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  • PRO-C ANTIOXIDANT FORMULA UPDATE + VIDEO

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

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

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

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

    FORMULATION HISTORY AND THE SCIENCE BEHIND PRO-C™

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

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

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

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

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

    PRO-C super antioxidant formula 180 cap 90 cap

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

    THE PRO-C™ SUPER ANTIOXIDANT FORMULA

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

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

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

    Dr. Packer continues:

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

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

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

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

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

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

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

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

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

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

    PRO-C™ ANTIOXIDANT FORMULA INGREDIENTS

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

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

    VITAMIN C

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

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

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

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

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

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

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

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

    GRAPE EXTRACT

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

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

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

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

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

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

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

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

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

    GREEN TEA EXTRACT

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

    Green tea antioxidant polyphenols catechins Green tea leaves are high in antioxidant polyphenols and catechins.

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

    Following the oral feeding of a polyphenolic fraction isolated from green tea (GTP) in drinking water, an increase in the activities of antioxidant and phase II enzymes in skin, small bowel, liver, and lung of female SKH-1 hairless mice was observed. GTP feeding (0.2%, w/v) to mice for 30 days significantly increased the activities of glutathione peroxidase, catalase, and quinone reductase in small bowel, liver, and lungs, and glutathione S-transferase in small bowel and liver. GTP feeding to mice also resulted in considerable enhancement of glutathione reductase activity in liver. In general, the increase in antioxidant and phase II enzyme activities was more pronounced in lung and small bowel as compared to liver and skin. The significance of these results can be implicated in relation to the cancer chemopreventive effects of GTP against the induction of tumors in various target organs.

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

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

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

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

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

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

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

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

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

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

    R-LIPOIC ACID / ALPHA-LIPOIC ACID

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

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

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

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

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

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

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

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

    SELENIUM

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

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

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

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

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

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

    VITAMINS B2 and B6 IN COENZYME FORMS

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

    MAGNESIUM, CALCIUM, AND ZINC

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

    PRO-C™ SUPER ANTIOXIDANT FORMULA BENEFITS

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

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

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

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

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

    COMPOSITION OF PRO-C™ SUPER ANTIOXIDANT FORMULA

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

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

    * No established Daily Value

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

    INGREDIENTS: PRO-C™ SUPER ANTIOXIDANT FORMULA contains only the highest-quality USP grade magnesium ascorbate, USP grade calcium ascorbate, BioVin® grape extract (greater than 75% polyphenols, 55% OPC, greater than 3.5% anthocyanidins from grape pulp, skins, and seeds, and a small amount of trans resveratrol), green tea extract (95% min. polyphenols and 45% min. EGCG), l-glutathione (reduced), USP grade n-acetyl-l-cysteine, USP grade zinc ascorbate, r-(+)-lipoic acid, riboflavin-5'-phosphate, pyridoxal-5'-phosphate, l-selenomethionine, the smallest amounts of microcrystalline cellulose and silica in a vegetarian capsule.

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

    Click here to order PRO-C™.

    SOURCES & RESOURCES

    BOOKS

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

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

    ARTICLES

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

    "Vitamin C – An Amazing Nutrient" by Hank Liers, PhD

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

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

    ABSTRACTS

    PRO-C™ / Vitamin C Abstracts

    Catechin Abstracts

    N-Acetyl-L-Cysteine (NAC) Abstracts

    Lipoic Acid Abstracts

    WEBSITES

    Orthomolecular.org
    (Therapeutic Nutrition Based Upon Biochemical Individuality)

    PRODUCTS

    PRO-C™Super Antioxidant Formula

    Ultimate Protector™Nrf2 Activator Formula

    OPC-C™

    HPDI Vitamin C Products

  • 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 freeze dried cranberries, as well as components from 29 different fruits, vegetables, and herbs. Each of these ingredients contain substances that may be considered to be polyphenols, antioxidants, and Nrf2 activators. In this article I explore the ingredient cranberries, which is a component of VitaBerry Plus® from Futureceuticals.

    VITABERRY PLUS®

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

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

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

    Cranberry Cranberry

    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.

    Cranberries are 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 cranberries.

    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 cranberries 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.
    • In 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.

    Ultimate Protector

    SUMMARY

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

  • ULTIMATE PROTECTOR INGREDIENTS - BLACK CURRANT EXTRACT

    Dr. Hank Liers, PhD biography about us HPDI integratedhealth formulator founder CEO scientist physicist wild bilberry and wild blueberryUltimate Protector contains black currant extract, as well as components from 29 different fruits, vegetables, and herbs. Each of these ingredients contain substances that may be considered to be polyphenols, antioxidants, and Nrf2 activators. In this article I explore the ingredient black currant extract, which is a component of Anthocomplete™ from Futureceuticals.

    ANTHOCOMPLETE™

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

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

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

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

    Black Currant Black Currant Berries

    HEALTH BENEFITS OF BLACK CURRANT EXTRACT

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

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

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

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

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

    Scientific Studies on the Antioxidant Effects of Black Currants

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

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

    Abstract

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

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

    Abstract

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

     

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

    From:http://www.ncbi.nlm.nih.gov/pubmed/22873220

    Abstract

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

     

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

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

    Abstract

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

     

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

    From: http://www.ncbi.nlm.nih.gov/pubmed/21216582

    Abstract

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

     

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

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

    Abstract

    Abstract Image

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

    SUMMARY

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

     

  • ULTIMATE PROTECTOR INGREDIENTS – RESVERATROL

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

    Ultimate Protector contains resveratrol, as well as components from 29 different fruits, vegetables, and herbs. Each of these ingredients contain substances that may be considered to be polyphenols, antioxidants, and Nrf2 activators. In this article I will explore the ingredient resveratrol, which is added as a separate ingredient in addition to being a component in VitaBerry Plus® from Futureceuticals.

    Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants in response to injury or when the plant is under attack by pathogens such as bacteria and fungi. Natural sources of resveratrol include giant knotweed (Polygonum cuspidatum) and the skin of grapes, blueberries, raspberries, and mulberries. Resveratrol has two isomers: cis and trans, with the latter being the most abundant.  Piceid, also known as polydatin, is a glucoside form of resveratrol found in Japanese knotweed. HPDI includes the very pure 99% resveratrol form from giant knotweed in Ultimate Protector. This material contains greater than 96% of the trans form.

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

     

    VITABERRY PLUS®

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

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

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

    HEALTH BENEFITS OF RESVERATROL

    Resveratrol provides anti-oxidant protection, boosts cellular energy, and balances the immune system. It has been proven in studies to activate the SIRT1 longevity gene and enhance cellular productivity. Several research studies have shown that trans-resveratrol significantly modulates biomarkers of bone metabolism, inhibits pro-inflammatory enzymes such as COX-1 and COX-2, and exhibits chemopreventive properties, cardioprotective effects, neuroprotective properties, and caloric restrictive behavior. Trans-resveratrol has shown the ability to increase the number of mitochondria thereby increasing total daily energy. Studies have shown that trans-resveratrol promotes an increase in mitochondrial function, that translates into an increase in energy availability, improved aerobic capacity, and enhanced sensorimotor function. Resveratrol has been shown to be a powerful Nrf2 activator that can support the body's endogenous production of protective enzymes.

    Scientific Studies on the Antioxidant Effects of Resveratrol

    Databases of scientific studies (like the National Institutes of Health (NIH) PubMed database) contain thousands of up-to-date studies and abstracts about resveratrol

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

    Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2.

    Abstract

    Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. Resveratrol was also shown to confer vasoprotection in animal models of type 2 diabetes and aging. However, the mechanisms by which resveratrol exerts its antioxidative vasculoprotective effects are not completely understood. Using a nuclear factor-E(2)-related factor-2 (Nrf2)/antioxidant response element-driven luciferase reporter gene assay, we found that in cultured coronary arterial endothelial cells, resveratrol, in a dose-dependent manner, significantly increases transcriptional activity of Nrf2. Accordingly, resveratrol significantly upregulates the expression of the Nrf2 target genes NAD(P)H:quinone oxidoreductase 1, gamma-glutamylcysteine synthetase, and heme oxygenase-1. Resveratrol treatment also significantly attenuated high glucose (30 mM)-induced mitochondrial and cellular oxidative stress (assessed by flow cytometry using MitoSox and dihydroethidine staining). The aforementioned effects of resveratrol were significantly attenuated by the small interfering RNA downregulation of Nrf2 or the overexpression of Kelch-like erythroid cell-derived protein 1, which inactivates Nrf2. To test the effects of resveratrol in vivo, we used mice fed a high-fat diet (HFD), which exhibit increased vascular oxidative stress associated with an impaired endothelial function. In HFD-fed Nrf2(+/+) mice, resveratrol treatment attenuates oxidative stress (assessed by the Amplex red assay), improves acetylcholine-induced vasodilation, and inhibits apoptosis (assessed by measuring caspase-3 activity and DNA fragmentation) in branches of the femoral artery. In contrast, the aforementioned endothelial protective effects of resveratrol were diminished in HFD-fed Nrf2(-/-) mice. Taken together, our results indicate that resveratrol both in vitro and in vivo confers endothelial protective effects which are mediated by the activation of Nrf2.

     

    Mitochondrial Protection by Resveratrol

    From: http://www.medscape.com/viewarticle/745451

    Abstract

    Mitochondrial dysfunction and oxidative stress are thought to play important roles in mammalian aging. Resveratrol is a plant-derived polyphenol that exerts diverse antiaging activities, mimicking some of the molecular and functional effects of dietary restriction. This review focuses on the molecular mechanisms underlying the mitochondrial protective effects of resveratrol, which could be exploited for the prevention or amelioration of age-related diseases in the elderly.

    Introduction

    Age-specific mortality rates from heart disease, stroke, complications of diabetes, Alzheimer disease, and cancer increase exponentially with age, which imposes a huge financial burden on the health care systems in the Western world. There is an urgent need for effective therapeutic strategies that have the potential to promote health in the elderly, simultaneously preventing or delaying the development of various diseases of aging. During the past decade, dietary supplementation with resveratrol (3,5,4′-trihydroxystilbene) has emerged as a promising approach to counteract age-related diseases. Resveratrol is a naturally occurring polyphenol found in more than 70 species of plants, including grapes (Vitis vinifera), cranberries (Vaccinium macrocarpon), and peanuts (Arachis hypogaea), which was shown to confer diverse physiological effects in laboratory animals including cancer protection, microvascular protection, neuroprotection, cardioprotection, and antidiabetic effects. In this review, we consider the evidence in support of the hypothesis that mitochondrial protective effects of resveratrol underlie its antiaging action that can prevent/delay the development of age-related diseases in the cardiovascular system and other organs. The use of resveratrol as a dietary supplement to promote mitochondrial health in the elderly and diabetic patients is discussed.

     

    Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells

    From: http://ajplung.physiology.org/content/294/3/L478 

    Abstract

    Nuclear erythroid-related factor 2 (Nrf2), a redox-sensitive transcription factor, is involved in transcriptional regulation of many antioxidant genes, including glutamate-cysteine ligase (GCL). Cigarette smoke (CS) is known to cause oxidative stress and deplete glutathione (GSH) levels in alveolar epithelial cells. We hypothesized that resveratrol, a polyphenolic phytoalexin, has antioxidant signaling properties by inducing GSH biosynthesis via the activation of Nrf2 and protects lung epithelial cells against CS-mediated oxidative stress. Treatment of human primary small airway epithelial and human alveolar epithelial (A549) cells with CS extract (CSE) dose dependently decreased GSH levels and GCL activity, effects that were associated with enhanced production of reactive oxygen species. Resveratrol restored CSE-depleted GSH levels by upregulation of GCL via activation of Nrf2 and also quenched CSE-induced release of reactive oxygen species. Interestingly, CSE failed to induce nuclear translocation of Nrf2 in A549 and small airway epithelial cells. On the contrary, Nrf2 was localized in the cytosol of alveolar and airway epithelial cells due to CSE-mediated posttranslational modifications such as aldehyde/carbonyl adduct formation and nitration. On the other hand, resveratrol attenuated CSE-mediated Nrf2 modifications, thereby inducing its nuclear translocation associated with GCL gene transcription, as demonstrated by GCL-promoter reporter and Nrf2 small interfering RNA approaches. Thus resveratrol attenuates CSE-mediated GSH depletion by inducing GSH synthesis and protects epithelial cells by reversing CSE-induced posttranslational modifications of Nrf2. These data may have implications in dietary modulation of antioxidants in treatment of chronic obstructive pulmonary disease.

     

    Effect of Nrf2 activators on release of glutathione, cysteinylglycine and homocysteine by human U373 astroglial cells

    From: http://www.sciencedirect.com/science/article/pii/S2213231713000645

    Abstract

    Neurons rely on the release and subsequent cleavage of GSH to cysteinylglycine (CysGly) by astrocytes in order to maintain optimal intracellular GSH levels. In neurodegenerative diseases characterised by oxidative stress, neurons need an optimal GSH supply to defend themselves against free radicals released from activated microglia and astroglia. The rate of GSH synthesis is controlled largely by the activity of γ-glutamyl cysteine ligase. Expression of γ-glutamyl cysteine ligase and of the Xc- system, which facilitates cystine uptake, is regulated by the redox-sensitive transcription factor, nuclear factor erythroid-2-related factor 2 (Nrf2). Compounds that can activate the Nrf2-ARE pathway, referred to as ‘Nrf2 activators’ are receiving growing attention due to their potential as GSH-boosting drugs.

    This study compares four known Nrf2 activators, R-α-Lipoic acid (LA), tert-butylhydroquinone (TBHQ), sulforaphane (SFN) and Polygonum cuspidatum extract containing 50% resveratrol (PC-Res) for their effects on astroglial release of GSH and CysGly. GSH levels increased dose-dependently in response to all four drugs. Sulforaphane produced the most potent effect, increasing GSH by up to 2.4-fold. PC-Res increased GSH up to 1.6-fold, followed by TBHQ (1.5-fold) and LA (1.4-fold). GSH is processed by the ectoenzyme, γ-glutamyl transpeptidase, to form CysGly. Once again, SFN produced the most potent effect, increasing CysGly by up to 1.7-fold, compared to control cells. TBHQ and PC-Res both induced fold increases of 1.3, followed by LA with a fold increase of 1.2. The results from the present study showed that sulforaphane, followed by lipoic acid, resveratrol and Polygonum multiflorum were all identified as potent “GSH and Cys-Gly boosters”.

    Resveratrol Upregulates Nrf2 Expression To Attenuate Methylglyoxal-Induced Insulin Resistance in Hep G2 Cells

    From: http://pubs.acs.org/doi/abs/10.1021/jf302831d

    Abstract

    Oxidative stress can result in insulin resistance, a primary cause of type-2 diabetes. Methylglyoxal (MG), a highly reactive dicarbonyl metabolite generated during glucose metabolism, has also been confirmed to cause pancreatic injury and induce inflammation, thereby resulting in insulin resistance. Recently, resveratrol has been reported to exert antioxidant properties, protecting cells from the generation of reactive oxygen species (ROS). The aim of this study was to evaluate resveratrol activation of nuclear factor erythroid 2-related factor 2 (Nrf2) to attenuate MG-induced insulin resistance in Hep G2 cells. Therefore, the molecular signaling events affecting resveratrol-mediated heme oxygenase-1 (HO-1) and glyoxalase expression levels were further investigated in this study. Our findings indicated that resveratrol activated the extracellular signal-regulated kinase (ERK) pathway but not the p38 or c-Jun N-terminal kinase (JNK) pathways, subsequently leading to Nrf2 nuclear translocation and elevation of HO-1 and glyoxalase expression levels. Moreover, resveratrol significantly elevated glucose uptake and protected against MG-induced insulin resistance in Hep G2 cells. In contrast, depletion of Nrf2 by small interfering RNA (si-RNA) resulted in the abrogation of HO-1 and glyoxalase expression in the MG-treated resveratrol group in Hep G2 cells. Administration of an appropriate chemopreventive agent, such as resveratrol, may be an alternative strategy for protecting against MG-induced diabetes.

     

    Resveratrol restores sirtuin 1 (SIRT1) activity and pyruvate dehydrogenase kinase 1 (PDK1) expression after hemorrhagic injury in a rat model.

    From: http://www.ncbi.nlm.nih.gov/pubmed/24395567

     Abstract

    Severe hemorrhage leads to decreased blood flow to tissues resulting in decreased oxygen and nutrient availability affecting mitochondrial function. A mitoscriptome profiling study demonstrated alteration in several genes related to mitochondria, consistent with the mitochondrial functional decline observed after trauma hemorrhage (T-H). Our experiments led to the identification of sirtuin 1 (SIRT1) as a potential target in T-H. Administration of resveratrol (a naturally occurring polyphenol and activator of SIRT1) after T-H improved left ventricular function and tissue ATP levels. Our hypothesis was that mitochondrial function after T-H depends on SIRT1 activity. In this study, we evaluated the activity of SIRT1, a mitochondrial functional modulator, and the mitochondrial-glycolytic balance after T-H. We determined the changes in protein levels of pyruvate dehydrogenase kinase (PDK)-1 and nuclear c-Myc, peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and NF-E2-related factor (NRF)2 after T-H and after treatment with resveratrol or a combination of sirtinol (a SIRT1 inhibitor) and resveratrol. We have also tested the activity of mitochondrial complex 1. SIRT1 enzyme activity was significantly decreased after T-H, whereas resveratrol treatment restored the activity. We found elevated PDK1 and c-Myc levels and decreased PGC-1α, NRF2 and mitochondrial complex I activity after T-H. The reduced SIRT1 activity after T-H may be related to declining mitochondrial function, since resveratrol was able to reinstate SIRT1 activity and mitochondrial function. The elevated level of PDK1 (an inhibitor of pyruvate dehydrogenase complex) after T-H indicates a possible shift in cellular energetics from mitochondria to glycolysis. In conclusion, SIRT1 modulation alters left ventricular function after T-H through regulation of cellular energetics.

     

    Resveratrol suppresses PAI-1 gene expression in a human in vitro model of inflamed adipose tissue.

    From: http://www.ncbi.nlm.nih.gov/pubmed/23819014

     Abstract

    Increased plasminogen activator inhibitor-1 (PAI-1) levels are associated with a number of pathophysiological complications; among them is obesity. Resveratrol was proposed to improve obesity-related health problems, but the effect of resveratrol on PAI-1 gene expression in obesity is not completely understood. In this study, we used SGBS adipocytes and a model of human adipose tissue inflammation to examine the effects of resveratrol on the production of PAI-1. Treatment of SGBS adipocytes with resveratrol reduced PAI-1 mRNA and protein in a time- and concentration-dependent manner. Further experiments showed that obesity-associated inflammatory conditions lead to the upregulation of PAI-1 gene expression which was antagonized by resveratrol. Although signaling via PI3K, Sirt1, AMPK, ROS, and Nrf2 appeared to play a significant role in the modulation of PAI-1 gene expression under noninflammatory conditions, those signaling components were not involved in mediating the resveratrol effects on PAI-1 production under inflammatory conditions. Instead, we demonstrate that the resveratrol effects on PAI-1 induction under inflammatory conditions were mediated via inhibition of the NF κ B pathway. Together, resveratrol can act as NF κ B inhibitor in adipocytes and thus the subsequently reduced PAI-1 expression in inflamed adipose tissue might provide a new insight towards novel treatment options of obesity.

     

    Effects of resveratrol in experimental and clinical non-alcoholic fatty liver disease.

    From: http://www.ncbi.nlm.nih.gov/pubmed/24799987

     Abstract

    The prevalence of obesity and related conditions like non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and therapeutic options are limited. Alternative treatment options are therefore intensively sought after. An interesting candidate is the natural polyphenol resveratrol (RSV) that activates adenosinmonophosphate-activated protein kinase (AMPK) and silent information regulation-2 homolog 1 (SIRT1). In addition, RSV has known anti-oxidant and anti-inflammatory effects. Here, we review the current evidence for RSV-mediated effects on NAFLD and address the different aspects of NAFLD and non-alcoholic steatohepatitis (NASH) pathogenesis with respect to free fatty acid (FFA) flux from adipose tissue, hepatic de novo lipogenesis, inadequate FFA β-oxidation and additional intra- and extrahepatic inflammatory and oxidant hits. We review the in vivo evidence from animal studies and clinical trials. The abundance of animal studies reports a decrease in hepatic triglyceride accumulation, liver weight and a general improvement in histological fatty liver changes, along with a reduction in circulating insulin, glucose and lipid levels. Some studies document AMPK or SIRT1 activation, and modulation of relevant markers of hepatic lipogenesis, inflammation and oxidation status. However, AMPK/SIRT1-independent actions are also likely. Clinical trials are scarce and have primarily been performed with a focus on overweight/obese participants without a focus on NAFLD/NASH and histological liver changes. Future clinical studies with appropriate design are needed to clarify the true impact of RSV treatment in NAFLD/NASH patients.

     

    Modulatory role of resveratrol on cytotoxic activity of cisplatin, sensitization and modification of cisplatin resistance in colorectal cancer cells.

    From: http://www.ncbi.nlm.nih.gov/pubmed/25815689

     Abstract

    Colorectal cancer (CRC) is a leading cause of cancer-associated mortality worldwide. Cisplatin (CIS) is one of the most active cytotoxic agents in current use and it has proven efficacy against various human malignancies. However, its clinical usefulness has been restricted by detrimental side effects, including nephrotoxicity and myelosuppression. The aim of the present study was to attempt to decrease the required dose of CIS, in order to minimize its side effects, and increase its capability to arrest, delay or reverse carcinogenesis. In addition, the present study aimed to ameliorate CIS‑resistance in CRC cells, using the natural compound resveratrol (RSVL). RSVL (3,4', 5‑trihydroxy‑trans‑stilbene) is a naturally occurring polyphenol present in the roots of white hellebore (Veratrum grandiflorum O. Loes) and extracted from >70 other plant species. RSVL can exert antioxidant and anti‑inflammatory activities, and it has been shown to be active in the regulation of numerous cellular events associated with carcinogenesis. The present study evaluated the effects of RSVL on sensitization of both parent and CIS‑resistant HCT‑116 CRC cells to the action of cisplatin. The CIS was administered at a dose of 5 and 20 µg/ml, and CIS cytotoxicity, apoptosis, cell cycle and cisplatin cellular uptake were examined in the presence and absence of RSVL (15 µg/ml). RSVL treatment showed anti‑proliferative effects and enhanced the cytotoxic effects of cis against the growth of both parent and CIS‑resistant HCT‑116 CRC cells, with a half maximal inhibitory concentration of 4.20 µg/ml and 4.72 µg/ml respectively. RSVL also induced a significant increase in the early apoptosis fraction and enhanced the subsequent apoptotic effects of CIS. The cellular uptake of CIS was significantly increased in the presence of RSVL, as compared with CIS treatment alone, and RSVL treatment sensitized the CIS‑resistant HCT‑116 cells. In conclusion, RSVL treatment increased the cytotoxic activity of CIS against the growth of both parent and CIS‑resistant HCT-116 CRC cells.

     

    Resveratrol treatment rescues hyperleptinemia and improves hypothalamic leptin signaling programmed by maternal high-fat diet in rats.

    From: http://www.ncbi.nlm.nih.gov/pubmed/25801629

     Abstract

    PURPOSE: Perinatal high-fat diet is associated with obesity and metabolic diseases in adult offspring. Resveratrol has been shown to exert antioxidant and anti-obesity actions. However, the effects of resveratrol on leptinemia and leptin signaling are still unknown as well as whether resveratrol treatment can improve metabolic outcomes programmed by maternal high-fat diet. We hypothesize that resveratrol treatment in male rats programmed by high-fat diet would decrease body weight and food intake, and leptinemia with changes in central leptin signaling.

    METHODS: Female Wistar rats were divided into two groups: control group (C), which received a standard diet containing 9 % of the calories as fat, and high-fat group (HF), which received a diet containing 28 % of the calories as fat. Dams were fed in C or HF diet during 8 weeks before mating and throughout gestation and lactation. C and HF male offspring received standard diet throughout life. From 150 until 180 days of age, offspring received resveratrol (30 mg/Kg body weight/day) or vehicle (carboxymethylcellulose).

    RESULTS: HF offspring had increased body weight, hyperphagia and increased subcutaneous and visceral fat mass compared to controls, and resveratrol treatment decreased adiposity. HF offspring had increased leptinemia as well as increased SOCS3 in the arcuate nucleus of the hypothalamus, which suggest central leptin resistance. Resveratrol treatment rescued leptinemia and increased p-STAT3 content in the hypothalamus with no changes in SOCS3, suggesting improvement in leptin signaling.

    CONCLUSIONS: Collectively, our data suggest that resveratrol could reverse hyperleptinemia and improve central leptin action in adult offspring from HF mothers attenuating obesity.

     

    SUMMARY

    Resveratrol is an important polyphenol, antioxidant, and Nrf2 activator that helps to make Ultimate Protector such an outstanding nutritional supplement.

     

    ADDITIONAL RESOURCES

  • ULTIMATE PROTECTOR INGREDIENTS – WILD BILBERRY AND WILD BLUEBERRY

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

    Ultimate Protector contains wild bilberry and wild blueberry, as well as components from 29 different fruits, vegetables, and herbs. Each of these ingredients contain substances that may be considered to be polyphenols, antioxidants, and Nrf2 activators. In this article I will explore the ingredients wild bilberry and wild blueberry, which are components of Anthocomplete™ and VitaBerry Plus® from Futureceuticals.

    ANTHOCOMPLETE™

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

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

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

    Bilberry / Blueberry wild bilberry and wild bluebery

    VITABERRY PLUS®

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

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

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

    HEALTH BENEFITS OF WILD BILBERRY AND WILD BLUEBERRY

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

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

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

    wild bilberry and wild blueberry Wild bilberry and wild blueberry (above) provide Nrf2 activators.

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

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

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

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

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

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

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

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

    In vitro anticancer activity of fruit extracts from Vaccinium species.

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

    Abstract

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

     

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

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

    Abstract

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

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

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

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

     

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

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

    Abstract

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

     

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

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

    Abstract

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

     

    Effect of blueberry on hepatic and immunological functions in mice.

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

    Abstract

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

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

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

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

     

    Anthocyanins: Janus Nutraceuticals Displaying Chemotherapeutic and Neuroprotective Properties

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

    Abstract

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

    Recent Research on Polyphenolics in Vision and Eye Health

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

    Abstract

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

     

    Bilberry Extracts Induce Gene Expression Through the Electrophile Response Element

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

    Abstract

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

     

    Bilberry (Vaccinium myrtillus)

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

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

    Pharmacology:

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

    Pharmacodynamics/Kinetics:

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

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

    SUMMARY

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

     

    up-4 elderberry wild bilberry and wild blueberry Ultimate Protector provides wild bilberry and wild blueberry, and 27 other Nrf2 activator-containing plant-based ingredients.

    ADDITIONAL RESOURCES

  • ULTIMATE PROTECTOR INGREDIENTS – ELDERBERRY

    Dr. Hank Liers, PhD biography about us HPDI integratedhealth formulator founder CEO scientist physicistUltimate Protector contains elderberry (Sambucus nigra), as well as components from 29 different fruits, vegetables, and herbs. Each of these ingredients contain substances that may be considered to be polyphenols, antioxidants and Nrf2 activators. In this article I will explore the ingredient elderberry which is a component of Anthocomplete® from Futureceuticals.

    ANTHCOMPLETE™

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

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

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

    HEALTH BENEFITS OF ELDERBERRY

    Elderberries were listed in the CRC Handbook of Medicinal Herbs as early as 1985, and are listed in the 2000 Mosby's Nursing Drug reference for colds, flu, yeast infections, nasal and chest congestion, and hay fever. In Israel, Hasassah's Oncology Lab has determined that elderberry stimulates the body's immune system and they are treating cancer and AIDS patients with it. The wide range of medical benefits (from flu and colds to debilitating asthma, diabetes, and weight loss) is probably due to the enhancement of each individual's immune system.

    Elderberry Tea Elderberry makes a great tea, too.

    At the Bundesforschungsanstalt research center for food in Karlsruhe, Germany, scientists conducting studies on Elderberry showed that elderberry anthocyanins enhance immune function by boosting the production of cytokines. These unique proteins act as messengers in the immune system to help regulate immune response, thus helping to defend the body against disease. Further research indicated that anthocyanins found in elderberries possess appreciably more antioxidant capacity than either vitamin E or vitamin C.

    Studies at Austria's University of Graz found that elderberry extract reduces oxidation of low-density lipoprotein (LDL) cholesterol. Oxidation of LDL cholesterol is implicated in atherogenesis, thus contributing to cardiovascular disease.

    The ORAC value of Elderberries is 14697 micromoles/litre of Trolox equivalents per 100 grams. This is among the highest values for fruits and berries.

     Scientific Studies on the Antioxidant Effects of Elderberries and Anthocyanidins

     

    Polyphenols pattern and correlation with antioxidant activities of berries extracts from four different populations of Sicilian Sambucus nigra L.

    Abstract

    Sambucus nigra L. is wide spread in temperate and sub-tropical zones. The consumption of its berries has been associated with health benefits especially for its high content of natural antioxidants such as polyphenols, in particular anthocyanins. In this work we investigated the polyphenolic composition and the in vitro antioxidant activities (ABTS, DPPH, BCB and FRAP-ferrozine (FRAP-FZ) assays) of S. nigra berries, collected in four different Sicilian areas (Italy). Elderberries are considered one of the fruits with highest anthocyanins content, the amount of phenolic compounds, other than anthocyanins, is approximately 1.5 times greater than the latter. The LC-MS analyses have revealed an opposite trend in the polyphenols pattern in Sicilian populations. Moreover, a statistical correlation was found between cyanidin-3-sambubioside-5-glucoside and antioxidant activity evaluated by FRAP-FZ and ABTS assays. In conclusion, Sicilian S. nigra berries are appealing for its antioxidant potential and for its particularly high content of anthocyanins.

    Total phenolic, anthocyanin contents and antioxidant capacity of selected elderberry (Sambucuscanadensis L.) accessions.

    Abstract

    Fourteen purple-black American elderberry accessions (Sambucus canadensis L.) obtained from various sites in midwestern USA and then grown at a single Ohio production site in USA were analyzed for their total phenolic (TP) and total monomeric anthocyanin (TMA) contents and for their antioxidant capacity by the ferric reducing antioxidant power (FRAP) and DPPH radical scavenging assays. Total phenolic and anthocyanin contents were measured using the Folin-Ciocalteu reagent and the pH differential methods, respectively. Overall, the phytonutrient contents and antioxidant capacity of our elderberry accessions were similar to those typically reported for black raspberries, blackberries and other dark-fleshed small fruits. Variability among accessions was greatest for TMA content (CV 37.5%); individuals ranged nearly threefold from 1308 to 4004 μg cy3-GE/g on a fresh weight basis. Variation among accessions was also evident for TP, FRAP and DPPH values (CV 14.4, 21.7 and 26.8%, respectively). TP and TMA values were very highly correlated (r = 0.93), although individuals differed in the estimated proportion of total phenolics attributable to anthocyanins. Both TP and TMA also highly correlated to antioxidant capacity values (r = 0.70-0.85). Within this limited study of 14 accessions, variability for phytonutrient content and antioxidant capacity suggested the employment of wild germplasm within an elderberry improvement program to incorporate an array of superior horticultural, post-harvest or processing traits into new or existing cultivars with superior phytonutrient profiles.

    The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines.

    Abstract

    Sambucus nigra L. products - Sambucol - are based on a standardized black elderberry extract. They are natural remedies with antiviral properties, especially against different strains of influenza virus. Sambucol was shown to be effective in vitro against 10 strains of influenza virus. In a double-blind, placebo-controlled, randomized study, Sambucol reduced the duration of flu symptoms to 3-4 days. Convalescent phase serum showed a higher antibody level to influenza virus in the Sambucol group, than in the control group. The present study aimed to assess the effect of Sambucol products on the healthy immune system - namely, its effect on cytokine production. The production of inflammatory cytokines was tested using blood - derived monocytes from 12 healthy human donors. Adherent monocytes were separated from PBL and incubated with different Sambucol preparations i.e., Sambucol Elderberry Extract, Sambucol Black Elderberry Syrup, Sambucol Immune System and Sambucol for Kids. Production of inflammatory cytokines (IL-1 beta, TNF-alpha, IL-6, IL-8) was significantly increased, mostly by the Sambucol Black Elderberry Extract (2-45 fold), as compared to LPS, a known monocyte activator (3.6-10.7 fold). The most striking increase was noted in TNF-alpha production (44.9 fold). We conclude from this study that, in addition to its antiviral properties, Sambucol Elderberry Extract and its formulations activate the healthy immune system by increasing inflammatory cytokine production. Sambucol might therefore be beneficial to the immune system activation and in the inflammatory process in healthy individuals or in patients with various diseases. Sambucol could also have an immunoprotective or immunostimulatory effect when administered to cancer or AIDS patients, in conjunction with chemotherapeutic or other treatments. In view of the increasing popularity of botanical supplements, such studies and investigations in vitro, in vivo and in clinical trials need to be developed.

    Characterization of anthocyanins and proanthocyanidins in some cultivars of Ribes, Aronia, and Sambucus and their antioxidant capacity.

    Abstract

    Anthocyanins and proanthocyanidins were characterized by HPLC-ESI-MS/MS coupled with a diode array and/or fluorescent detector in seven cultivars of Ribes nigrum (black currant) and Ribes rubrum (red currant, Red Lake), six cultivars of Ribes grossularia (gooseberries), Aronia melanocarpa(chokeberry), and Sambucus nigra (elderberry). Thirty-one different anthocyanins were detected in these berries, but not every anthocyanin was observed in each berry. A number of minor anthocyanins were identified from these berries for the first time. The concentrations of individual anthocyanins in all of the berries were quantified using relevant anthocyanidin 3-glucoside standards. Among the berries studied in this paper and in berries in general, chokeberry has the highest total anthocyanin concentrations [1480 mg/100 g of fresh weight (FW)], whereas the lowest total anthocyanin concentration in the berries studied was found in the gooseberry cv. Careless, which contained only 0.07 mg/100 g of FW. Two cultivars of gooseberries (Marigold and Leveller) did not contain any anthocyanins. Total proanthocyanidin concentrations in the berries studied ranged from 23 to 664 mg/100 g of FW in elderberry and chokeberry, respectively. Procyanidin or prodelphinidin polymers were the predominant components (>65% w/w) in most of the berries. The lipophilic and hydrophilic antioxidant capacities were measured by the oxygen radical absorbance capacity (ORAC(FL)) procedure. The total antioxidant capacity varied from 21 micromol of TE/g of FW in Careless gooseberry to 161 micromol of TE/g of FW in chokeberry. Total phenolics in the berries in general paralleled hydrophilic antioxidant capacity.

    Inhibitory activity of a standardized elderberry liquid extract against clinically-relevant human respiratory bacterial pathogens and influenza A and B viruses.

    Abstract

    BACKGROUND:

    Black elderberries (Sambucus nigra L.) are well known as supportive agents against common cold and influenza. It is further known that bacterial super-infection during an influenza virus (IV) infection can lead to severe pneumonia. We have analyzed a standardized elderberry extract (Rubini, BerryPharma AG) for its antimicrobial and antiviral activity using the microtitre broth micro-dilution assay against three Gram-positive bacteria and one Gram-negative bacteria responsible for infections of the upper respiratory tract, as well as cell culture experiments for two different strains of influenza virus.

    METHODS:

    The antimicrobial activity of the elderberry extract was determined by bacterial growth experiments in liquid cultures using the extract at concentrations of 5%, 10%, 15% and 20%. The inhibitory effects were determined by plating the bacteria on agar plates. In addition, the inhibitory potential of the extract on the propagation of human pathogenic H5N1-type influenza A virus isolated from a patient and an influenza B virus strain was investigated using MTT and focus assays.

    RESULTS:

    For the first time, it was shown that a standardized elderberry liquid extract possesses antimicrobial activity against both Gram-positive bacteria of Streptococcus pyogenes and group C and G Streptococci, and the Gram-negative bacterium Branhamella catarrhalis in liquid cultures. The liquid extract also displays an inhibitory effect on the propagation of human pathogenic influenza viruses.

    CONCLUSION:

    Rubini elderberry liquid extract is active against human pathogenic bacteria as well as influenza viruses. The activities shown suggest that additional and alternative approaches to combat infections might be provided by this natural product.

    Anthocyanins protect human endothelial cells from mild hyperoxia damage through modulation of Nrf2 pathway.

    Abstract

    The detrimental effects of high oxygen supplementation have been widely reported. Conversely, few is known about the effects of exposure to mild hyperoxic conditions, an interesting issue since the use of oxygen-enriched mixture is now increasingly used in clinical practice and especially for professional and recreational reasons. Our study investigated if in vitro exposure of human umbilical vein endothelial cells (HUVECs) to moderate hyperoxia (O2 32 %) induces cellular alterations, measured as changes in cell signaling pathways. Furthermore, by means of an ex vivo experimental model where human volunteers were used as bioreactors, we studied whether anthocyanin metabolites are able to protect HUVECs against mild hyperoxia-induced damage. We observed that the cytotoxic effect of mild hyperoxia came along with a significant decrease in nuclear accumulation of the transcription factor Nrf2, as well as in the expression of Nrf2-regulated antioxidant and cytoprotective genes. Furthermore, under normoxic conditions, anthocyanin metabolites appeared able to activate the Nrf2 pathway, through the involvement of specific kinases (ERK1/2); this adaptive effect may explain the protective effect observed in mild hyperoxia-exposed HUVECs following anthocyanin pretreatment. This study confirms that dietary anthocyanins and/or their metabolites can protect endothelial cells against mild hyperoxia-induced alterations acting as cell signaling modulators.

    A comparative evaluation of the anticancer properties of European and American elderberry fruits.

    From: http://www.ncbi.nlm.nih.gov/pubmed/17201636

    Abstract

    European elderberry (Sambucus nigra), recognized in Europe for its health-promoting properties for many generations, is known to contain a range of anthocyanins, flavonoids, and other polyphenolics that contribute to the high antioxidant capacity of its berries. American elderberry (Sambucus canadensis), on the other hand, has not been cultivated, bred, and promoted as a medicinal plant like its better-characterized European counterpart. In this study, aqueous acetone extracts of the berries from these two species were fractionated and tested in a range of assays that gauge anticarcinogenic potential. Both cultivated S. nigra and wild S. canadensis fruits demonstrated significant chemopreventive potential through strong induction of quinone reductase and inhibition of cyclooxygenase-2, which is indicative of anti-initiation and antipromotion properties, respectively. In addition, fractions of S. canadensis extract showed inhibition of ornithine decarboxylase, an enzyme marker related to the promotion stage of carcinogenesis. Analysis of active fractions using mass spectrometry and liquid chromatography-mass spectrometry revealed, in addition to flavonoids, the presence of more lipophilic compounds such as sesquiterpenes, iridoid monoterpene glycosides, and phytosterols.

    Incorporation of the elderberry anthocyanins by endothelial cells increases protection against oxidative stress.

    From: http://www.ncbi.nlm.nih.gov/pubmed/10962205

    Abstract

    The objective of this study was to investigate the ability of endothelial cells (EC) to incorporate anthocyanins and to examine their potential benefits against various oxidative stressors. Endothelial dysfunction has been proposed to play an important role in the initiation and development of vascular disease, with studies having shown that administration of antioxidants improves endothelial function. Elderberry extract contains 4 anthocyanins, which where incorporated into the plasma membrane and cytosol of EC following 4 h incubation at 1 mg.ml(-1). However, incorporation within the cytosol was considerably less than that in the membrane. Uptake within both regions appeared to be structure dependent, with monoglycoside concentrations higher than that of the diglucosides in both compartments. The enrichment of EC with elderberry anthocyanins conferred significant protective effects in EC against the following oxidative stressors: hydrogen peroxide (H(2)O(2)); 2, 2'-azobis(2-amidinopropane) dihydrochloride (AAPH); and FeSO(4)/ascorbic acid (AA). These results show for the first time that vascular EC can incorporate anthocyanins into the membrane and cytosol, conferring significant protective effects against oxidative insult. These findings may have important implications on preserving EC function and preventing the initiation of EC changes associated with vascular diseases.

    SUMMARY

    Elderberry is an important fruit full of polyphenols, anthocyanins, antioxidants and Nrf2 activators that help to make Ultimate Protector such an outstanding nutritional supplement. This ingredient is becoming much more well known as research studies identify its many benefits.

     

    up-4 elderberry

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