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Trained Immunity: One Step Closer to Superhuman

trained-immunity:-one-step-closer-to-superhuman

There are several components that contribute to a robust immune system.

Among them are having good genes, eating a nutritious diet, and participating in regular exercise. We should also avoid stress, pollution, and potentially harmful chemicals in our food and water.

Lastly, it might be a good idea to carry a 10-foot bamboo pole to keep people at a safe distance and bathe nightly in a bathtub filled with Purell. Simple!

Yeah right.

Okay, the last one was a joke. But most of us can’t even check off the first three boxes. It’s a complex world we live in, with many health stressors to negotiate in our everyday lives.

Doing nothing special is no longer acceptable. It makes perfect sense to boost the immune system for the healthiest life possible — and for making better gains in the gym.

Trained Immunity

In the science community, there is great interest in safe and natural substances that can strengthen the innate immune system. The term for this effect is “trained immunity.” Similar to muscle, the immune system requires repeated bouts of targeted stimulation to grow stronger, and continued stimulation to maintain optimal function.

Biotest used trained immunity as its design goal when developing its I-Well™ supplement. It strengthens and supports the body’s natural immune system through an ingenious combination of four proven, immune-system fortifying substances:

  • Beta-1,3-Glucan (from Euglena gracilis algae)
  • Solid Lipid Curcumin Particles
  • Microencapsulated Vitamin D3
  • EGCG (epigallocatechin gallate)

Beta-1,3-glucan — A Very Big Deal

Primes, strengthens, and maintains healthy immunity.

Beta-1,3-glucan is a non-digestible polysaccharide isolated from Euglena gracilis algae. It’s well established that beta-1,3-glucan acts as an immunomodulatory agent.

This means the body’s pattern-recognition receptors (PPRs; Dectin-1) identify beta-1,3-glucan as “non-self” or foreign, which activates healthy immune responses. Triggering these responses with beta-1,3-glucan can prime, strengthen, and support sustained healthy immune function (1-17).

Beta-1,3-glucan also fuels the growth of good bacteria (lactobacillus and bifidobacteria) in the gut, and supports the health of intestinal cells that act as a protective physical barrier (15, 16).

There’s nothing else like it. Beta-1,3-glucan is a breakthrough for anyone wanting to maintain a strong, healthy immune system — it’s a very big deal.

Curcumin’s Great Potential Realized

Promotes a healthy inflammatory response, and supports neurological and cardiovascular health.

Medical researchers have had a longtime interest in curcumin for its positive effects on inflammatory response, neurological health, and cardiovascular health.

But the frustrating problem has always been its poor bioavailability. Curcumin isn’t soluble in the gastrointestinal tract, making it difficult to absorb, and it’s vulnerable to something called glucuronidation, which converts curcumin into what amounts to inactive waste.

An example of curcumin’s poor bioavailability is a study where patients were given a whopping 3.6 grams of ordinary curcumin a day (about 7 capsules). Even at those large doses, detectable blood and liver levels of free-form curcumin were almost non-existent (18).

Absorb 95X More Curcumin*

There is a solution for optimal curcumin uptake. Research shows solid lipid curcumin particles produce 95 times more free curcumin in the bloodstream than highly pure, standardized curcumin (Gota VS et al, 2010).*

That’s a bold claim. Fortunately, solid lipid curcumin particles are backed up with convincing science, invented by neuroscientists at UCLA, funded by the University of California (Oakland) and the Federal Government, supported by peer-reviewed research on humans, and patented (9,192,644).

Microencapsulated Vitamin D3

Supplies a required micronutrient for optimal inflammatory response.

Research shows Vitamin D3 (choleocalciferol) is a required micronutrient for maintaining an optimal inflammatory response and healthy immune system (40-44).

Unfortunately, vitamin D deficiencies are rampant, especially in the areas with the least exposure to the sun. That’s because the body naturally produces Vitamin D when skin has direct exposure to sunlight. Adding to the problem, it’s difficult to absorb enough D3 in our diets.

Without proper or optimal vitamin D levels, T cells aren’t effective and flat out don’t activate (40). To make matters worse, it’s really difficult to achieve or maintain adequate levels of D3 with most supplementation (45).

The I-Well™ formula contains microencapsulated vitamin D3, which presents as tiny, water dispersible “beadlets” that enhance uptake.

Studies show that this microencapsulated form is the most bioavailable and longest lasting. Its effects remain constant for up to 14 days, making it clearly superior to the oil-based vitamin D3 supplements that make up most of the market (45).

EGCG (Epigallocatechin-3-Gallate)

Supports cardiovascular, brain, metabolic, and cellular health.

EGCG (epigallocatechin-3-gallate) is a powerful health-promoting polyphenol found in green tea — having positive effects on the body’s inflammation response and on various target tissues (46-54).

A host of studies (mostly in vitro) show EGCG has protective effects on the cardiovascular (47, 48) and nervous systems (47, 52-54). It promotes cellular health (50, 52), and stimulates metabolic function (48, 49).

I-Well™ Supplement Facts

Each of these ingredients has its own super power, and warrants its inclusion in the I-Well Immune Support formula:

  • Beta-1,3-glucan primes, strengthens, and maintains healthy immunity.
  • Solid lipid curcumin particles promote a healthy inflammatory response, neurological health, and cardiovascular health.
  • Vitamin D3 supplies a required micronutrient for optimal inflammatory response.
  • EGCG supports cellular, cardiovascular, brain, and metabolic health.

It’s simple. If you want to attain and maintain a strong, healthy natural immunity, the I-Well™ formula is for you.

    References: Beta-1,3-glucan

  1. Moorlag S et al. B-Glucan Induces Protective Trained Immunity against Mycobacterium tuberculosis Infection: A Key Role for IL-1 Cell Reports 31, 107634, May 19, 2020. DOI: doi.org/10.1016/j.celrep.2020.107634. Abstract: B-glucan is a potent inducer of epigenetic and functional reprogramming of innate immune cells, a process called “trained immunity,” resulting in an enhanced host response against secondary infections. We investigate whether B-glucan exposure confers protection against pulmonary Mycobacterium tuberculosis (Mtb) infection. B-glucan induces trained immunity via histone modifications at gene promoters in human monocytes, which is accompanied by the enhanced production of proinflammatory cytokines upon secondary Mtb challenge and inhibition of Mtb growth. Mice treated with B-glucan are significantly protected against pulmonary Mtb infection, which is associated with the expansion of hematopoietic stem and progenitor cells in the bone marrow and increased myelopoiesis. The protective signature of B-glucan is mediated via IL-1 signaling, as B-glucan shows no protection in mice lacking a functional IL-1 receptor (IL1R). The administration of B-glucan may be used as a novel strategy in the treatment of mycobacterial infections and possibly as an adjuvant to improve anti-tuberculosis vaccines.
  2. Del Cornò M et al. Shaping the Innate Immune Response by Dietary Glucans: Any Role in the Control of Cancer? Cancers 2020, 12, 15. DOI: 10.3390/cancers12010155. Abstract: B-glucans represent a heterogeneous group of naturally occurring and biologically active polysaccharides found in many kinds of edible mushrooms, baker’s yeast, cereals and seaweeds, whose health-promoting effects have been known since ancient times. These compounds can be taken orally as food supplements or as part of daily diets, and are safe to use, nonimmunogenic and well tolerated. A main feature of B-glucans is their capacity to function as biological response modifiers, exerting regulatory effects on inflammation and shaping the effector functions of different innate and adaptive immunity cell populations. The potential to interfere with processes involved in the development or control of cancer makes B-glucans interesting candidates as adjuvants in antitumor therapies as well as in cancer prevention strategies. Here, the regulatory effects of dietary B-glucans on human innate immunity cells are reviewed and their potential role in cancer control is discussed.
  3. Borchani C et al. Structural Characterization, Technological Functionality, and Physiological Aspects of Fungal B-D-glucans: A Review. Crit Rev Food Sci Nutr, 56(10:1746-52, PMIC 25830657, Jul 2016. Abstract: Quote: “Thus, they [(1-3)(1-6)-B-glucans] are effective in inhibiting growth of cancer cells and metastasis and preventing bacterial infection. In humans, B-glucans reduce blood cholesterol, improve glucose absorption by body cells, and so help wound healing.”
  4. Vetvicka V, Vetvickova I. Glucans and Cancer: Comparison of Commercially Available B-glucans – Part IV. Anticancer Res, 38(3):1327-1333, Mar 2018. Abstract: Quote: “Among the well-studied effects of B-glucans, we can mention stimulation of both humoral and cellular immunity, metabolic control of diabetes, stimulation of wound healing, stress reduction, attenuation of chronic fatigue syndrome, lowering cholesterol levels, and inhibition of cancer. …Chronic respiratory problems. In Japan, glucan has been widely used, for over 30 years, in the treatment of gastrointestinal cancer.”
  5. Davis JM et al. Effects of oat beta-glucan on innate immunity and infection after exercise stress. Med Sci Sports Exerc. 2004, Aug;36(8):1321-7. Abstract: These data suggest that daily ingestion of beta glucan may offset the increased risk of upper respiratory tract infections (URTI) associated with exercise stress, which may be mediated, at least in part, by an increase in macrophage antiviral resistance.
  6. Volman JJ et al. Dietary modulation of immune function by B-glucans. Physiology & Behavior, Volume 94, Issue 2, 23 May 2008, Pages 276-284. Abstract: The immune response can be modulated by nutrients like B-glucans, which are glucose polymers that are major structural components of the cell wall of yeast, fungi, and bacteria, but also of cereals like oat and barley. In this review the current status concerning possibilities to modulate immune function by B-glucans is discussed. In vitro as well as in vivo studies in animals and humans show that especially B-glucans derived from fungi and yeast have immune modulating properties. Most frequently evaluated are effects on leukocyte activity, which has been suggested to contribute to the increased resistance against infections observed after B-glucan interventions.
  7. Rondanelli M et al. The biological activity of beta-glucans. Minerva Med. 2009 Jun;100(3):237-45. Abstract: This review summarizes the recent knowledge about the positive effect of beta glucans on human health. Quote: “A growing body of science indicates that beta-glucans promote health in a number of important ways. For instance, several studies have also shown that oat beta-glucans blunt the glycemic and insulin response. Moreover, beta-1,3-glucans improve the body’s immune system defense against foreign invaders by enhancing the ability of macrophages, neutrophils and natural killer cells to respond to and fight a wide range of challenges such as bacteria, viruses, fungi, and parasites.”
  8. Vetvicka V, Vetvickova J. B-Glucan Improves Conditions of Chronic Fatigue in Mice by Stimulation of Immunity. The Open Biochemistry Journal, 2-18-2020. Abstract: This study found that glucan supplementation strongly improved the suppressed phagocytosis and changes in cytokine and levels of oxidative stress markers caused by fatigue. In addition, glucan supplementation also increased the motor functioning of tested animals.
  9. Akramiene D et al. Effects of ß-glucans on the immune system. Medicinia, 11 August 2007. Abstract: This paper explains how ß-Glucans are naturally occurring polysaccharides. These glucose polymers are constituents of the cell wall of certain pathogenic bacteria and fungi. These substances increase host immune defense by activating the complement system, enhancing macrophages and natural killer cell function. ß-Glucans also show anti-carcinogenic activity. They can prevent oncogenesis due to the protective effect against potent genotoxic carcinogens. As immunostimulating agents, which act through the activation of macrophages and NK cell cytotoxicity, ß-glucan can inhibit tumor growth in promotion stage, too.
  10. Graugaum HJ et al. A double-blind, randomized, placebo-controlled nutritional study using an insoluble yeast beta-glucan to improve the immune defense system. Dood Nutr Sci, 3(6):738-746, June 2012. Abstract: In a placebo-controlled, double-blind, randomized clinical trial, the effect of an insoluble yeast beta-glucan preparation on the incidences of common colds and its effect on common cold symptoms were compared to placebo. …the beta-glucan group had significantly less infections compared to placebo. Beta-glucan significantly reduced the typical cold symptoms (‘sore throat and/or difficulty swallowing’, ‘hoarseness and/or cough’ and ‘runny nose’) as opposed to placebo. The present study demonstrated a prophylactic [preventative] effect of yeast beta-glucan on the occurrence of common colds as opposed to placebo. In addition, when these episodes occurred, they were from the beginning less pronounced and subsided faster.
  11. Carlos AF et al. B-Glucan successfully stimulated the immune system in different jawed vertebrate species. Comparative Immunology, Microbiology and Infectious Diseases, Volume 62, February 2019, Pages 1-6. Abstract: Several reports have shown the positive effects of B-glucans on the immune system. For 28 days, scientists, fed four different vertebrate species: mice, dogs, piglets and chicks, with two B-glucan molecules (BG01 and BG02). They measured the serum interleukin 2 as an indicator of innate immune response, the neutrophils and monocytes phagocytosis index as a cellular response, and antibody formation as an adaptive response. The results clearly showed that the different B-glucan molecules exhibited biologically differently behaviors, but both molecules stimulate the immune system in a similar pattern in these four species. This finding suggests that vertebrates shared similar mechanisms/patterns in recognizing the B-glucans and confirms the benefits of B-glucans across different vertebrate species.
  12. Garcia-Valtanen p et al. Evaluation of trained immunity by B-1, 3 (D)-glucan on murine monocytes in vitro and duration of response in vivo. Immunology and Cell Biology (2017) 95, 601–610; DOI: 10.1038/icb.2017.13. Abstract: The B-1, 3 (D)-glucan (B-glucan) present in the cell wall of Candida albicans induces epigenetic changes in human monocytes resulting in primed macrophages exhibiting increased cytokine responsiveness to reinfection. This phenomenon is referred to as trained immunity or innate immune memory. However, whether B-glucan can reprogramme murine monocytes in vitro or induce lasting effects in vivo has yet to be elucidated. Thus, purified murine spleen-derived monocytes were primed with B-glucan in vitro and assessed for markers of differentiation and survival. Important macrophage cell markers during monocyte-to- macrophage differentiation were downregulated and survival enhanced due to partial inhibition of apoptosis. Increased survival and not the B-glucan training effect explained the elevated production of tumour necrosis factor-A (TNFA) and interleukin-6 (IL-6) induced by subsequent lipopolysaccharide (LPS) challenge. In vivo, 4 days after systemic administration of B-glucan, mice were more responsive to LPS challenge as shown by the increased serum levels of TNFA, IL-6 and IL-10, an effect shown to be short lived as enhanced cytokine production was lost by day 20. Here, we have characterised murine macrophages derived from B-glucan-primed monocytes based on their surface marker expression and for the first time provide evidence that the training effect of B-glucan in vivo declines within a 3-week period.
  13. Paris S et al. B-Glucan-Induced Trained Immunity in Dogs. Front. Immunol. 09 October 2020. 11:566893. DOI: 10.3389/fimmu.2020.566893. Abstract: Several observations in the world of comparative immunology in plants, insects, fish and eventually mammals lead to the discovery of trained immunity in the early 2010’s. The first demonstrations provided evidence that innate immune cells were capable of developing memory after a first encounter with some pathogens. Trained immunity in mammals was initially described in monocytes with the Bacille Calmette-Guerin vaccine (BCG) or prototypical agonists like B-glucans. This phenomenon relies on epigenetic and metabolic modifications leading to an enhanced secretion of inflammatory cytokines when the host encounters homologous or heterologous pathogens. The objective of our research was to investigate the trained immunity, well-described in mouse and human, in other species of veterinary importance. For this purpose, we adapted an in vitro model of trained innate immunity in dogs. Blood enriched monocytes were stimulated with B-glucans and we confirmed that it induced an increased production of pro-inflammatory and anti-microbial compounds in response to bacterial stimuli. These results constitute the first demonstration of trained immunity in dogs and confirm its signatures in other mammalian species, with an implication of cellular mechanisms similar to those described in mice and humans regarding cellular epigenetics and metabolic regulations.
  14. Byrne K et al. Differential induction of innate memory in porcine monocytes by b-glucan or bacillus Calmette-Guerin. Innate Immunity. 0(0) 1–13. 2020. DOI: 10.1177/1753425920951607. Abstract: Innate immunomodulation via induction of innate memory is one mechanism to alter the host’s innate immune response to reduce or prevent disease. Microbial products modulate innate responses with immediate and lasting effects. Innate memory is characterized by enhanced (training) or depressed (tolerance) innate immune responses, including pro- inflammatory cytokine production, to secondary exposure following a priming event. To investigate the ability of b-glucans and bacillus Calmette-Guerin to induce innate training or tolerance in pig cells, porcine monocytes were cultured with priming agonist (b-glucans or bacillus Calmette-Guerin) then re-stimulated 5 d later with a heterologous microbial agonist to determine induction of innate memory. Priming with b-glucan from Saccharomyces cerevisiae depressed IL-1b and TNF-a cytokine responses to re-stimulation with LPS, indicative of a tolerized state. However, bacillus Calmette-Guerin priming induced a trained state in porcine monocytes, as LPS re-stimulation enhanced IL-1b and TNF-a gene expression and protein production. We present the first evidence of innate memory in pig monocytes, with bacillus Calmette-Guerin (training) or Saccharomyces cerevisiae b-glucan (tolerance). Induction of a trained or tolerized state in vitro is a first step to identify agonists to alter the innate immune system at the animal level with the intent of enhancing disease resistance.
  15. Petit J et al. Long-lived effects of administering b-glucans: Indications for trained immunity in fish. Developmental and Comparative Immunology 64 (2016) 93e102. 2016. DOI: dx.doi.org/10.1016/j.dci.2016.03.003. Abstract: Over the past decades, it has become evident that immune-modulation of fish with b-glucans, using injection, dietary or even immersion routes of administration, has stimulating but presumed short-lived effects on both intestinal and systemic immunity and can increase protection against a subsequent pathogenic challenge. Although the exact effects can be variable depending on, among others, fish species and administration route, the immune-stimulating effects of b-glucans on the immune system of fish appear to be universal. This review provides a condensed update of the most recent literature describing the effects of b-glucans on the teleost fish immune system. We shortly discuss possible mechanisms influencing immune-stimulation by b-glucans, including microbial composition of the gut, receptor recognition and downstream signalling. Of interest, in mammalian monocytes, b-glucans are potent inducers of trained immunity. First, we screened the literature for indications of this phenomenon in fish. Criteria that we applied include indications for at least one out of three features considered characteristic of trained immunity; (i) providing protection against a secondary infection in a T- and B- lymphocyte independent manner, (ii) conferring increased resistance upon re-infection and, (iii) relying on key roles for innate immune cell types such as natural killer cells and macrophages. We conclude that several indications exist that support the notion that the innate immune system of teleost fish can be trained. Second, we screened the literature for indications of long-lived effects on innate immunity of fish after administering b-glucans, a criterion which could help to identify key roles for macrophages on resistance to infection. We discuss whether b-glucans, as well-known immune-stimulants, are able to train the immune system of fish and argue in favour of further studies designed to specifically investigate this phenomenon in fish.
  16. Kwanghook, K et al. Algae-derived B-glucan enhanced gut health and immune responses of weaned pigs experimentally infected with a pathogenic E. coli. Animal Feed Science and Technology, Volume 248, February 2019. Abstract: Quote: “Feed supplementation of algae-derived B-glucan alleviated diarrhea of F18 E. coli infected pigs by enhancing gut integrity. Feeding B-glucan also boosted host immune response against E. coli infection.”
  17. Abraham A et al. A novel vaccine platform using glucan particles for induction of protective responses against Francisella tularensis and other pathogens. Clinical and Experimental Immunology, 198: 143–152. 2019. DOI: 10.1111/cei.13356. Abstract: accines are considered the bedrock of preventive medicine. However, for many pathogens, it has been challenging to develop vaccines that stimulate protective, long-lasting immunity. We have developed a novel approach using B-1,3-D-glucans (BGs), natural polysaccharides abundantly present in fungal cell walls, as a biomaterial platform for vaccine delivery. BGs simultaneously provide for receptor-targeted antigen delivery to specialized antigen-presenting cells together with adjuvant properties to stimulate antigen-specific and trained non-specific immune responses. This review focuses on various approaches of using BG particles (GPs) to develop bacterial and fungal vaccine candidates. A special case history for the development of an effective GP tularaemia vaccine candidate is highlighted.
  18. References: Curcumin

  19. Gota VS et al. Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers. J Agric Food Chem. 2010 Feb 24;58(4):2095-9. DOI: 10.1021/jf9024807. Abstract: Curcumin is the lipid-soluble antioxidant compound obtained from the rhizome of Curcuma longa Linn, also known as turmeric. Curcumin targets multiple chemotherapeutic and inflammatory pathways and has demonstrated safety and tolerability in humans, supporting its potential as a therapeutic agent; however, the clinical literature lacks conclusive evidence supporting its use as a therapeutic agent due to its low bioavailability in humans. The purpose of this study was to quantify plasma levels of free curcumin after dosing of a solid lipid curcumin particle (SLCP) formulation versus unformulated curcumin in healthy volunteers and to determine its tolerability and dose-plasma concentration relationship in late-stage osteosarcoma patients. Doses of 2, 3, and 4 g of SLCP were evaluated in 11 patients with osteosarcoma. Plasma curcumin levels were measured using a validated high-performance liquid chromatography method. The limit of detection of the assay was 1 ng/mL of curcumin. In healthy subjects, the mean peak concentration of curcumin achieved from dosing 650 mg of SLCP was 22.43 ng/mL, whereas plasma curcumin from dosing an equal quantity of unformulated 95% curcuminoids extract was not detected. In both healthy individuals and osteosarcoma patients, high interindividual variability in pharmacokinetics and nonlinear dose dependency was observed, suggesting potentially complex absorption kinetics. Overall, good tolerability was noted in both healthy and osteosarcoma groups.
  20. Cox KHM et al. Further evidence of benefits to mood and working memory from lipidated curcumin in healthy older people: A 12-week, double-blind, placebo-controlled, partial replication study. Nutrients. 2020 Jun 04. 12(6): 1678. DOI: 10.3390/nu12061678. Abstract: A partial replication study by researchers at Swinburne University reveals [lipidated curcumin] improves aspects of mood, memory, and working memory in a healthy older cohort. The pattern of results is consistent with improvements in hippocampal function and may hold promise for alleviating cognitive decline in some populations. This study examined a similar population with slightly elevated cognitive abilities, while eliciting similar results to the first clinical published in 2014 – see Cox KH et al, 2014.
  21. Esfahani K et al. A phase I open prospective cohort trial of curcumin plus tyrosine kinase inhibitors for EGFR-mutant advanced non-small cell lung. J Clin Oncol. 2019. 37(15_suppl): e20611-e20611. DOI: 10.1200/JCO.2019.37.15_suppl.e20611. Abstract: This study further provides evidence that short-term use of Longvda® curcumin in patients is feasible and safe. Researchers report high treatment adherence and improved quality of life with curcumin. These findings, as well as efficacy data and the effect of curcumin on other inflammation-associated biomarkers, warrant investigation in a larger phase 2 study.
  22. Scholey A et al. Curcumin improves hippocampal function in healthy older adults: A three month randomized controlled trial. Poster Presentation in: 13th European Nutrition Conference — Malnutrition in an Obese World: European Perspectives (FENS). Dublin, Ireland. 2019: P3-01-02. Abstract: Additional results confirm that [lipidated curcumin] improves aspects of mood, memory, and working memory in a healthy older cohort. The pattern of results is consistent with improvements in hippocampal function and may hold promise for alleviating cognitive decline in some populations.
  23. Scholey A et al. A highly bioavailable curcumin extract improves neurocognitive function and mood in healthy older people: A 12-week randomized, double-blind, placebo-controlled trial (OR32-05-19). Current Dev Nut. 2019 Jun. Poster Presentation. Volume 3(Issue Supplement 1): nzz052.OR32–05–19. DOI: 10.1093/cdn/nzz052.OR32-05-19. Abstract: Previously, researchers at Swinburne University showed significant improvements in measures of memory, attention, fatigue, stress, and mood (Cox KH et al, 2015). This trial was a follow up to the results previously seen in 1 and 3 hrs and in 4-weeks. The results of this second trial further confirm that a single daily dose of 400mg of [lipidated curcumin] improves aspects of mood and working memory in healthy older adults, with measures at 12-weeks.
  24. Gupte PA et al. Evaluation of the efficacy and safety of capsule solid lipid curcumin particles in knee: A pilot clinical study. J Inflamm Res. 2019. 12: 145-152. DOI: 10.2147/JIR.S205390. Abstract: A comparative examination of (solid lipid curcumin particles) showed that administration was not only faster-acting and safe, but had equal efficacy to the control.
  25. Koronyo, Y et al. Retinal amyloid pathology and proof-of-concept imaging trial. JCI Insight. 2017. 2(16). DOI: 10.1172/jci.insight.93621. Abstract: A proof-of-concept retinal imaging trial showing increased fluorescent intensity in retinal amyloid deposits and the highest brain concentrations of free curcumin obtained with [lipidated curcumin]. This trial confirmed one more time the ability of [lipidated curcumin] to deliver free curcumin to targeted tissues, more specifically the brain and retina, and to support cognitive and complete neuronal health. *Winner of NutraIngredients-USA Nutrition Research Project of the Year 2019 for ground-breaking initiatives as “most innovative and impactful nutrition research project pushing the boundaries of nutritional science.” Read more here.
  26. Santos-Parker JR et al. Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailiability and reducing oxidative stress. Aging. 2017 Jan. 3. Vol 9(No1): 187-208.
  27. McFarlin et al. Reduced inflammatory and muscle damage biomarkers following oral supplementation with bioavailable curcumin. University of North Texas. BBA Clinical. 2016 Feb 18. 5: 72-78. DOI: 10.1016/j.bbacli.2016.02.003. Abstract: Collectively, the findings demonstrated that consumption of [lipidated curcumin] (400mg/day) reduced key inflammatory biomarkers during recovery after exercise-induced muscle damage (EIMD). The observed improvements in biological inflammation may translate to faster recovery and improved functional capacity during subsequent exercise sessions.
  28. Santos-Parker JR et al. Curcumin supplement improves vascular endothelial function in middle-aged and older adults. Geront. 2015 Dec. 55(Suppl 2): 195. DOI: 10.1093/geront/gnv554.01. Abstract: [lipidated curcumin] administered at a dose of 2000mg/day (n=16), or placebo (n=13) for 12 weeks increased brachial artery flow-mediation dilation (FMDba) by 34% and forearm blood flow in response to incremental brachial artery infusions of acetylcholine (FBFach) by 44% in middle-aged and older (MA/O) adults (45-74 yrs). Findings support supplementation with [lipidated curcumin] improves endothelial-dependent dilation (EDD) in MA/O adults mediated, in part, by an increase in nitric oxide bioavailability.
  29. Rafii MS et al. The biomarker initiative DSBI pilot: Proof of concept for deep phenotyping of biomarkers. Front Behav Neurosci. 2015. 9: 1-11. Abstract: Retina, being part of the CNS, has previously been difficult to analyze directly; however, retinal amyloid imaging could now be a tool to demonstrate the presence of plaques in the brain in a non-invasive manner. In line with previous findings, this study supports [lipidated curcumin] quickly labeling retinal beta amyloid and inducing fluorescent plaque in the neural layers of the retina of humans.
  30. Cox KH et al. Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population. Centre for Human Psychopharmacology, Swinburne University. J Psychopharmacol. 2015 May. Vol 29(No 5): 642-651. DOI: 10.1177/0269881114552744. Abstract: This landmark study is one of the first to show a curcumin supplement improves cognitive function in healthy subjects. The trial recruited 60 subjects aged 60-80, and found daily [lipidated curcumin] (400mg) supplementation led to significant improvements in cognitive function versus the placebo group. Excellent safety was reported, including no dropouts or reports of gastrointestinal upset. Significant improvements were observed in measures for memory, attention, fatigue, stress, and mood in as little as one hour after the first dose.
  31. Hazarey VK et al. Efficacy of curcumin in the treatment for oral health – A randomized clinical trial. Government Dental College and Hospital. Nagpur, Maharashtra, India. J Oral Maxillofac Pathol. 2015. 19: 145-52. DOI: 10.4103/0973-029X.164524. Abstract: A randomized, controlled clinical trial in 30 clinically diagnosed patients with OSF concluded that [lipidated curcumin] lozenges could be effective in combination strategies for the management of OSF in comparison to single therapeutic modality. In this study, 15 OSF patients in each group (test & control) were treated with either [lipidated curcumin] lozenges (400 mg lozenges for total daily dose of 2 g) or Tenovate ointment (clobetasol propionate (0.05%)). The treatment was given for 3 months and follow-up was done for 6 months.
  32. Machida N et al. Effects of Solid, Lipid Curcumin Particles on alcohol metabolism — An expiatory and a randomized, double-blind, placebo-controlled, parallel-group crossover study. Jpn Pharmacol Ther. 2020 Apr. 48(5): 867-873. Abstract: This study further provides evidence that [lipidated curcumin] curcumin is safe and efficacious. Previously examined in 2014, and recently published, researchers report reduced side effects typically associated with alcohol consumption and suggest that [lipidated curcumin] may offer liver health support through the acceleration of ethanol and acetaldehyde metabolism.
  33. Frost S et al. Retinal amyloid fluorescence imaging predicts cerebral amyloid burden. Alz Dement. 2014. 10(4): P234-P235. Abstract: Retinal AB plaques are similar to plaques in the brain. [lipidated curcumin’s] ability to cross the BBB and its affinity for binding to amyloid beta have led to its use as a novel, more cost-effective alternative and imaging tool for screening through the eyes.
  34. DiSilvestro et al. Diverse effects of a low-dose supplement of lipidated curcumin in healthy middle-aged people. The Ohio State University. Nutr. J. 2012 Sep 26. 11(79). DOIi: 10.1186/1475-2891-11-79. Abstract: This study is believed to be the first curcumin trial in healthy people to show improvement in a number of key biomarkers related to healthy aging. Randomized, placebo-controlled study in 39 subjects showing excellent safety as well as significant improvements in markers supporting cognitive health, cardiovascular health, and anti-aging versus placebo.
  35. Khattry N et al. Curcumin decreases cytokine levels involved in mucositis in autologous transplant setting: A pharmacokinetic-pharmacodynamic study. Poster presented at 54th American Society of Hematology (ASH) Annul Meeting. Atlanta, GA. 2012 Dec 08. Blood. 120(21): 3039. Abstract: The absorption and efficacy of [lipidated curcumin] in lozenge form in a common oral inflammatory and fibrotic condition was tested compared to the standard of care (clobetasol steroid ointment). Subjects taking [lipidated curcumin] observed improvements in endpoints significantly better than those receiving steroid treatment; and therapeutic plasma levels were detected through buccal absorption.
  36. Shah et al. Acute human pharmacokinetics of a lipid-dissolved turmeric extract. Planta Med. 2012. 48-PH5. Abstract: This study concluded that a dose as low as 200mg of [lipidated curcumin] reaches blood levels of free curcumin required for healthy brain aging. Analyzed blood samples with and without the use of glucuronidase enzyme, finding very little of the glucuronidated form compared to previous studies on curcumin.
  37. Pharmacokinetics of [lipidated curcumin]: Dose-concentration correlation. Unpublished, UCLA 2011-2012. Abstract: Pilot studies demonstrating absorption and metabolism of [lipidated curcumin] using various dosage forms.
  38. Gota et al. Safety and pharmacokinetics of a solid lipid curcumin particle formulation in patients and healthy volunteers. Tata Memorial Cancer Centre. J Ag Food Chem. 2010. 58(4): 2095-2099. Abstract: Human bioavailability study demonstrating significantly greater plasma levels of free (unconjugated) curcumin after a single dose of [lipidated curcumin] in both healthy and disease states with 65x greater Cmax and >100x greater AUC than 95% curcuminoids.
  39. [Lipidated curcumin] binds to amyloid in human CNS after a single dose. Unpublished.
  40. A phase 1 open-label prospective cohort trial of curcumin plus tyrosin kinase inhibitors for EGFR-mutant advanced NSCLC. McGill U & Jewish General Hospital, Canada. Ongoing.
  41. References: Vitamin D3

  42. Aranow C. Vitamin D and the Immune System. J Investigative Medicine, 2011 Aug;59(6):881-886. Abstract: Quote: “It is now clear that vitamin D has important roles in addition to its classic effects on calcium and bone homeostasis. As the vitamin D receptor is expressed on immune cells (B cells, T cells and antigen presenting cells) and these immunologic cells are all are capable of synthesizing the active vitamin D metabolite, vitamin D has the capability of acting in an autocrine manner in a local immunologic milieu. Vitamin D can modulate the innate and adaptive immune responses. Deficiency in vitamin D is associated with increased autoimmunity as well as an increased susceptibility to infection. As immune cells in autoimmune diseases are responsive to the ameliorative effects of vitamin D, the beneficial effects of supplementing vitamin D deficient individuals with autoimmune disease may extend beyond the effects on bone and calcium homeostasis.”
  43. Autier P, Gandini S. Vitamin D Supplementation and Total Mortality: A Meta-analysis of Randomized Controlled Trials. Arch Intern Med. Sept. 10, 2007;167(16):1730-1737. Abstract: This study identified 18 independent randomized controlled trials, including 57 311 participants. A total of 4777 deaths from any cause occurred during a trial size-adjusted mean of 5.7 years. Daily doses of vitamin D supplements varied from 300 to 2000 IU. The trial size-adjusted mean daily vitamin D dose was 528 IU. In 9 trials, there was a 1.4- to 5.2-fold difference in serum 25-hydroxyvitamin D between the intervention and control groups. Intake of ordinary doses of vitamin D supplements seems to be associated with decreases in total mortality rates.
  44. Adit A et al. Association Between Serum 25-Hydroxyvitamin D Level and Upper Respiratory Tract Infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009;169(4):384-390. Abstract: Study performed a secondary analysis of the Third National Health and Nutrition Examination Survey, a probability survey of the US population conducted between 1988 and 1994. They examined the association between 25(OH)D level and recent URTI in 18 883 participants 12 years and older. The analysis adjusted for demographics and clinical factors (season, body mass index, smoking history, asthma, and chronic obstructive pulmonary disease). Serum 25(OH)D levels were inversely associated with recent upper respiratory tract infections.
  45. Marineua AR et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ, 15 February 2017. Abstract: 25 eligible randomized control trials totaling 11321 participants aged 0 to 95 years were identified. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants.
  46. Urshima M et al. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010, May;91(5):1255-60. Abstract: This randomized, double-blind, placebo-controlled trial compared vitamin D(3) supplements (1200 IU/d) with placebo in schoolchildren. The results suggested that vitamin D(3) supplementation during the winter may reduce the incidence of influenza A, especially in specific subgroups of schoolchildren.
  47. Simoliunas E et al. Bioavailability of Different Vitamin D Oral Supplements in Laboratory Animal Model. Medicina, 2019, 55(6), 265. 2597 C. Abstract: The results of this study suggest that the oral vitamin D supplement vehicle has an impact on its bioavailability, thus it is important to take into account how much of the supplied vitamin D will be absorbed. To maximize the full exploit of supplement, the best delivery strategy should be employed. In this study, the microencapsulated form of vitamin D was the most bioavailable.
  48. References: EGCG (Epigallocatechin-3-gallate)

  49. Chu C et al. Green Tea Extracts Epigallocatechin-3-gallate for Different Treatments. Biomed Research International. Volume 2017, 13 Aug. Abstract: Epigallocatechin-3-gallate (EGCG), a component extracted from green tea, has been proved to have multiple effects on human pathological and physiological processes, and its mechanisms are discrepant in cancer, vascularity, bone regeneration, and nervous system. This review focuses on effects of EGCG, including anti-cancer, antioxidant, anti-inflammatory, anticollagenase, and antifibrosis effects, to express the potential of EGCG and necessity of further studies in this field.
  50. Kishimoto Y et al. Pleiotropic preventive effects of dietary polyphenols in cardiovascular diseases. European Journal of Clinical Nutrition, vol. 67, no. 5, pp. 532–535, 2013. Abstract: The purpose of this study was to review recent findings highlighting daily dietary polyphenol intake and the diverse function of polyphenols and their possible relationships to cardiovascular disease (CVD). their previous findings provide that Japanese people intake polyphenols mainly from beverages, especially coffee and green tea (in descending order of polyphenol content). Many kinds of polyphenols act as an antioxidant against low-density lipoprotein oxidation, which is known to promote atherosclerosis. Recent accumulating evidence suggests that dietary polyphenols could exert their cardioprotective actions through their potential to improve metabolic disorder and vascular inflammation. These findings raise the possibility that polyphenols have a wide variety of roles in the intestine, liver and vascular tissue.
  51. Qian Yi Eng et al. Molecular understanding of Epigallocatechin gallate (EGCG) in cardiovascular and metabolic diseases. Journal of Ethnopharmacology, Volume 210, 10 January, 2018, pp. 296-310. Abstract: EGCG was found to exhibit a wide range of therapeutic properties including anti-atherosclerosis, anti-cardiac hypertrophy, anti-myocardial infarction, anti-diabetes, anti-inflammatory and antioxidant. These therapeutic effects are mainly associated with the inhibition of LDL cholesterol (anti-atherosclerosis), inhibition of NF-KB (anti-cardiac hypertrophy), inhibition of MPO activity (anti-myocardial infarction), reduction in plasma glucose and glycated haemoglobin level (anti-diabetes), reduction of inflammatory markers (anti-inflammatory) and the inhibition of ROS generation (antioxidant).
  52. Xu Y et al. Inhibition of Tobacco-specific Nitrosamine-induced Lung Tumorigenesis in A/J Mice by Green Tea and Its Major Polyphenol as Antioxidants. Cancer Research, Published July 1992. Abstract: This study examined the effects of green tea and its major components, (-)-epigallocatechin gallate (EGCG) and caffeine, on the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice. They also studied the effects of green tea and EGCG on O6-methylguanine and 8-hydroxydeoxyguanosine (8-OH-dGuo) formation in lung tissues caused by NNK treatment. Mice were given 2% tea, 560 ppm EGCG, or 1120 ppm caffeine in drinking water for 13 weeks. The inhibition of 8-OH-dGuo formation in lung DNA by green tea and EGCG is consistent with their ability to inhibit lung tumorigenesis by NNK.
  53. Jung YD et al. EGCG, a major component of green tea, inhibits tumour growth by inhibiting VEGF induction in human colon carcinoma cells. British Journal of Cancer, vol. 84, no. 6, pp. 844–850, 2001. Abstract: Catechins are key components of teas that have anti-proliferative properties. This study investigated the effects of green tea catechins on intracellular signaling and VEGF induction in vitro in serum-deprived HT29 human colon cancer cells and in vivo on the growth of HT29 cells in nude mice. In the in vitro studies, (-)-epigallocatechin gallate (EGCG), the most abundant catechin in green tea extract, inhibited Erk-1 and Erk-2 activation in a dose-dependent manner. Treatment with EGCG inhibited tumour growth (58%), microvessel density (30%), and tumor cell proliferation (27%) and increased tumor cell apoptosis (1.9-fold) and endothelial cell apoptosis (3-fold) relative to the control condition (P
  54. Guang-Jian Du et al. Epigallocatechin Gallate (EGCG) Is the Most Effective Cancer Chemopreventive Polyphenol in Green Tea. Nutrients 2012, 4(11), 1679-1691. Abstract: Previous studies have shown that some polyphenol compounds from green tea possess anticancer activities. In this study, they determined the cancer chemopreventive potentials of 10 representative polyphenols. Among the 10 polyphenols, EGCG showed the most potent antiproliferative effects, and significantly induced cell cycle arrest in the G1 phase and cell apoptosis.
  55. Mandel S et al. Multifunctional Activities of Green Tea Catechins in Neuroprotection. Neurosignals. 2005;14(1-2):46-60. DOI: 10.1159/000085385. Abstract: Many lines of evidence suggest that oxidative stress resulting in reactive oxygen species (ROS) generation and inflammation play a pivotal role in the age-associated cognitive decline and neuronal loss in neurodegenerative diseases including Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s diseases. One cardinal chemical pathology observed in these disorders is the accumulation of iron at sites where the neurons die. The buildup of an iron gradient in conjunction with ROS (superoxide, hydroxyl radical and nitric oxide) are thought to constitute a major trigger in neuronal toxicity and demise in all these diseases. Thus, promising future treatment of neurodegenerative diseases and aging depends on availability of effective brain permeable, iron-chelatable/radical scavenger neuroprotective drugs that would prevent the progression of neurodegeneration. Tea flavonoids (catechins) have been reported to possess potent iron-chelating, radical-scavenging and anti-inflammatory activities and to protect neuronal death in a wide array of cellular and animal models of neurological diseases. Recent studies have indicated that in addition to the known antioxidant activity of catechins, other mechanisms such as modulation of signal transduction pathways, cell survival/death genes and mitochondrial function, contribute significantly to the induction of cell viability. This review will focus on the multifunctional properties of green tea and its major component (-)-epigallocatechin-3-gallate (EGCG) and their ability to induce neuroprotection and neurorescue in vitro and in vivo. In particular, their transitional metal (iron and copper) chelating property and inhibition of oxidative stress.
  56. Biasibetti R et al. Green tea (-)epigallocatechin-3-gallate reverses oxidative stress and reduces acetylcholinesterase activity in a streptozotocin-induced model of dementia. Behav Brain Res. 2013 Jan 1. DOI: 10.1016/j.bbr.2012.08.039. Abstract: Alzheimer’s disease (AD) is the most prevalent form of dementia. Intracerebroventricular (ICV) infusion of streptozotocin (STZ) provides a relevant animal model of chronic brain dysfunction that is characterized by long-term and progressive deficits in learning, memory, and cognitive behavior, along with a permanent and ongoing cerebral energy deficit. Numerous studies on green tea epigallocatechin gallate (EGCG) demonstrate its beneficial effects on cognition and memory. As such, this study evaluated, for the first time, the effects of sub-chronic EGCG treatment in rats that were submitted to ICV infusion of STZ (3mg/kg). Male Wistar rats were divided into sham, STZ, sham+EGCG and STZ+EGCG groups. EGCG was administered at a dose of 10mg/kg/day for 4 weeks per gavage. Learning and memory was evaluated using Morris’ Water Maze. Oxidative stress markers and involvement of the nitric oxide (NO) system, acetylcholinesterase activity (AChE) and glucose uptake were evaluated as well as glial parameters including S100B content and secretion and GFAP content. Our results show that EGCG was not able to modify glucose uptake and glutathione content, although cognitive deficit, S100B content and secretion, AChE activity, glutathione peroxidase activity, NO metabolites, and reactive oxygen species content were completely reversed by EGCG administration, confirming the neuroprotective potential of this compound. These findings contribute to the understanding of diseases accompanied by cognitive deficits and the STZ-model of dementia.
  57. Rasoolijazi H et al. The Beneficial Effect of (-)-Epigallocatechin-3-Gallate in an Experimental Model of Alzheimer’s Disease in Rat: a Behavioral Analysis. Iranian Biomedical Journal. October 2007. Abstract: rogressive cognitive decline is one of the hallmark symptoms of Alzheimer’s disease (AD) which can be modeled by B-amyloid injection into specific regions of brain. Since epigallocatechin-3-gallate (EGCG) is a potent antioxidant agent which its role against oxidative stress and inflammation has been shown in prior studies, we tried to determine whether EGCG administration protects against B-amyloid-induced memory and coordination impairment in rats. Methods: Animals (male Wistar rats) were divided into four groups: sham operated, EGCG-pretreated sham operated (sham + EGCG), untreated lesion (lesion), and EGCG-pretreated lesion (lesion + EGCG). Animals in lesion, lesion + EGCG, and sham + EGCG groups received sterile saline or saline plus EGCG (10 mg/kg) intraperitoneally one day pre-surgery and every other day for three weeks. The lesion was induced one day after EGCG pretreatment by injection of 4 microliter of sterile saline or water containing 2 nmol/microliter B-amyloid (1-40) into the hippocampal fissure. For behavioral analysis, psychomotor coordination (PMC) index and spontaneous alternation behavior were assessed using Rota-rod Treadmill and Y-maze, respectively at the third week post-lesion. Results: We found that B-amyloid (1-40) injection into hippocampus can decrease these behavioral indexes in lesion group in comparison with sham group which is similar to behavioral changes in AD. On the other hand, pretreatment with EGCG can improve the PMC index and spatial Y-maze alternation in the lesion + EGCG group in comparison with lesion group. Conclusion: We concluded that EGCG can be effective in restoring B-amyloid-induced behavioral derangements in rats regarding coordination and memory abilities.

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