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ULTIMATE PROTECTOR+ NRF2 ACTIVATOR FORMULA – NEW DESIGN!

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.

ULTIMATE PROTECTOR+ ADVANCED CELL PROTECTION & NRF2 ACTIVATOR FORMULA

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.

ELEMENTS OF ULTIMATE PROTECTOR+ FORMULA

1 – NON-GMO VITAMIN C

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.

2 – HIGH-ORAC5.0 VALUE INGREDIENTS

By means of carefully choosing plant ingredients with the highest ORAC 5.0 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 ORAC5.0 values. These include green tea extract, whole grape extract, curcumin, resveratrol, bilberry, and mangosteen.

ultimate protector+ nrf2 activator formula uses three modes of action

Ultimate Protector utilizes three modes of action

3 – POTENT NRF2 ACTIVATORS

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 available from HPDI: ULTIMATE PROTECTOR+
(http://www.integratedhealth.com/ultimate-protector.html)

12 plant-based Nrf2 activators

ULTIMATE PROTECTOR+ RESOURCES

Ultimate Protector+: http://www.integratedhealth.com/ultimate-protector.html

BLOG ARTICLES

Amazing Healing Potential of Natural Nrf2 Activators:
http://www.integratedhealthblog.com/amazing-healing-potential-natural-nrf2-activators/

Preventing Free Radical Damage with Ultimate Protector+:
http://www.integratedhealthblog.com/amazing-healing-potential-natural-nrf2-activators/

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

Natural Phytochemical Nrf2 Activators for Chemoprevention:
http://www.integratedhealthblog.com/natural-phytochemical-nrf2-activators-for-chemoprevention/

New Directions For Preventing Free Radical Damage:
http://www.integratedhealthblog.com/new-directions-for-preventing-free-radical-damage/

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ULTIMATE PROTECTOR+ INGREDIENTS – WHOLE GRAPE EXTRACT

Dr. Hank Liers, PhD biography about us HPDI integratedhealth formulator founder CEO scientist physicist wild bilberry and wild blueberryUltimate Protector+ contains whole grape extract, as well as components from 12 different fruits, vegetables, and herbs. Each of these ingredients contain substances that may be considered to be polyphenols, antioxidants, and Nrf2 activators. In this article, I explore the ingredient whole grape extract (including seeds, pulp, and skin), which is a component of SFB® – Standardized Fruit Blend and VinCare® from Ethical Naturals, Inc.

Ultimate Protector+ Includes Whole Grape Extract

Ultimate Protector+ Includes Whole Grape Extract

SFB® – Standardized Fruit Blend

SFB® Standardized Fruit Blend is a proprietary formula that combines extracts from Grape, Cranberry, Pomegranate, Blueberry, Apple, Mangosteen, Bilberry, Chokeberry, and Goji Berry. High in fruit polyphenols, anthocyanidins, proanthocyanidins, catechins, ellagic acid, chlorogenic acid, resveratrol, and quinic acid. With its diverse blend, SFB® offers 40-50% polyphenols as well as >9,000 ORAC units in a single gram.

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

VinCare® – Standardized Whole Grape Extract

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

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

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

It has been shown that grape seed OPCs activate nuclear erythroid2-related factor2 (Nrf2), which is a key antioxidative transcription factor, with the concomitant elevation of downstream hemeoxygenase-1 (HO-1).

grape extract

HISTORY OF HEALTH PRODUCTS DISTRIBUTORS USE OF WHOLE GRAPE AND GRAPE SEED EXTRACTS

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 Formula, Diabetes Support Formula, Eye & Vision Formula, Joint Health FormulaChewable Kid’s Mighty-MultiHank & Brian’s Mighty Multi-vite!Mini MultiMulti Two, OPC-C, PRO-CProlytRejuvenate! Pro, and Rejuvenate! Berries & Herbs.

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 and grape seeds

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

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.

SUMMARY

Whole Grape and Grape Seed Extracts (GSE) is an exciting natural ingredient full of important polyphenols, anthocyanidins, oligomeric proanthocyanidins (OPCs), 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.

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ULTIMATE PROTECTOR+ INGREDIENTS – CRANBERRY

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

Ultimate Protector+ Includes Cranberry

Ultimate Protector+ Includes Cranberry Extract

SFB® – Standardized Fruit Blend

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, carotenoids, polysaccharides, quinic acid, and more. With its diverse blend, SFB® offers over 40-50% polyphenols as well as >9,000 ORAC units in a single gram.

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

HEALTH BENEFITS OF CRANBERRIES

Cranberries (Vaccinium macrocarpon) are native to the boggy regions of temperate and subalpine North America and Europe. Although Native Americans used them extensively, they were first cultivated in the U.S. in the early 19th century. Cranberries grow on viney plants belonging to the heath family Ericaceae that also includes blueberries, bilberries, huckleberries, and bearberries (Arctostaphylos uva ursi). Cranberries contain tannins, fiber, anthocyanins (and other flavonoids), and Vitamin C. Their tannins prevent bacteria from attaching to cells. Consequently, cranberries have been used against infections, including urinary tract infections. In addition, cranberries may be helpful in protecting against heart disease and stroke.

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

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

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

OTHER CRANBERRY INFORMATION

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

For more information on cranberries visit: http://www.whfoods.com/genpage.php?tname=foodspice&dbid=145

SCIENTIFIC STUDIES ON THE ANTIOXIDANT EFFECTS OF CRANBERRIES

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

PREVENTION OF OXIDATIVE STRESS, INFLAMMATION AND MITOCHONDRIAL DYSFUNCTION IN THE INTESTINE BY DIFFERENT CRANBERRY PHENOLIC FRACTIONS.

ABSTRACT

Cranberry fruit has been reported to have high antioxidant effectiveness that is potentially linked to its richness in diversified polyphenolic content. The aim of the present study was to determine the role of cranberry polyphenolic fractions in oxidative stress (OxS), inflammation and mitochondrial functions using intestinal Caco-2/15 cells. The combination of HPLC and UltraPerformance LC®-tandem quadrupole (UPLC-TQD) techniques allowed us to characterize the profile of low, medium and high molecular mass polyphenolic compounds in cranberry extracts. The medium molecular mass fraction was enriched with flavonoids and procyanidin dimers whereas procyanidin oligomers (DP > 4) were the dominant class of polyphenols in the high molecular mass fraction. Pre-incubation of Caco-2/15 cells with these cranberry extracts prevented iron/ascorbate-mediated lipid peroxidation and counteracted lipopolysaccharide-mediated inflammation as evidenced by the decrease in pro-inflammatory cytokines (TNF-α and interleukin-6), cyclo-oxygenase-2 and prostaglandin E2. Cranberry polyphenols (CP) fractions limited both nuclear factor κB activation and Nrf2 down-regulation. Consistently, cranberry procyanidins alleviated OxS-dependent mitochondrial dysfunctions as shown by the rise in ATP production and the up-regulation of Bcl-2, as well as the decline of protein expression of cytochrome c and apoptotic-inducing factor. These mitochondrial effects were associated with a significant stimulation of peroxisome-proliferator-activated receptor γ co-activator-1-α, a central inducing factor of mitochondrial biogenesis and transcriptional co-activator of numerous downstream mediators. Finally, cranberry procyanidins forestalled the effect of iron/ascorbate on the protein expression of mitochondrial transcription factors (mtTFA, mtTFB1, mtTFB2). Our findings provide evidence for the capacity of CP to reduce intestinal OxS and inflammation while improving mitochondrial dysfunction.

 CHEMICAL CHARACTERIZATION AND CHEMO-PROTECTIVE ACTIVITY OF CRANBERRY PHENOLIC POWDERS IN A MODEL CELL CULTURE. RESPONSE OF THE ANTIOXIDANT DEFENSES AND REGULATION OF SIGNALING PATHWAYS

ABSTRACT

Oxidative stress and reactive oxygen species (ROS)-mediated cell damage are implicated in various chronic pathologies. Emerging studies show that polyphenols may act by increasing endogenous antioxidant defense potential. Cranberry has one of the highest polyphenol content among commonly consumed fruits. In this study, the hepato-protective activity of a cranberry juice (CJ) and cranberry extract (CE) powders against oxidative stress was screened using HepG2 cells, looking at ROS production, intracellular non-enzymatic and enzymatic antioxidant defenses by reduced glutathione concentration (GSH), glutathione peroxidase (GPx) and glutathione reductase (GR) activity and lipid peroxidation biomarker malondialdehyde (MDA). Involvement of major protein kinase signaling pathways was also evaluated. Both powders in basal conditions did not affect cell viability but decreased ROS production and increased GPx activity, conditions that may place the cells in favorable conditions against oxidative stress. Powder pre-treatment of HepG2 cells for 20 h significantly reduced cell damage induced by 400 μM tert-butylhydroperoxide (t-BOOH) for 2 h. Both powders (5–50 μg/ml) reduced t-BOOH-induced increase of MDA by 20% (CJ) and 25% (CE), and significantly reduced over-activated GPx and GR. CE, with a significantly higher amount of polyphenols than CJ, prevented a reduction in GSH and significantly reduced ROS production. CJ reversed the t-BOOH-induced increase in phospho-c-Jun N-terminal kinase. This study demonstrates that cranberry polyphenols may help protect liver cells against oxidative insult by modulating GSH concentration, ROS and MDA generation, antioxidant enzyme activity and cell signaling pathways.

CRANBERRY EXTRACT SUPPRESSES INTERLEUKIN-8 SECRETION FROM STOMACH CELLS STIMULATED BY HELICOBACTER PYLORI IN EVERY CLINICALLY SEPARATED STRAIN BUT INHIBITS GROWTH IN PART OF THE STRAINS

From: http://www.sciencedirect.com/science/article/pii/S1756464613000364

ABSTRACT

It is known that cranberry inhibits the growth of Helicobacter pylori (HP). In human stomach, HP basically induces chronic inflammation by stimulating stomach cells to secrete interleukin (IL)-8 and other inflammatory cytokines, and causes stomach cancer, etc. The aim of this study was to investigate the inhibiting effects of cranberry on HP growth and IL-8 secretion from stomach cells induced by HP, using clinically separated HP strains. HP growth in liquid culture and on-plate culture was evaluated by titration after 2-day incubation and by agar dilution technique, respectively. For IL-8 experiments, MKN-45, a stomach cancer cell line, was incubated with HP for 24 h and IL-8 in the medium was assayed by ELISA. Cranberry suppressed growth of the bacteria only in six of the 27 strains. Meanwhile, it suppressed IL-8 secretion in all the strains. The results may suggest a possible role of cranberry in prevention of stomach cancer by reducing gastric inflammation.

EFFECTS OF CRANBERRY POWDER ON BIOMARKERS OF OXIDATIVE STRESS AND GLUCOSE CONTROL IN DB/DB MICE

From: http://www.ncbi.nlm.nih.gov/pubmed/24353827

ABSTRACT

Increased oxidative stress in obese diabetes may have causal effects on diabetic complications, including dyslipidemia. Lipopolysccharides (LPS) along with an atherogenic diet have been found to increase oxidative stress and insulin resistance. Cranberry has been recognized as having beneficial effects on diseases related to oxidative stress. Therefore, we employed obese diabetic animals treated with an atherogenic diet and LPS, with the aim of examining the effects of cranberry powder (CP) on diabetic related metabolic conditions, including lipid profiles, serum insulin and glucose, and biomarkers of oxidative stress. Forty C57BL/KsJ-db/db mice were divided into the following five groups: normal diet + saline, atherogenic diet + saline, atherogenic diet + LPS, atherogenic diet + 5% CP + LPS, and atherogenic diet + 10% CP + LPS. Consumption of an atherogenic diet resulted in elevation of serum total cholesterol and atherogenic index (AI) and reduction of high density lipoprotein (HDL)-cholesterol. However, with 10% CP, the increase in mean HDL-cholesterol level was close to that of the group with a normal diet, whereas AI was maintained at a higher level than that of the group with a normal diet. LPS induced elevated serum insulin level was lowered by greater than 60% with CP (P < 0.05), and mean serum glucose level was reduced by approximately 19% with 5% CP (P > 0.05). Mean activity of liver cytosolic glutathione peroxidase was significantly increased by LPS injection, however it was reduced back to the value without LPS when the diet was fortified with 10% CP (P < 0.05). In groups with CP, a reduction in mean levels of serum protein carbonyl tended to occur in a dose dependent manner. Particularly with 10% CP, a reduction of approximately 89% was observed (P > 0.05). Overall results suggest that fortification of the atherogenic diet with CP may have potential health benefits for obese diabetes with high oxidative stress, by modulation of physical conditions, including some biomarkers of oxidative stress.

SUMMARY

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

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ULTIMATE PROTECTOR+ INGREDIENTS – MANGOSTEEN

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

Ultimate Protector+ Includes Mangosteen

Ultimate Protector+ Includes Mangosteen

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

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

HEALTH BENEFITS OF MANGOSTEEN

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

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

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

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

Metabolite Composition of Mangosteen

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

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

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

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

SCIENTIFIC STUDIES ON THE ANTIOXIDANT EFFECTS OF MANGOSTEEN

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

Recent updates on metabolite composition and medicinal benefits of mangosteen plant

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

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

ABSTRACT

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

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

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

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

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

Abstract

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

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

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

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

Abstract

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

 

γ-Mangostin, a xanthone from mangosteen, attenuates oxidative injury in liver via NRF2 and SIRT1 induction

Abstract

γ-Mangostin (γ-man), an active compound from Garcinia mangostana L., has been discovered as a hepatoprotective agent against oxidative injury. However, the underlying mechanisms remained unclear. The current study showed that γ-man stimulated the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) to enhance antioxidant capacity under oxidative stress, which was partially reversed by treatment of the NRF2 inhibitor, all-trans-retinoic acid. Moreover, γ-man increased the expression and activity of SIRT1 (silent mating type information regulation 2 homolog 1), which facilitated the deacetylation of peroxisome proliferator-activated receptor γ coactivator 1α to improve the mitochondrial function in L02 cells. The protective effect of γ-man was partially blocked by treatment of the SIRT1 inhibitor tenovin-1 or SIRT1 knockdown. In vivo studies showed γ-man protected mice from carbon tetrachloride-induced acute liver injury, through up-regulation of NRF2 and SIRT1. Thus, γ-man might be a candidate to protect liver from acute oxidative injury.

SUMMARY

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

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

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AMAZING IMMUNE-ASSIST™ MUSHROOM FORMULA

Dr. Hank Liers, PhD Immune-Assist™ medicinal mushroom extracts

HPDI’s amazing IMMUNE-ASSIST™ mushroom formula is a combination of more than 200 different polysaccharides, derived from the enzymatic breakdown of complex organic plant material from six different species of organically grown medicinal mushrooms. These include Agaricus blazei, Cordyceps hybrid (sinensis and militaris), Lentinula edodes (shiitake)Grifola frondosa (maitake)Ganoderma lucidum (Reishi), and Coriolus versicolor.

IMMUNE-ASSIST™ Daily Formula contains simple polysaccharides similar to many other products on the market, but it also contains much more complex polysaccharides like the cross-linked beta mannans and beta-glucans into the same molecule. This is why Immune-Assist™ shows such a greater range of immuno-modulation bioactivity than other bran based supplements. Included among the important substances in Immune-Assist™ are Arabinoxylane, Lentinan, Grifolan (Dr. Nanba’s original Maitake D-Fraction), PSK and PSP, and Active Hemicellulose Correlated Compound (AHCC).

Many mushroom-derived polysaccharides appear to fit the accepted criteria for immunomodulators or biological response modifiers (BRM) compounds. They cause no harm and place no additional stress on the body, they assist the body to adapt to the various environmental and psychological stresses, and they have a non-specific action on the body, supporting all the major systems, including nervous, hormonal, and immune systems, as well as regulatory functions.

MEDICINAL MUSHROOM EXTRACTS: ONE OF THE MOST POWERFUL IMMUNE MODULATORS KNOWN

Recent scientific research has shown that medicinal mushrooms grown on vegetable sources (such as millet, rice bran, buckwheat, milo, etc.) enzymatically activate a process whereby complex cross-linked polysaccharides from the vegetable sources are converted to biologically active immunomodulators. As you will see from the discussion below, the polysaccharides produced by this process are effective and safe immune stimulants.

Medicinal mushroom research has focused on discovering compounds that can modulate positively or negatively the biological response of immune cells. Certain mushroom derived-glucans and polysaccharide-bound proteins have been shown to act as immunomodulators, where these polymers interact with the immune system to upregulate or downregulate specific aspects of the responses of the host and this may result in various therapeutic effects.

Whether certain compounds enhance or suppress immune responses can depend on a number of factors including dosage, route of administration, timing and frequency of administration, mechanism of action or the site of activity.

The most effective polysaccharides isolated from mushrooms (fruit-body, submerged, cultured mycelial biomass or liquid culture broth) are either water-soluble β-D-glucans, β-D-glucans with heterosaccharide chains of xylose, mannose, galactose, or uronic acid or β-D-glucan-protein complexes – proteoglycans.

While the role of medicinal mushrooms in immunomodulation represents the central theme of much of the conducted research, it is pertinent to observe that many of the medicinal mushrooms have been highly valued for other medicinal properties including cholesterols control, blood pressure support, blood sugar support, assistance with viral and bacterial balance, and antioxidant and free radical scavenging.

The safety criteria for mushroom-derived β-glucans have been exhaustively carried out in pre-clinical experiments. Acute, subacute, and chronic toxicity tests have been carried out together with administration during pregnancy and lactation with no adverse effects. There were no anaphylactic reactions and no effects in mutagenicity and haemolysis tests, blood coagulation and a wide range of other regulatory tests. There was no evidence of genotoxicity. Similar results have been obtained with other β-glucans. When applied to humans in Phase 1 clinical tests, the β-glucans demonstrate remarkably few adverse clinical reactions.

In the 2001 report Medicinal Mushrooms: Their Therapeutic Properties and Current Medical Usage, a wide variety of mushroom polysaccharides, including Lentinan (from L. edodes), Schizophyllan (from S. commune), PSK and PSP (from Trametes versicolor), and Grifron-D (from the Maitake mushroom G. frondosa) and others are described, and their properties are shown to satisfy the criteria for biological response modifiers. Many of these mushroom-derived polymers potentiate the host’s innate (non-specific) and acquired (specific) immune responses in a similar manner, where they activate many kinds of immune cells that are vitally important for the maintenance of homeostasis.

Key innate responses that are stimulated by these mushroom derived-β-glucans or polysaccharide-protein complexes include host T-cells (such as cytotoxic macrophages, monocytes, neutrophils, natural killer cells, and dendritic cells) and chemical messengers (cytokines such as interleukins, interferon and colony stimulating factors) that trigger complement and acute phase responses. Moreover, mushroom polysaccharides or polysaccharide-protein complexes are considered as multi-cytokine inducers that are able to induce gene expression of various immunomodulatory cytokines and cytokine receptors.

In addition, acquired responses are also enlisted, where lymphocytes that govern antibody production (B cells) and cell-mediated cytotoxicity (T-cells) are stimulated. While the immune system is shrouded in tremendous complexity, our current understanding shows that it is regulated in an orchestrated dynamic manner.

Mushroom-derived polysaccharides have shown therapeutic activities in both pre-clinical models and in clinical trials. Although the mechanism of their action is still not completely clear, Lentinan, Schizophyllan, PSP, PSK and other mushroom polysaccharides appear to mediate their activity by activation or augmentation of the host’s immune system (via stimulated cytotoxic macrophages, cytotoxic T-cells and antibody-mediated cytoxicity of targeted cells), rather than direct cytotoxicity.

Thus, both cell-mediated immune responses against the target T-cells initiated by macrophage-lymphocyte interactions and cytoxicity induced by antibodies to target T-cells are believed to contribute to the elimination of abnormal cells. Recent evidence suggests that several mushroom polysaccharides may also possess cytotoxic properties. Grifron-D from G. fondosa mushroom was reported to induce apoptosis (programmed cell death) in human prostate cell-lines.

IMMUNE-ASSIST™ DAILY FORMULA INCORPORATES POLYSACCHARIDE EXTRACTS FROM SIX MEDICINAL MUSHROOMS

In China, Japan, Korea, and more recently in the USA, hundreds of mushroom species have been studied during the past 30 years. Extracts from most of the medicinal mushrooms show a common property of enhancing immune function by modulating cell-mediated immunity. Simply put, such mushroom extracts seem to turn on cells in the immune system, which appear to have significant healing properties. In fact, three different drugs extracted from mushrooms have been approved by the Japanese equivalent of FDA (that is, the Japanese Health and Welfare Ministry). These three are lentinan, derived from shiitake; PSK, derived from coriolus versicolor; and schizophyllan, derived from suehirotake.

Based on the latest research a USA-based company (Aloha Medicinals, Inc.) has formulated for Health Products Distributors, Inc. IMMUNE-ASSIST™ Daily Formula. This formula contains more than 200 different polysaccharides, derived from the enzymatic breakdown of complex organic plant material from six different species of medicinal mushrooms. These include Agaricus blazei, Cordyceps hybrid (sinensis and militaris), Lentinula edodes (shiitake)Grifola frondosa (maitake)Ganoderma lucidum (Reishi), and Coriolus versicolor.

Immune-Assist™ Medicinal Mushrooms

RESEARCH RELATED TO MUSHROOMS CONTAINED IN IMMUNE-ASSIST™

Shiitake is now the most popular and most cultivated exotic mushroom in the world. In China, shiitake has a history that dates back to the Ming Dynasty (1368–1644 ACE). The mushroom was used not only as a food but was taken as a remedy for upper respiratory diseases, poor blood circulation, liver trouble, exhaustion and weakness, and to boost chi, or life energy. It was also believed to prevent premature aging.

Coriolus (or Trametes) versicolor is the most thoroughly clinically researched mushroom. An extract of Coriolus versicolor known as PSK is sold in Europe and Japan. It is an immunostimulant; demonstrates anti-viral activity; enhances T-cell proliferation; and has been shown to improve both disease-free and survival rates in patients.

Maitake may be even more potent than any of the other mushrooms previously studied. This legendary giant mushroom has been studied for its anti neoplastic, anti-diabetic, anti-hypertensive, and anti-hyperlipemic effects since the mid-1980s. Its anti-HIV activity in vitro was demonstrated in tests conducted by the Japan Institute of Health and the US National Cancer Institute in early 1992. Among various extracts obtained from the Maitake mushroom, a specific extracted fraction named Maitake D-fraction is the active constituent. This extract contains beta-1, 3-glucans and beta-1, 6-glucans protein-bound polysaccharides. It has demonstrated remarkable cell-protective activity by activating the immune system through oral administration.

The Chinese have long used Cordyceps sinensis and militaris to promote overall good health, and modern research indicates that it does indeed support liver, kidney, heart, and immune system function. Cordyceps has been used to protect the bone marrow and digestive systems of mice from whole body irradiation. One experiment noted that Cordyceps may protect the liver. An experiment with mice indicated the mushroom may have an anti-depressant effect.

Researchers have observed that Cordyceps has a hypoglycemic effect and may be beneficial for people with insulin resistance. Cordyceps mushroom extracts have been shown to stimulate the number of T helper cells, prolong the survival of lymphocytes, enhance TNF-alpha and interleukin 1 production, and increase the activity of natural killer cells. One study indicates that cordyceps can stimulate progesterone production in animal cells.

Reishi possess immunomodulary and immunotherapeutic activities supported by studies on polysaccharides, terpene, and other bioactive compounds isolated from fruiting bodies and mycelia of this fungus. It has also been found to inhibit platelet aggregation, and to lower blood pressure (via inhibition of angiotensin-converting enzyme), cholesterol, and blood sugar.

In an animal model, Reishi has been reported to prevent metastasis, with potency comparable to Lentinan from shiitake mushrooms. The mechanisms by which Reishi may target different stages of abnormal growth development include: 1) inhibition of angiogenesis (formation of new blood vessels created to supply nutrients to the abnormal cell) mediated by cytokines, 2) cytotoxicity, 3) inhibition of migration of the cells and 4) inducing and enhancing apoptosis. Besides effects on mammalian physiology, Reishiis reported to have anti-bacterial and anti-viral activities. Reishi is reported to exhibit direct anti-viral effects with the following viruses: HSV-1, HSV-2, and influenza.

Agaricus blazei is an edible mushroom native to Brazil and cultivated in Japan and the USA for its medicinal uses. It has been used to treat arteriosclerosis, hepatitis, hyperlipidemia, diabetes, dermatitis, and neoplasms. In vitro experiments and studies done in mice have shown that Agaricus has immunomodulatory and antimutagenic properties. The polysaccharides and anti-angiogenic compounds present in Agaricus are thought to be responsible for its therapeutic properties. Such effects are believed to be exerted by immunopotentiation or direct inhibition of angiogenesis.

ACTIVE HEMICELLULOSE CORRELATED COMPOUND (AHCC) AS A COMPONENT OF IMMUNE-ASSIST™ DAILY FORMULA

AHCC is produced by from the enzymatic action of vegetable sources with mycelial extracts from several different mushrooms. There is about four times more AHCC in each dose of Immune-Assist™ than there is in other AHCC products on the market.

AHCC is a food substance that contains a broad range of polysaccharides. It is believed that a special polysaccharide with a molecular weight of about 5,000 and an alpha 1,4 glucan linkage in this mushroom extract is primarily responsible for the powerful immune enhancing effects on natural killer cells. A heavier polysaccharide in the extract appears to have a powerful stimulating effect on macrophages which, in turn, further stimulates the immune system including a number of cytokines (Interleukin-2, Interleukin-12, TNF, and Interferon). Furthermore, some research has indicated that components of AHCC may have direct cytotoxic effects on unhealthy cells.

NATURAL KILLER CELLS

The human immune system is comprised of more than 130 subsets of white blood cells. Natural Killer (NK) cells make up roughly 15% of all human white blood cells. They provide the first line of defense for dealing with any form of invasion to the body. Each NK cell contains several small granules that act as chemical destroyers. Once an NK cell has recognized an unwanted cell, for example, it attaches itself to the cell’s outer membrane and injects these granules directly into the interior of the cell. The granules then destroy the cell within five minutes. The undamaged NK cell then moves on to other cells and repeats the process. When the immune system is particularly strong, active NK cells will often take on more than one cell or other infected cells at the same time.

NK CELL ACTIVITY, NOT NUMBER, DETERMINES THE STRENGTH OF THE IMMUNE SYSTEM

Unlike other white blood cells, inadequate numbers of NK cells are very rarely a problem. Instead, it is the activity of the cells that generally determines whether one is sick or healthy. As long as the NK cells are active, everything remains under control. If NK cells lose their ability to either recognize or destroy the invader, however, the situation can deteriorate rapidly. In many patients with serious health conditions, NK cell activity is probably the primary criteria for estimating the chances of survival. It is commonly accepted that when NK cells cease to function, the end is near.

In addition, research has now confirmed that individuals with low NK cell activity are significantly more susceptible to autoimmune diseases, chronic fatigue syndrome, viral infections and the development of abnormal growths.

Doctors can test NK cell activity with a test called the NK cell function test. Basically, a blood sample is taken from the patient and placed in a vial containing appropriate live cells. After four hours, a count is taken to determine what percentage of the cells have been destroyed by the NK cells. The higher the percentage, the more active the cells. This test is referred to as the four hour Chromium-release assay. Your doctor can order the test from Immune Sciences Lab in Beverly Hills, CA at (310) 657-1077.

HOW IMMUNE-ASSIST™ DAILY FORMULA INCREASES NK CELL ACTIVITY AND IMMUNITY

The capacity of Immune-Assist™ to boost NK activity and overall immunity appears to stem from the following:

1) It increases the number of explosive granules in NK cells. The more granules an NK cell carries, the more unhealthy cells it can destroy.

2) Oral ingestion can increase NK activity as much as 300% (or even higher).

3) It increases interferon (IFN) levels. Interferon is another potent compound produced by the body that both inhibits the replication of viruses and other parasites and increases NK cell activity.

4) It increases the formation of TNFs. TNFs are a group of proteins that help destroy unwanted cells.

5) It increases number and the activity of other lymphocytes, especially T-cells (up to 200%) and macrophages.

6) It stimulates cytokine (IL-2, IL-12, TNF, and IFN) production, which stimulates immune function.

SUPPLEMENT FACTS

COMPOSITION: Two vegetarian capsules provide the following percentage of the Daily Value:

NUTRIENT AMOUNT % Daily Value
Proprietary Beta-Glucan complex plus nucleosides and other bioactive compounds extracted from six well-known, organically grown medicinal mushrooms: Agaricus blazei, Cordyceps sinensis and Cordyceps militaris, Lentinula edodes, Grifola frondosa, Ganoderma lucidum, and Coriolus versicolor. 1,000 mg *

* No established Daily Value

USAGE

DIRECTIONS: As a dietary supplement take two capsules per day in divided doses, or as recommended by a health care professional. In severe conditions, we suggest six (6) capsules per day for two weeks to build up immune activity, then maintaining a dosage of two (2) capsules per day. Alternatively, Immune-Assist™ can be taken at the time of exposure or first signs of illness, in which case we recommend taking two caps three times per day.

INGREDIENTS: IMMUNE-ASSIST™ contains a proprietary organic grown blend grown on organic white milo (growing substrate) and veggie capsule.

IMMUNE-ASSIST™ does not contain: wheat, rye, oats, corn, barley, gluten, soy, egg, dairy, yeast, GMOs, sugar, wax, preservatives, colorings, or artificial flavorings.

REFERENCES

1) Healing Mushrooms by Dr. Georges Halpern, MD, PhD, 2007.

2) Medicinal Mushrooms: Their Therapeutic Properties and Current Medical Usage with Special Emphasis on Cancer Treatments. Smith, Rowan and Sullivan, 2001.

3) Medicinal mushrooms as a source of antitumor and immunomodulating polysaccharides (PDF 269 kb). A peer-reviewed article by Dr. Solomon Wasser of University of Haifa, Israel, 2002.