibited. Upstream of caspase cascade, GSE showed disappearance of mitochondrial membrane potential and an increase in cytochrome c release in cytosol. Together, these results suggest that GSE possibly causes mitochondrial damage leading to cytochrome c release in cytosol and activation of caspases resulting in PARP cleavage and execution of apoptotic death of human PCA DU145 cells. Furthermore, GSE-caused caspase 3-mediated apoptosis also involves other pathway(s) including caspase 9 activation.

 

Differential effect of grape seed extract against human non-small-cell lung cancer cells: the role of reactive oxygen species and apoptosis induction.

From: http://www.ncbi.nlm.nih.gov/pubmed/23682782

Abstract

The present study examines grape seed extract (GSE) efficacy against a series of non-small-cell lung cancer (NSCLC) cell lines that differ in their Kras and p53 status to establish GSE potential as a cytotoxic agent against a wide range of lung cancer cells. GSE suppressed growth and induced apoptotic death in NSCLC cells irrespective of their k-Ras status, with more sensitivity toward H460 and H322 (wt k-Ras) than A549 and H1299 cells (mutated k-Ras). Mechanistic studies in A549 and H460 cells, selected, based on comparative efficacy of GSE at higher and lower doses, respectively, showed that apoptotic death involves cytochrome c release associated caspases 9 and 3 activation, and poly (ADP-ribosyl) polymerase cleavage, strong phosphorylation of ERK1/2 and JNK1/2, downregulation of cell survival proteins, and upregulated proapoptotic Bak expression. Importantly, GSE treatment caused a strong superoxide radical-associated oxidative stress, significantly decreased intracellular reduced glutathione levels, suggesting, for the first time, the involvement of GSE-caused oxidative stress in its apoptotic inducing activity in these cells. Because GSE is a widely-consumed dietary agent with no known untoward effects, our results support future studies to establish GSE efficacy and usefulness against NSCLC control.

Role of oxidative stress in cytotoxicity of grape seed extract in human bladder cancer cells.

From: http://www.ncbi.nlm.nih.gov/pubmed/23831192

Food Chem Toxicol. 2013 Nov;61:187-95. doi: 10.1016/j.fct.2013.06.039. Epub 2013 Jul 3. Raina K1, Tyagi AKumar DAgarwal RAgarwal C.

Abstract

In present study, we evaluated grape seed extract (GSE) efficacy against bladder cancer and associated mechanism in two different bladder cancercell lines T24 and HTB9. A significant inhibitory effect of GSE on cancer cell viability was observed, which was due to apoptotic cell death. Cell death events were preceded by vacuolar appearance in cytoplasm, which under electron microscopy was confirmed as swollen mitochondrial organelle and autophagosomes. Through detailed in vitro studies, we established that GSE generated oxidative stress that initiated an apoptotic response as indicated by the reversal of GSE-mediated apoptosis when the cells were pre-treated with antioxidants prior to GSE. However, parallel to a strong apoptotic cell death event, GSE also caused a pro-survival autophagic event as evidenced by tracking the dynamics of LC3-II within the cells. Since the pro-death apoptotic response was stronger than the pro-survival autophagy induction within the cells, cell eventually succumbed to cellular death after GSE exposure. Together, the findings in the present study are both novel and highly significant in establishing, for the first time, that GSE-mediated oxidative stress causes a strong programmed cell death in human bladder cancer cells, suggesting and advocating the effectiveness of this non-toxic agent against this deadly malignancy.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Target identification of grape seed extract in colorectal cancer using drug affinity responsive target stability (DARTS) technique: role of endoplasmic reticulum stress response proteins.

From: http://www.ncbi.nlm.nih.gov/pubmed/24724981

Abstract

Various natural agents, including grape seed extract (GSE), have shown considerable chemopreventive and anti-cancer efficacy against different cancers in pre-clinical studies; however, their specific protein targets are largely unknown and thus, their clinical usefulness is marred by limited scientific evidences about their direct cellular targets. Accordingly, herein, employing, for the first time, the recently developed drug affinity responsive target stability (DARTS) technique, we aimed to profile the potential protein targets of GSE in human colorectal cancer (CRC) cells. Unlike other methods, which can cause chemical alteration of the drug components to allow for detection, this approach relies on the fact that a drug bound protein may become less susceptible to proteolysis and hence the enriched proteins can be detected by Mass Spectroscopy methods. Our results, utilizing the DARTS technique followed by examination of the spectral output by LC/MS and the MASCOT data, revealed that GSE targets endoplasmic reticulum (ER) stress response proteins resulting in overall down regulation of proteins involved in translation and that GSE also causes oxidative protein modifications, specifically on methionine amino acids residues on its protein targets. Corroborating these findings, mechanistic studies revealed that GSE indeed caused ER stress and strongly inhibited PI3k-Akt-mTOR pathway for its biological effects in CRC cells. Furthermore, bioenergetics studies indicated that GSE also interferes with glycolysis and mitochondrial metabolism in CRC cells. Together, the present study identifying GSE molecular targets in CRC cells, combined with its efficacy in vast pre-clinical CRC models, further supports its usefulness for CRC prevention and treatment.

 

Polyphenolics in grape seeds-biochemistry and functionality.

From: http://www.ncbi.nlm.nih.gov/pubmed/14977436

J Med Food. 2003 Winter;6(4):291-9.

Abstract

Grape seeds are waste products of the winery and grape juice industry. These seeds contain lipid, protein, carbohydrates, and 5-8% polyphenols depending on the variety. Polyphenols in grape seeds are mainly flavonoids, including gallic acid, the monomeric flavan-3-ols catechin, epicatechin, gallocatechin, epigallocatechin, and epicatechin 3-O-gallate, and procyanidin dimers, trimers, and more highly polymerized procyanidins. Grape seed extract is known as a powerful antioxidant that protects the body from premature aging, disease, and decay. Grape seeds contains mainly phenols such as proanthocyanidins (oligomeric proanthocyanidins). Scientific studies have shown that the antioxidant power of proanthocyanidins is 20 times greater than vitamin E and 50 times greater than vitamin C. Extensive research suggests that grape seed extract is beneficial in many areas of health because of its antioxidant effect to bond with collagen, promoting youthful skin, cell health, elasticity, and flexibility. Other studies have shown that proanthocyanidins help to protect the body from sun damage, to improve vision, to improve flexibility in joints, arteries, and body tissues such as the heart, and to improve blood circulation by strengthening capillaries, arteries, and veins. The most abundant phenolic compounds isolated from grapeseed are catechins, epicatechin, procyanidin, and some dimers and trimers.

 

Anti-tumor-promoting activity of a polyphenolic fraction isolated from grape seeds in the mouse skin two-stage initiation-promotion protocol and identification of procyanidin B5-3′-gallate as the most effective antioxidant constituent.

From: http://www.ncbi.nlm.nih.gov/pubmed/10469619

Abstract

Procyanidins present in grape seeds are known to exert anti-inflammatory, anti-arthritic and anti-allergic activities, prevent skin aging, scavenge oxygen free radicals and inhibit UV radiation-induced peroxidation activity. Since most of these events are associated with the tumor promotion stage of carcinogenesis, these studies suggest that grape seed polyphenols and the procyanidins present therein could be anticarcinogenic and/or anti-tumor-promoting agents. Therefore, we assessed the anti-tumor-promoting effect of a polyphenolic fraction isolated from grape seeds (GSP) employing the 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol 13-acetate (TPA)-promoted SENCAR mouse skin two-stage carcinogenesis protocol as a model system. Following tumor initiation with DMBA, topical application of GSP at doses of 0.5 and 1.5 mg/mouse/application to the dorsal initiated mouse skin resulted in a highly significant inhibition of TPA tumor promotion. The observed anti-tumor-promoting effects of GSP were dose dependent and were evident in terms of a reduction in tumor incidence (35 and 60% inhibition), tumor multiplicity (61 and 83% inhibition) and tumor volume (67 and 87% inhibition) at both 0.5 and 1.5 mg GSP, respectively. Based on these results, we directed our efforts to separate and identify the individual polyphenols present in GSP and assess their antioxidant activity in terms of inhibition of epidermal lipid peroxidation. Employing HPLC followed by comparison with authentic standards for retention times in HPLC profiles, physiochemical properties and spectral analysis, nine individual polyphenols were identified as catechin, epicatechin, procyanidins B1-B5 and C1 and procyanidin B5-3′-gallate. Five of these individual polyphenols with evident structural differences, namely catechin, procyanidin B2, procyanidin B5, procyanidin C1 and procyanidin B5-3′-gallate, were assessed for antioxidant activity. All of them significantly inhibited epidermal lipid peroxidation, albeit to different levels. A structure-activity relationship study showed that with an increase in the degree of polymerization in polyphenol structure, the inhibitory potential towards lipid peroxidation increased. In addition, the position of linkage between inter-flavan units also influences lipid peroxidation activity; procyanidin isomers with a 4-6 linkage showed stronger inhibitory activity than isomers with a 4-8 linkage. A sharp increase in the inhibition of epidermal lipid peroxidation was also evident when a gallate group was linked at the 3′-hydroxy position of a procyanidin dimer. Procyanidin B5-3′-gallate showed the most potent antioxidant activity with an IC(50) of 20 microM in an epidermal lipid peroxidation assay. Taken together, for the first time these results show that grape seed polyphenols possess high anti-tumor-promoting activity due to the strong antioxidant effect of procyanidins present therein. In summary, grape seed polyphenols in general, and procyanidin B5-3′-gallate in particular, should be studied in more detail to be developed as cancer chemopreventive and/or anticarcinogenic agents.

 

Aronia (Chokeberry)

 

SUMMARY

Grape Seed Extract (GSE) is an exciting natural ingredient full of important polyphenols, antioxidants and Nrf2 activators that help to make Ultimate Protector such an outstanding nutritional supplement. This ingredient has been used extensively in nutritional supplement formulations for almost 25 years now. Continued research shows an amazing list of health benefits for this substance including its ability to function as a powerful stimulator of Nrf2 activity. It truly belongs in the Ultimate Protector™ formula.

1

ULTIMATE PROTECTOR DESIGN CONSIDERATIONS

Dr. Hank Liers, PhD ultimate protectorIn early 2012 a friend of mine told me about a new product he was taking from a company called LifeVantage. He informed me all he needed to take on a daily basis was one small tablet in order to be protected against free-radical damage of any sort. And that he didn’t even need to take Vitamin C!

I have formulated nutritional supplements for a long time, so I knew there was something not quite right about what I was hearing. When I learned he was buying from a multi-level marketing company his story became understandable, but not believable.

I decided I would investigate the product in order to better understand the logic behind it. I watched videos regarding the science underpinning this product, and I read the scientific literature for months.

What I learned was intriguing, so I decided I would formulate a product dealing with free-radical protection that would take the science and the art of formulation to new levels. I would name the product (drumroll please) “Ultimate Protector”!!

ultimate protector bottle capsules

BACKGROUND

According to Dr. Joe McCord, in the last 10 years or so there have been over 80,000 papers in peer reviewed publications that relate to Nrf2 activators. Many of these have clearly demonstrated that plant polyphenols are perhaps the best way to intake substances that will stimulate the endogenous production of protective enzymes. In fact, many reputable scientists believe the best way to prevent cancer is via the use of plant polyphenols.

There are also many papers in the scientific literature that have shown the consumption of fruits and vegetables (including herbs) that are inherently high in polyphenols to be one of the best ways to improve health and prevent conditions of poor health. Please see my blog article on this subject: “The Amazing Healing Potential of Natural Nrf2 Activators” (http://www.integratedhealthblog.com/amazing-healing-potential-natural-nrf2-activators/).

In the world of nutritional supplements it is not often that significant scientific/clinical studies are conducted on specific products. The reason for this is primarily economic. However, just as in the case of Nrf2 activators, hundreds of thousands of studies have been conducted by organizations around the world that show the benefits of specific ingredients or groups of ingredients, and these ingredients are used in the development of healthful nutritional supplements.

It is laudable that LifeVantage has had a few scientific/clinical studies done on their product containing five specific Nrf2 activators. This positively supports the huge amount of scientific papers on the subject. However, these few studies do not imply it is a better product than products developed using additional carefully-selected ingredients highlighted in the scientific literature. Progress is made continuously in the area of nutritional supplements allowing us to improve on existing products.

As an example of how being aware of the scientific literature on Nrf2 activators, as well as being experienced in the design of groundbreaking new nutritional products, I was recently delighted to observe that high ORAC5.0 values are associated with many of the best Nrf2 activators identified in the scientific literature. This is discussed in my blog article referenced above.

Indeed, this observation is in contrast to the statements by many (even the scientists) that taking antioxidants is unnecessary and perhaps harmful. It appears that these antioxidants may perform double duty by first operating as antioxidants in the body (including the gastrointestinal tract) and in the process become weak pro-oxidants that function as powerful Nrf2 activators. Of course, if you are not aware of ORAC5.0 testing, then it would not be possible to make such an observation.

ULTIMATE PROTECTOR GOALS

My goal when I formulated Ultimate Protector™ was to create a product with three basic functions. That is, 1) a source of non-GMO Vitamin C (1.5 gm/daily serving), 2) provide powerful antioxidant protection via proven high ORAC sources, and 3) a multiple ingredient source of many Nrf2 activators, thereby providing the body with means to produce a wide variety of protective enzymes endogenously.

VITAMIN C IN ULTIMATE PROTECTOR

It is important to realize Vitamin C is a vitamin that is a cofactor in at least eight enzymatic reactions, including several collagen syntheses reactions that when dysfunctional (usually because of lack of Vitamin C) cause the most severe symptoms of scurvy. In animals, these reactions are especially important in wound healing and in preventing bleeding from capillaries. It is important to understand that no other substance can provide these functions.

Vitamin C acts as an electron donor and/or hydrogen donor, and this ability makes it a potent antioxidant. It rapidly reduces superoxide and nitroxide radicals and scavenges hydroxyl, alkoxyl, and peroxyl radicals. It also reacts with non-radical species such as singlet oxygen and hypochlorous acid. It has been observed in in vitro experiments that Vitamin C acts as the first line of defense in the plasma. In order to learn more about the important role of Vitamin C, please see my blog article: “Vitamin C – An Amazing Nutrient” (www.integratedhealthblog.com/vitamin-c-an-amazing-nutrient/).

ORAC5.0 VALUES OF ULTIMATE PROTECTOR

The full spectrum of antioxidants derived from high ORAC fruits, vegetables, and herbs (as well as Vitamin C) provide extremely powerful exogenous sources of protection against oxidative stress. To obtain a quantitative measure of just how powerful these external sources are we elected to conduct ORAC testing.

The fact is that there are a variety of “free radicals” that operate in humans. The most important are the primary radicals hydroxyl, peroxyl, peroxynitrite, singlet oxygen, and superoxide anion. Recently, Brunswick Labs has introduced a new test called ORAC5.0™ (also known as ORACFN). This test expands the ORAC platform to measure the antioxidant capacity against each of the five primary reactive oxygen species mentioned above (not just against the peroxyl radical as ORAC does). ORAC5.0™ substantially improves broad-spectrum antioxidant analysis and gives evidence of the diverse antioxidant potential of natural products against radicals.

Brunswick Labs has tested Ultimate Protector™ using the new ORAC5.0™ tests. The results reveal an incredible overall ORAC5.0 value of 173,000 µmole TE/gram, an exceptionally high value. In addition, the results show that the formula offers excellent protection against all of the five major types of free radicals. Specifically, the results show values of 6,300 (µmole TE/gram) for peroxyl radicals, 5,900 (µmole TE/gram) for hydroxyl radicals, 2,500 (µmole TE/gram) for peroxynitrite, 106,000 (µmole TE/gram) for superoxide anion, and 52,000 (µmole TE/gram) for singlet oxygen.

The overall daily ORAC5.0™ value per serving obtained by adding the values for each free radical type is 486,000 units (173,000 units x 2.81 g)!! To the best of our knowledge there is no other product that even comes close to providing such complete protection both in terms of breadth of coverage and overall strength. The Brunswick Labs ORAC5.0™ test results for Ultimate Protector are posted on our website. View the test results.

Nrf2 CONSIDERATIONS REGARDING ULTIMATE PROTECTOR

In the development of Ultimate Protector™, I was fortunate to obtain a license regarding the use of four complex nutritional ingredients manufactured by Futureceuticals, Inc. (http://www.futureceuticals.com). FutureCeuticals uses target-specific acute clinical studies to create benefit-driven products. This type of testing is central to the company’s TargeTest™ research program.

The program focuses on a number of blood targets, including CETP, PON1, SIRT, Elastase, and ACE, among others. Acute clinical studies that show how dietary supplements affect these targets and can help product developers to identify what nutraceutical ingredients are best to include in blends designed to benefit specific health conditions.

For example, TargeTest measures an ingredient’s ability to help manage inflammation by analyzing activity of NF-κB in blood cells for two to three hours after ingestion of the ingredient. The results lead to two important conclusions. One is whether or not that ingredient is bioavailable, which is determined by measuring its effect in human blood. Second, the results can show whether or not the ingredient inhibits NF-κB. A positive result indicates that the tested ingredient could help regulate inflammation if used over a longer period of time.

The four products we have licensed are 1) AnthoComplete®, 2) CoffeeBerry®, 3) VitaBerry® Plus, and 4) VitaVeggie®. They contain a very broad variety of plant substances that have been optimized for their antioxidant value and support of human health.

The selection of these four products provides phytonutrients from 27 of the most healing fruits and vegetables, most of which are identified as Nrf2 activators in the scientific literature. These include: Wild Blueberry, Wild Bilberry, Acai, Black Currant Extract, Sweet Cherry, Raspberry, Elderberry, Blackberry, Aronia (Chokeberry), Black Soybean Hull Extract, Blue Corn, CoffeeBerry®, Grape Seed, Cranberry, Tart Cherry, Prune, Raspberry Seed, Strawberry, Quercetin, Broccoli, Broccoli Sprouts, Tomato, Kale, Carrot, Brussels Sprouts, Onion, and Spinach.

 

Ultimate Protector NRF2 Activator

 

We added curcumin (95% min. curcuminoids) and resveratrol (greater than 98%) to the formula because they are important in the Nrf2 literature, and were not adequately included in the Futureceuticals products we selected. The total amount of these plant ingredients per daily serving (six veggie caps) amounts to a total of 630 mg, which is consistent with the idea expressed in the scientific literature that only small amounts are necessary for powerful Nrf2 activation.

The total combination of freeze-dried and concentrated fruits, vegetables, and herbs in Ultimate Protector provides a wide range of choices to the body in terms of specific substances, including polyphenols, phenolic acids, anthocyandins, sulforaphane, glucosinolates, lutein, lycopene, beta carotene, chlorogenic acid, ellagic acid, quercetin, quinic acid, proanthocyanidins, resveratrol, ferulic acid, caffeic acid, and polysaccharides.

 

Ultimate Protector

 

After testing the final product for ORAC5.0 value we were truly amazed to find that a single serving (2.81 gm) of Ultimate Protector provides 486,000 ORAC5.0 units (see my blog article on Ultimate Protector ORAC5.0 test results at http://www.integratedhealthblog.com/orac5-0-and-ultimate-protector/). This value is more than 10 times greater than a serving size of any other product of which we are aware!! Our observation that high ORAC5.0 and effective Nrf2 activation appear to be correlated indicates that with Ultimate Protector we have made a major breakthrough in the development of nutritional supplements containing Nrf2 activators.

ULTIMATE PROTECTOR SUMMARY

Ultimate Protector has been on the market about two years. Our customers say they like it very much, including the fact that all ingredients are non-GMO and contained in a small veggie capsule with a minimal amount of excipients. Heavy metals testing indicates no detectable amounts of lead, mercury, and arsenic and insignificant amounts of cadmium per capsule. To date we have no complaints of any allergic reactions, possibly due to the purity of the ingredients. Below is a testimonial from one of our customers who posted on Amazon.com:

“This product is very powerful, after taking only one capsule I feel a tremendous balanced energy take over, and my thinking is razor sharp. This may not be everyone’s experience as I am super sensitive. This product is for real!!!!” – By Adam D Da Virro on April 10, 2014

We hear similar reports from many other customers, including a few enthusiastic ones who have written entire blog articles about Ultimate Protector. We often hear about increased energy levels, enhanced mental acuity, improved capacity to combat illness (e.g., colds and flu), and overall greater well-being. These are just a few benefits reported to us by customers using the formula.

I am especially pleased because I succeeded in formulating a product from which everyone can truly benefit, not only individuals seeking optimal mental or physical performance, such as athletes. And we see it happening every day.

We encourage you to learn the facts, and consider trying Ultimate Protector. While it is formulated as a foundational supplement designed for best results to be taken daily along with a high-potency multivitamin, essential fats, and Rejuvenate! superfoods, it’s also highly effective when used alone. Given the remarkable benefits Ultimate Protector provides, you’ve got nothing to lose and everything to gain.

Learn more about Ultimate Protector™.

 

Ultimate Protector Super Antioxidant Formula

Ultimate Protector Supplement Facts Table

ADDITIONAL RESOURCES

1

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.

I soon published several blog articles on this subject including a June 2012 article entitled New Directions For Preventing Free-Radical Damage and a July 2012 article entitled Natural Phytochemical Nrf2 Activators for Chemoprevention.

Also, I actively began the development of a new product called Ultimate Protector™ that contains many concentrates and extracts from fruits and vegetables. This product functions as 1) an excellent source of many Nrf2 activators contained in 29 different fruits and vegetables, 2) a source of powerful antioxidants exhibiting an ORAC5.0 value of 486,000 units in six small capsules, and 3) a source of non-GMO Vitamin C.

NRF2 Activators in Ultimate Protector

Ultimate Protector™ Nrf2 Activator Formula

In October 2012, I published a blog article titled Ultimate Protector™ Brunswick Labs ORAC5.0™ Test Results summarizing the laboratory test results that showed Ultimate Protector’s extremely high antioxidant values for the top five free-radical types found in the body.

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

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

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

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

SOME KEY ENZYMES MODULATED BY Nrf2 ACTIVATORS

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

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

NATURAL FOODS AND FOOD EXTRACTS PROMOTE THE EXPRESSION OF Nrf2

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

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

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

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

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

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

Ultimate Protector NRF2 Activator ORAC

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 Nrf2 activator

INTERESTING FACTS REGARDING NRF2 ACTIVATORS

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

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

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

TABLE 2: ORAC5.0™ COMPARATIVE RESULTS

Ingredient Peroxyl Radical Hydroxyl Radical Peroxy-nitrite Radical Super-
oxide Radical
Singlet O2 Radical Total ORAC5.0
Curcumin 98% 5,750 8,920 906 597 66,290 82,500
Bilberry 25% 7,000 25,000 1,000 16,000 5,000 54,000
Cocoa 10,000 28,000 1,000 11,000 2,000 52,000
Grape Seed Extract 17,000 47,000 1,000 25,000 4,000 94,000
Green Tea Extract 11,000 41,000 2,000 56,000 3,000 113,000
Coffee Berry Extract 5,000 29,000 1,000 1,000 2,000 38,000
Mangosteen 4,000 8,000 1,000 18,000 4,000 35,000
Pine Bark 7,000 23,000 1,000 17,000 2,000 50,000
Resveratrol 12,000 50,000 1,000 8,000 22,000 93,000
ULTIMATE PROTECTOR 6,300 5,900 2,500 106,000 52,000 173,000
Results are expressed in micro mole TE/g
4) Here is a list of the ingredients in ULTIMATE PROTECTOR™:  USP-grade non-GMO Buffered Vitamin C, AnthoComplete™ (high-ORAC powder from Wild Blueberry, Wild Bilberry, Acai, Black Currant Extract, Sweet Cherry, Raspberry, Elderberry, Blackberry, Aronia, Black Soybean Hull Extract, and Blue Corn), CoffeeBerry®Forte (high-ORAC powder from Coffee Berry), Curcumin (standardized extract with 95% curcuminoids), Trans-Resveratrol (98% from Giant Knotweed), VitaBerry®Plus (high-ORAC powder: from freeze-dried Grape Seed, Wild Blueberry, Wild Bilberry, Cranberry, Tart Cherry, Prune, Raspberry Seed, Strawberry, Trans-Resveratrol, and Quercetin), VitaVeggie® (high-ORAC powder from Broccoli, Broccoli Sprouts, Tomato, Kale, Carrot, Brussels Sprouts, Onion and Spinach), and Bioperine® (a patented black pepper extract that enhances absorption of all ingredients).

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