Fred Liers PhD megavitamin myth busting orthomolecular vitamins andrew saul omnsAs the year draws to a close, it is a good time to reflect on the past year, as well as to look forward to the New Year with respect to one’s health goals. This includes assessing your nutritional supplement regimen. There is more confusion about nutritional supplements than ever. With this in mind, we present “Megavitamin Myth-Busting” from Andrew W. Saul, PhD and Helen Saul Case from the Orthomolecular Medicine News Service to clear confusion about vitamins and other nutritional supplements, and set the record straight. Enjoy! ~


Commentary by Andrew W. Saul and Helen Saul Case

(Orthomolecular Medicine News Service, Dec 23, 2019)

People are so confused about endless internet vitamin legends. Now it’s time to be blunt and set the record straight.

The media says that taking vitamins will kill me. Is that so? NO.


It’s been said that the FDA does not regulate nutritional supplements. Is that true? NO. “FDA regulates both finished dietary supplement products and dietary ingredients.” [U.S. Food and Drug Administration, http://www.fda.gov/Food/DietarySupplements/ ]


I have heard that “vitamin supplements are useless” and that “supplements do not prevent or cure disease, and they do not help you live longer.” Is that accurate? NO.


I get enough vitamins from my diet. NO, you don’t.


Aren’t foods a more economical vitamin source than supplements? NO.


Should I really stop all vitamin supplements for a week (or more) prior to surgery? NO.


Do I need special vitamin preparations for my body to absorb them? NO. With vitamins, there is usually no absorption issue. All animals need and absorb nutrients, including vitamins. If they didn’t, they’d be long extinct. The surface area of your small intestine, if all the nooks and crannies were flatted out, would be half the size of a regulation basketball court. There is ample opportunity for nutrient absorption.


Doesn’t taking vitamins just make expensive urine? NO.




Does vitamin C causes kidney stones? NO.


Does vitamin C interfere with chemotherapy? NO, vitamin C actually enhances chemotherapy.
http://www.doctoryourself.com/Cancer_Why_IV_C.html and


I have heard that ascorbic acid is not really vitamin C. Is that true? NO.
http://orthomolecular.org/resources/omns/v09n27.shtml and


Will vitamin C from a genetically modified (GMO) source hurt me? NO.


Does the acidity of ascorbic acid vitamin C destroy probiotics? NO.


If I take too much vitamin C during pregnancy, will it cause a miscarriage? NO, vitamin C is highly protective of your developing baby.


Does taking too much vitamin C during pregnancy causes infantile rebound scurvy? NO.


Is liposomal vitamin C as good as intravenous vitamin C? NO.


Will I get to much sodium from taking sodium ascorbate vitamin C? NO, says cardiologist Thomas Levy, MD, JD.


Does G6PD mean no supplemental vitamin C? NO. The Riordan Clinic has administered 15,000 mg vitamin C by IV to G6PD patients without harm.


But since Linus Pauling died from cancer, didn’t he fail to benefit from all the vitamin C he took? NO.




Some persons have a genetic trait that makes it more difficult for them to convert dietary carotene into active vitamin A. Does this mean they must take preformed oil retinol A? NO. Even a poor converter can still make sufficient vitamin A from carotene if they eat lots of fruits and vegetables . . . which we should all be doing anyway.


Does beta carotene cause cancer? NO. (But cigarettes do.)
http://www.orthomolecular.org/resources/omns/v04n09.shtml and




Does niacin hurt the liver? NO.
http://www.doctoryourself.com/news/v4n21.html and


Is niacin clinically incompatible for people with methylation issues? NO. Theoretically, perhaps. But Dr. Abram Hoffer, the world’s most experienced niacin physician, has said it is not clinically significant.


Aren’t B-vitamins so poorly absorbed that they need to be methylated? NO. Comparing their molecular weights with the simplest of all sugars, we find:

Glucose (C6H12O6) weighs 180 grams/mole
Niacin (C6H5NO2) weighs 123 g/mol
Pyridoxine 169 g/mol
Pantothenic acid 219 g/mol
Biotin 244 g/mol
Thiamin 265 g/mol
Riboflavin 376 g/mol
Folic acid or folate 441 [Methylated may be better. However: 1) See: Bailey LB. Dietary reference intakes for folate: the debut of dietary folate equivalents. Nutr Rev. 1998;56(10):294-299. And 2) The Linus Pauling Institute says: “Unmetabolized folic acid concentrations returned to baseline levels at the end of the study, suggesting that adaptive mechanisms eventually converted folic acid to reduced forms of folate.”
Cobalamin 1,355 g/mol [methylated is probably better in this case]




I get plenty of magnesium in my diet! NO, you probably don’t.
http://www.orthomolecular.org/resources/omns/v13n22.shtml and




Is vitamin E dangerous? NO. The safety record of all forms of vitamin E is exceptionally good.




Do I need to consume vitamin K-2 because K-1 in foods is ineffective? NO. Your body will make the conversion for you. John Cannell, MD, writes that the conversion “occurs through an intermediary molecule, vitamin K3, which is made in the intestine from vitamin K1. [Hirota Y, et al. J Biol Chem. 2013 Sep 30.] “[M]odern humans are deficient in K2 because they do not eat large quantities of vitamin K1 containing foods. If we look at Paleolithic humans, they probably got high amount of vitamin K2 from eating large quantities of kale and spinach-like foods, very high in K1, which then supplied their tissues with all the vitamin K2 they needed. [A]s far as getting enough vitamin K2, the best thing to do is eat your greens.”


I drink milk, and I spend time in the sunshine. Don’t I get plenty of vitamin D? NO. If your shadow is longer than you are, you are not making vitamin D from sunlight, says William Grant, PhD. Thus, little vitamin D is made by your body in the six colder months of the year. This is also true in the summer months if only exposed to sun mornings and afternoons.




(Andrew W. Saul, OMNS founder and Editor-in-Chief, has coauthored four books with Abram Hoffer, MD, and is editor of the textbook The Orthomolecular Treatment of Chronic Disease. OMNS Assistant Editor Helen Saul Case is the author of The Vitamin Cure for Women’s Health Problems, Vitamins & Pregnancy: The Real Story, and Orthomolecular Nutrition for Everyone.)


Nutritional Medicine is Orthomolecular Medicine

Orthomolecular medicine uses safe, effective nutritional therapy to fight illness. For more information: http://www.orthomolecular.org

The peer-reviewed Orthomolecular Medicine News Service is a non-profit and non-commercial informational resource.

Comments and media contact: drsaul@doctoryourself.com OMNS welcomes but is unable to respond to individual reader emails. Reader comments become the property of OMNS and may or may not be used for publication.

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Dr. Hank Liers, PhDHPDI’s new product ULTIMATE PROTECTOR+ is a next generation cell protection formula that simultaneously meets the needs for high levels of Vitamin C, full spectrum antioxidants* (high ORAC values), and protective enzyme activators (Nrf2 activators from plant-based polyphenols) in a single product. This potent combination of characteristics distinguishes the formula because no other single product available today offers such complete protection.

All three of ULTIMATE PROTECTOR+‘s components provide significant protection against the various types of free radicals that cause cellular damage in the body. In particular, 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 have elected to conduct ORAC testing.


ORAC (standing for “Oxygen Radical Absorption Capacity”) was developed by Brunswick Labs as an analytical tool for estimating the antioxidant capacity of substances. It is an in vitro test that was an important advancement in commercially available analysis of the peroxyl free-radical’s trapping ability of foods and ingredients. It has become a de facto standard in the natural products industry. However, the original ORAC method was considered to be just a starting point for comprehensive antioxidant analysis.

The fact is that there are a variety of “free radicals” that operate in humans — the most important of which are the primary radicals hydroxyl, peroxyl, peroxynitrite, singlet oxygen, and superoxide anion. Brunswick Labs has reported that even though the peroxyl is the major free radical in the body, it represents no more than 27% of the total antioxidant potential of selected fruits and vegetables. In addition, the original ORAC method favors certain antioxidant substances over others (e.g., anthocyanins over carotenoids) due to the use of a single free radical source (peroxyl radical).

These radicals are formed, behave, and are defended against differently. They all contribute to: 1) a general condition called “oxidative stress,” or cellular damage, and 2) broad human health concerns caused, for example, by inflammation, and DNA and protein damage. They are each implicated in different health problems – from cardiovascular disease to macular degeneration and Alzheimer’s disease and to skin damage and aging. Below we provide a brief summary of these free radicals.

The Peroxyl Radical is very important in many biological systems, including lipid peroxidation, DNA cleavage, and protein backbone modification. Hydroxyl is highly reactive and cannot be eliminated by our endogenous enzymes (such as SOD and glutathione). It can damage virtually all types of macromolecules: carbohydrates, nucleic acids, lipids, and amino acids. In the skin, hydroxyl radicals are created by UV exposure. Peroxynitrite is a reactive nitrogen species that is particularly harmful to proteins. It has been implicated in the development of certain cancers, hepatitis, and chronic inflammation. In the skin, peroxynitrite contributes to the breakdown of vital proteins, such as collagen.

Singlet Oxygen is generated in the skin by by UV. In vivo, it is linked to the oxidation of LDL cholesterol and cardiovascular disease. Singlet oxygen is highly unstable and durable. Carotenoids are very effective at scavenging singlet oxygen. Superoxide Anion is a precursor of all other reactive oxygen species and sometimes is referred to as “the mother of free radicals.” It is highly toxic and contributes to lipid and DNA damage. Antioxidants that scavenge superoxide anion also help prevent the formation of radicals such as hydrogen peroxide and hydroxyl. Superoxide anion has been linked to hypertension and cardiovascular damage.

Recently, Brunswick Labs has introduced a new test called ORAC6.0. This test expands the ORAC platform to measure the antioxidant capacity against each of the five primary reactive oxygen species mentioned above as well as Hypochlorite (HOCl) which is another important free radical that is commonly found in the body as a by-product of the metabolism of other free radicals. Direct reaction of HOCl with plasmid DNA gives rise to single- and double-strand breaks via chloramine-mediated reactions. ORAC6.0 substantially improves broad-spectrum antioxidant analysis and gives evidence of the diverse antioxidant potential of natural products against radicals other than just peroxyl.  Brunswick Labs’ research shows that the antioxidants found in a wide range of natural products are effective against these primary radicals, and that in many cases a preponderance of a product’s antioxidant capacity is described by performance against the six free radicals included to the ORAC6.0 panel.


Recently [August/2019] Brunswick Labs has tested ULTIMATE PROTECTOR+™ using the new ORAC6.0 tests. The results reveal an incredible overall ORAC6.0 value of 272,743 µmole TE/gram (i.e., 272,743 per gram!). In addition, the results show that the formula offers excellent protection against all of the six types of free radicals. Specifically, the results show values of 3,376 µmole TE/gram for peroxyl radicals, 5,569 µmole TE/gram for hydroxyl radicals, 2,758 µmole TE/gram for peroxynitrite radicals, 221,866 µmole TE/gram for superoxide anion radicals, 34,169 µmole TE/gram for singlet oxygen radicals, and 5,005 µmole TE/gram for hypochlorite radicals. The table (below) shows for each free radical type the ORAC6.0 daily values for six capsules of ULTIMATE PROTECTOR+™ containing 3.55 grams of the formula.

The overall daily ORAC6.0™ value for six capsules  obtained by adding the values for each free radical type is 968,237 units (272,743 units x 3.55 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 ORAC6.0™ test results for ULTIMATE PROTECTOR+™ are posted on our blog.

Ultimate Protector+ nrf2 activator formula


The bottom line is that you (or anyone) can stand to benefit dramatically from an advanced antioxidant formula that provides exceedingly high ORAC6.0 values and hence amazingly high cell protection…with just a modest daily dose of six small capsules. If you are at all interested to see how well this formula can protect your heath, then we suggest you try a bottle. See for yourself how ULTIMATE PROTECTOR+™ acts to provide you with the ultimate level of protection against free radicals. It’s 100% guaranteed.

ULTIMATE PROTECTOR+™ ORAC6.0 Units Per Serving (six capsules)

ORAC6.0 Units
Per Serving*

Free Radical Type
11,985 Peroxyl Radical is very important in many biological systems, including lipid peroxidation, DNA cleavage, and protein backbone modification.
19,770 Hydroxyl is highly reactive and cannot be eliminated by our endogenous enzymes. It damages virtually all types of macromolecules: carbohydrates, nucleic acids, lipids, and amino acids. In the skin, hydroxyl radicals are created by UV exposure.
9,791 Peroxynitrite is a reactive nitrogen species that is particularly harmful to proteins. It has been implicated in the development of certain cancers, hepatitis, and chronic inflammation. In the skin, peroxynitrite contributes to the breakdown of vital proteins, such as collagen.
121,300 Singlet Oxygen is generated in the skin by UV exposure. It is linked to the oxidation of LDL cholesterol and cardiovascular disease.
787,624 Superoxide Anion is a precursor of all other reactive oxygen species – sometimes referred to as “the mother of free radicals.” It is highly toxic and contributes to lipid and DNA damage.


Hypochlorite HOCl – direct reaction of HOCl with plasmid DNA gives rise to single- and double-strand breaks via chloramine-mediated reactions.


Total ORAC6.0 Per Daily Serving of Six Capsules (3.55 g)

View the Brunswick Labs Ultimate Protector™ ORAC6.0 Test Report Here


ULTIMATE PROTECTOR+™ contains USP-grade non-GMO Vitamin C, SFB® standardized fruit blend (~50% polyphenols, high-ORAC powder: 9,000 µmole TE/g) from Grape, Cranberry, Pomegranate, Blueberry, Apple, Mangosteen, Bilberry, Chokeberry, and Goji Berry), Curcumin (standardized extract with 95% curcuminoids), Trans-Resveratrol (98% from Giant Knotweed), Green Tea Extract (93% polyphenols, 50% EGCG), VinCare® Whole Grape Extract (>80% polyphenols, ORAC>19,000 µmole TE/g), Calcium Malate, Magnesium Malate, and Bioperine® (a patented black pepper extract that enhances absorption of all ingredients and is a known Nrf2 activator).

* Full-spectrum antioxidants in Ultimate Protector+ include polyphenols, flavonoids, anthocyanidins, oligomeric proanthocyanidins, catechins, curcuminoids, ellagic acid, pterostilbene, resveratrol, chlorogenic acid, xanthines, punicalagins, quercetin, zeaxanthin, carotenoids, polysaccharides, quinic acid, and others.



Dr. Hank Liers, PhD ultimate protector+ antioxidant Nrf2 activator formulaToday I discuss HPDI’s newly updated ULTIMATE PROTECTOR+ antioxidant, cell protection, and Nrf2 activator formula. I first formulated Ultimate Protector in 2012 after I learning about plant-based Nrf2 activators.

My original idea behind developing Ultimate Protector was to unite three design elements in a single formula preventing and ameliorating free-radical damage in the body. I recently updated Ultimate Protector (now Ultimate Protector+) based on availability of improved ingredients and additional research studies on Nrf2 activators.


The three design elements include: 1) non-GMO Vitamin C, 2) high ORAC5.0 antioxidants, and 3) multiple plant-based Nrf2 activators. Nrf2 activators cause release of Nrf2 proteins that are bound in every call of the body. Once released they migrate to the cell nucleus where they cause genetic transcription of antioxidant enzymes that can neutralize excess free-radicals in the body.



The new Ultimate Protector+ includes the same amount of Vitamin C as before—owing to its ability to rapidly reduce superoxide and nitroxide radicals, and scavenge hydroxyl, alkoxyl, and peroxyl radicals. Vitamin C also reacts with non-radical species like singlet oxygen and hypochlorous acid. Vitamin C ‘recycles’ other antioxidants (in its role as electron donor) and allows them to quench more free radicals. Vitamin C itself was recently shown to be a Nrf2 activator.

ultimate protector+ nrf2 activator formula uses three modes of action

Ultimate Protector+ uses three modes of action


By means of carefully choosing plant ingredients with the highest ORAC 6.0 values, the product can neutralize all five major types of free radicals commonly found in the body, including: 1) peroxyl, 2) hydroxyl, 3) peroxynitrite, 4) singlet oxygen, and 5) superoxide anion. Ultimate Protector+ includes many plant-based ingredients with high ORAC6.0 values. These include green tea extract, whole grape extract, curcumin, resveratrol, bilberry, and mangosteen.

Brunswick Labs tested Ultimate Protector+™using the ORAC6.0™ test. The results reveal an extremely high overall ORAC6.0 value of 272,743 µmole TE/gram (i.e., 272,743 per gram!). In addition, the results show that the formula offers excellent protection against all six types of free radicals measured. Specifically, the results show values of 3,376 µmole TE/gram for peroxyl radicals, 5,569 µmole TE/gram for hydroxyl radicals, 2,758 µmole TE/gram for peroxynitrite radicals, 221,866 µmole TE/gram for superoxide anion radicals, 34,169 µmole TE/gram for singlet oxygen radicals, and 5,005 µmole TE/gram for hypochlorite radicals. The table (below) shows for each free radical type the ORAC6.0 daily values for six capsules of Ultimate Protector+™ containing 3.55 grams of the formula.ORAC6.0 test results

The overall daily ORAC6.0™ value for six capsules obtained by adding the values for each free radical type is 968,237 units (272,743 units multiplied by 3.55 gram (serving size)! To my knowledge, no other product comes close to providing such complete protection both in terms of breadth of coverage and overall strength. For a fuller explanation of Brunswick Labs ORAC6.0™ test results for Ultimate Protector+™ please read my article “Ultimate Protector+ Brunswick Labs ORAC6.0 Test Report.”


The science on Nrf2 activators clearly shows a wide variety of plant polyphenols act endogenously to cause genetic transcription of many protective enzymes, like superoxide dismutase, glutathione transferase, and heme oxygenase. Many well-known, well-researched Nrf2 activators are high ORAC5.0 antioxidants. These first act as antioxidants giving up an electron, and then act as weak pro-oxidants needed to stimulate Nrf2 activity. In Ultimate Protector+ these ingredients include green tea extract, whole grape extract, curcumin, resveratrol, bilberry, and mangosteen. In addition, ingredients such as extracts of apple, blueberry, cranberry, pomegranate, blueberry, apple, chokeberry, and goji berry are shown in studies to be important Nrf2 activators.


Ultimate Protector+ is a powerful antioxidant and Nrf2 activator formula. Both ORAC6.0™ test results and user experience confirm its effectiveness for quenching free radicals and preventing or reducing oxidative damage from all major types of free radicals. There is currently no other antioxidant and/or Nrf2 activator formula available that provides the level of cell protection afforded by Ultimate Protector+.

Ultimate Protector+ is available from HPDI: ULTIMATE PROTECTOR+

12 plant-based Nrf2 activators


ULTIMATE PROTECTOR+: http://www.integratedhealth.com/ultimate-protector.html



Ultimate Protector+ Brunswick Labs ORAC6.0™ Test Report

Amazing Healing Potential of Natural Nrf2 Activators:

Preventing Free Radical Damage with Ultimate Protector+:

Ultimate Protector+ Design Considerations: http://www.integratedhealthblog.com/scientific-basis-ultimate-protector/

Natural Phytochemical Nrf2 Activators for Chemoprevention:

New Directions For Preventing Free Radical Damage:



Dr. Hank Liers, PhD natural nrf2 activators healing potential

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

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

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


Ultimate Protector+

New Ultimate Protector+


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

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

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

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


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

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


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

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

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

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

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

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


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+


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

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

3) We have observed that the natural plant substances with the highest ORAC5.0 values appear to be among the most effective Nrf2 activators. For example, see the table below. In particular, note that Curcumin (98%), Grape Seed Extract, Green Tea Extract, and Reservatrol which are commonly used for their excellent Nrf2 activator effects are the most powerful in-vitro antioxidants . Please note that Ultimate Protector+ is over 100% more powerful as an antioxidant than the best single plant ingredient.


Ingredient Peroxyl Radical Hydroxyl Radical Peroxy-nitrite Radical Super-
oxide Radical
Singlet O2 Radical Total ORAC5.0
Curcumin 98% 5,750 8,920 906 597 66,290 82,500
Bilberry 25% 7,000 25,000 1,000 16,000 5,000 54,000
Cocoa 10,000 28,000 1,000 11,000 2,000 52,000
Grape Seed Extract 17,000 47,000 1,000 25,000 4,000 94,000
Green Tea Extract 11,000 41,000 2,000 56,000 3,000 113,000
Coffee Berry Extract 5,000 29,000 1,000 1,000 2,000 38,000
Mangosteen 4,000 8,000 1,000 18,000 4,000 35,000
Pine Bark 7,000 23,000 1,000 17,000 2,000 50,000
Resveratrol 12,000 50,000 1,000 8,000 22,000 93,000
ULTIMATE PROTECTOR+    3,376    5,569 2,758 221,866 34,169 267,738
Results are expressed in micro mole TE/g

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

4) Here is a list of the ingredients in ULTIMATE PROTECTOR+: USP-grade non-GMO Vitamin C, SFB® standardized fruit blend (~50% polyphenols, high-ORAC powder: 9,000 µmole TE/g) from Grape, Cranberry, Pomegranate, Blueberry, Apple, Mangosteen, Bilberry, Chokeberry, and Goji Berry), Curcumin (standardized extract with 95% curcuminoids), Trans-Resveratrol (98% from Giant Knotweed), Green Tea Extract (93% polyphenols, 50% EGCG), VinCare® Whole Grape Extract (>80% polyphenols, ORAC>19,000 µmole TE/g), Calcium Malate, Magnesium Malate, and Bioperine® (a patented black pepper extract that enhances absorption of all ingredients and is a known Nrf2 activator).


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)


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)


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)


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.


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!







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

apple extract

Ultimate Protector+ Includes Apple

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

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


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

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


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

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

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

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

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

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


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

Apple phytochemicals and their health benefits

Jeanelle Boyer1 and Rui Hai Liu1


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

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

 Gerhauser C1.

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


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

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

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


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


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


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


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


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