I-Well References

    Beta-1,3-glucan References

  1. Moorlag S et al. Beta-Glucan Induces Protective Trained Immunity against Mycobacterium tuberculosis Infection: A Key Role for IL-1 Cell Rep. 2020 May 19;31(7):107634. doi: 10.1016/j.celrep.2020.107634. ABSTRACT: Beta-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 beta-glucan exposure confers protection against pulmonary Mycobacterium tuberculosis (Mtb) infection. Beta-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 beta-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 beta-glucan is mediated via IL-1 signaling, as beta-glucan shows no protection in mice lacking a functional IL-1 receptor (IL1R−/−). The administration of beta-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 (Basel). 2020 Jan 8;12(1):155. doi: 10.3390/cancers12010155. ABSTRACT: Beta-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 beta-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 beta-glucans interesting candidates as adjuvants in antitumor therapies as well as in cancer prevention strategies. Here, the regulatory effects of dietary beta-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. 2016 Jul 26;56(10):1746-52. doi: 10.1080/10408398.2013.854733. ABSTRACT: B-D-glucans are a (1-3)-linked glucose polymer with (1→6)-linked side chains and a major component of fungal cell walls. They exhibit structural integrity to the fungal cell wall. In addition, beta-glucans are widely used as food adjuvant in food and pharmaceutical industries because of their physico-chemical properties. Several studies have focused on different isolation processes of (1-3) (1-6)-beta-glucan that could affect the physico-chemical and functional properties of beta-glucan such as chemical composition, solubility, viscosity, hydration properties, and oil binding capacity. Immunological activity is one of the most important properties of beta-glucans. Thus, they are effective in inhibiting growth of cancer cells and metastasis and preventing bacterial infection. In humans, beta-glucans reduce blood cholesterol, improve glucose absorption by body cells, and so help wound healing. This review described the prebiotic potentiality of fungal B-D-glucans with the objective to detail the methodologies applied for their extraction, their structure and techno-functional properties, and finally their biological effect.
  4. Vetvicka V et al. Glucans and Cancer: Comparison of Commercially Available Beta-glucans – Part IV. Anticancer Res. 2018 Mar;38(3):1327-1333. doi: 10.21873/anticanres.12355. ABSTRACT: Background/Aim: Beta-glucans are well-established immunomodulators with strong effects across all immune reactions. Due to the extensive amount of studies, glucans are steadily progressing from a non-specific immunomodulator to a licensed drug. However, direct comparisons of higher numbers of different glucans are rare. Materials and Methods: In this study, we used 16 different glucans isolated from yeasts, mushroom, algae, and oat and compared their effects on phagocytosis, IL-2 production, antibody secretion, and inhibition of three experimental cancer models. Results: Our results showed significant differences among tested glucans, showing that despite the fact that glucans in general have strong stimulating effects on most aspects of the immune system, it is necessary to choose the right glucan. Conclusion: Based on our studies, we can conclude that highly purified and active glucans have significant pleiotropic effects.
  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. doi: 10.1249/01.mss.0000135790.68893.6d. ABSTRACT: Purpose: To test the effects of oat beta-glucan (ObetaG) on respiratory infection, macrophage antiviral resistance, and NK cytotoxicity. Methods: Mice were randomly assigned to one of four groups: Ex-H2O, Ex-ObetaG, Con-H2O, or Con-ObetaG. ObetaG was fed in the drinking water for 10 d before intranasal inoculation of HSV-1 or sacrifice. Exercise consisted of treadmill running to volitional fatigue (approximately 140 min) for three consecutive days. Fifteen minutes after the last bout of exercise or rest, mice (N = 24) were intranasally inoculated with a standardized dose of HSV-1. Mice were monitored twice daily for morbidity and mortality. Additional mice were sacrificed after exercise, peritoneal macrophages were obtained via i.p. lavage and assayed for antiviral resistance to HSV-1 (N = 18), and spleens were harvested and assayed for NK cell cytotoxicity (N = 12). Results: Exercise stress was associated with a 28% increase in morbidity (P = 0.036) and 18% increase in mortality (P = 0.15). Ingestion of ObetaG before infection prevented this increase in morbidity (P = 0.048) and mortality (P = 0.05). Exercise stress was associated with a decrease in macrophage antiviral resistance (P = 0.007), which was blocked by ingestion of ObetaG (P < 0.001). There were no effects of exercise or ObetaG on NK cytotoxicity. Conclusion: These data suggest that daily ingestion of ObetaG may offset the increased risk of 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 beta-glucans. Physiol Behav. 2008 May 23;94(2):276-84. doi: 10.1016/j.physbeh.2007.11.045. Abstract: The immune response can be modulated by nutrients like beta-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. There is a lot of structural variation in the beta-glucans from these different sources, which may influence their physiological functions. In this review the current status concerning possibilities to modulate immune function by beta-glucans is discussed. In vitro as well as in vivo studies in animals and humans show that especially beta-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 beta-glucan interventions. Although most studies supply the beta-glucans parenteral (e.g. intravenous or subcutaneous), also enteral administrated (dietary) beta-glucan influence the immune response. Although more human studies are needed, it is tempting to suggest that dietary beta-glucans may be a useful tool to prime the host immune system and increase resistance against invading pathogens.
  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. Beta-glucans are polysaccharides occurring in the bran of cereal grains (barley and oats and to a much lesser degree in rye and wheat, in amounts of about 7%, 5%, 2% and less than 1%, respectively), the cell wall of baker's yeast, certain types of fungi, and many kinds of mushrooms. The differences between soluble and insoluble beta-glucans are significant in regards to application, mode of action, and overall biological activity. A growing body of science indicates that beta-glucans promote health in a number of important ways. Beta-glucans have been studied for their hypocholesterolemic effects; these mechanisms include: reducing the intestinal absorption of cholesterol and bile acids by binding to glucans; shifting the liver from cholesterol syntheses to bile acid production; and fermentation by intestinal bacteria to short-chain fatty acids, which are absorbed and inhibit hepatic cholesterol syntheses. 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. Finally, there is renewed interest in the potential usefulness of beta-glucan as a radioprotective drug for chemotherapy, radiation therapy and nuclear emergencies, particularly because glucan can be used not only as a treatment, but also as a prophylactic.
  8. Vetvicka V et al. Beta-glucan improves conditions of chronic fatigue in mice by stimulation of immunity. Open Biochem J. 2020 Feb;14(1):1-8. doi: 10.2174/1874091X02014010001. ABSTRACT: Background Various natural molecules have been studied for the enhancement of physical endurance. Glucan has been found to improve various stress-related conditions and to improve fatigue and endurance. Objective In our study, we focused on evaluation of glucan effects on some reactions involved in chronic fatigue. Methods We measured phagocytosis of neutrophils, the production of IL-2, IL-4, and IL-10 by spleen cells, and levels of antioxidant glutathione and oxidative stress marker superoxide dismutase in brain. In addition, we measured the effects of glucan on water immersion and on rotarod. Results The 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. Conclusion Our data suggested that anti-fatigue properties of glucan are related with its well-established effects as stimulator of immune reactions.
  9. Akramiene D et al. Effects of beta-glucans on the immune system. Medicina (Kaunas). 2007;43(8):597-606. Abstract: Beta-glucans are naturally occurring polysaccharides. These glucose polymers are constituents of the cell wall of certain pathogenic bacteria and fungi. The healing and immunostimulating properties of mushrooms have been known for thousands of years in the Eastern countries. These mushrooms contain biologically active polysaccharides that mostly belong to group of beta-glucans. These substances increase host immune defense by activating complement system, enhancing macrophages and natural killer cell function. The induction of cellular responses by mushroom and other beta-glucans is likely to involve their specific interaction with several cell surface receptors, as complement receptor 3 (CR3; CD11b/CD18), lactosylceramide, selected scavenger receptors, and dectin-1 (betaGR). beta-Glucans also show anticarcinogenic activity. They can prevent oncogenesis due to the protective effect against potent genotoxic carcinogens. As immunostimulating agent, which acts through the activation of macrophages and NK cell cytotoxicity, beta-glucan can inhibit tumor growth in promotion stage too. Anti-angiogenesis can be one of the pathways through which beta-glucans can reduce tumor proliferation, prevent tumor metastasis. beta-Glucan as adjuvant to cancer chemotherapy and radiotherapy demonstrated the positive role in the restoration of hematopiesis following by bone marrow injury. Immunotherapy using monoclonal antibodies is a novel strategy of cancer treatment. These antibodies activate complement system and opsonize tumor cells with iC3b fragment. In contrast to microorganisms, tumor cells, as well as other host cells, lack beta-glucan as a surface component and cannot trigger complement receptor 3-dependent cellular cytotoxicity and initiate tumor-killing activity. This mechanism could be induced in the presence of beta-glucans.
  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. Beta-glucan successfully stimulated the immune system in different jawed vertebrate species. Comp Immunol Microbiol Infect Dis. 2019 Feb;62:1-6. doi: 10.1016/j.cimid.2018.11.006. ABSTRACT: Several reports have shown the positive effects of beta-glucans on the immune system. For 28 days, scientists, fed four different vertebrate species: mice, dogs, piglets and chicks, with two beta-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 beta-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 beta-glucans and confirms the benefits of beta-glucans across different vertebrate species.
  12. Garcia-Valtanen p et al. Evaluation of trained immunity by beta-1, 3 (D)-glucan on murine monocytes in vitro and duration of response in vivo. Immunol Cell Biol. 2017 Aug;95(7):601-610. doi: 10.1038/icb.2017.13. ABSTRACT: The beta-1, 3 (D)-glucan (beta-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 beta-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 beta-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 beta-glucan training effect explained the elevated production of tumour necrosis factor-α (TNFα) and interleukin-6 (IL-6) induced by subsequent lipopolysaccharide (LPS) challenge. In vivo, 4 days after systemic administration of beta-glucan, mice were more responsive to LPS challenge as shown by the increased serum levels of TNFα, 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 beta-glucan-primed monocytes based on their surface marker expression and for the first time provide evidence that the training effect of beta-glucan in vivo declines within a 3-week period.
  13. Paris S et al. Beta-glucan-Induced Trained Immunity in Dogs. Front Immunol. 2020 Oct 9;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 beta-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 beta-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 beta-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 beta-glucans and bacillus Calmette-Guerin to induce innate training or tolerance in pig cells, porcine monocytes were cultured with priming agonist (beta-glucans or bacillus Calmette-Guerin) then re-stimulated 5 d later with a heterologous microbial agonist to determine induction of innate memory. Priming with beta-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 beta-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 beta-glucans: Indications for trained immunity in fish. Developmental and Comparative Immunology. 2016 Nov;64 93-102. doi: 10.1016/j.dci.2016.03.003. ABSTRACT: Over the past decades, it has become evident that immune-modulation of fish with beta-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 beta-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 beta-glucans on the teleost fish immune system. We shortly discuss possible mechanisms influencing immune-stimulation by beta-glucans, including microbial composition of the gut, receptor recognition and downstream signalling. Of interest, in mammalian monocytes, beta-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 beta-glucans, a criterion which could help to identify key roles for macrophages on resistance to infection. We discuss whether beta-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 beta-glucan enhanced gut health and immune responses of weaned pigs experimentally infected with a pathogenic E. coli. Animal Feed Science and Technology. 2019 Feb;248 114-125. doi: 10.1016/j.anifeedsci.2018.12.004. ABSTRACT: Most of the commercially available beta-glucans are derived from yeast, while there are limited research on algae-derived beta-glucan in pigs. Therefore, the objective of this experiment was to investigate the influence of dietary supplementation of algae-derived beta-glucan on diarrhea, gut permeability, and immune responses of weaned pigs experimentally infected with a pathogenic Escherichia coli (E. coli). Thirty-six weaned pigs (7.69 ± 0.77 kg BW) were individually housed in disease containment rooms and randomly allotted to one of three dietary treatments (n = 12): control diet and 2 additional diets containing either 54 or 108 mg/kg of beta-glucan. The experiment lasted 17 d [5 d before and 12 d post inoculation (PI)]. The inoculum used in this experiment was F18 E. coli, containing heat-labile toxin, heat-stable toxin b, and shiga-lie toxin 2. The inoculation doses were 1010 cfu/3 mL oral dose daily for 3 days. Diarrhea score (1, normal, to 5, watery diarrhea) was recorded for each pig daily to calculate frequency of diarrhea. Blood samples were collected on d 0 before E. coli challenge, and on d 2, 5, 8, and 12 PI to measure total and differential blood cell count in whole blood and several inflammatory markers in serum. Fresh jejunal tissues were collected from 4 pigs in the control group and high dose beta-glucan group to analyze gut permeability on d 5 and d 12 PI with Ussing Chamber. Jejunal and ileal mucosa were also collected to measure the mRNA expression of several genes related to gut barrier function and immune responses. Results of this experiment revealed that inclusion of high dose beta-glucan reduced (P 
  17. Abraham A et al. A novel vaccine platform using glucan particles for induction of protective responses against Francisella tularensis and other pathogens. Clin Exp Immunol. 2019 Nov;198(2):143-152. doi: 10.1111/cei.13356. Epub 2019 Sep 12. ABSTRACT: Vaccines 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 beta-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. Curcumin References

  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 [lipidated] 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. Medicine. 2020 Proceedings of the Nutrition Society. doi:10.1017/S0029665120003882. ABSTRACT: The flavonoid curcumin is believed to be responsible for the purported health benefits of turmeric. Like other flavonoids, curcumin affects several systemic and central processes involved in neurocognitive aging. We have previously shown that one month administration of a highly bioavailable curcumin extract ([lipidated curcumin]) improved working memory and reduced fatigue and workload stress in an older, cognitively intact cohort(1). This study focused on the effects of the same extract, focusing on memory tasks subserved by the hippocampus, one of two areas of the adult brain believed to be capable of adult neurogenesis. Eighty healthy older participants (aged 50–80 years, mean = 68.1, ± SD 6.34) took part in this double-blind, placebo-controlled, parallel-groups trial. Volunteers were randomised to receive administration of 400 mg daily [lipidated curcumin] (containing 80 mg curcumin) or a matching placebo. Assessment took place at baseline and 4 and 12 weeks thereafter. Outcomes included two tasks evaluating memory processes relevant to hippocampal function. These were i) a human analogue of the widely used rodent Morris Water Maze - the virtual Morris Water Maze (vMWM) and ii) a Mnemonic Similarity task evaluating pattern separation. Measures of mood, cardiovascular function and other blood biomarkers were collected, and a subset of the cohort underwent neuroimaging using functional magnetic resonance imaging. Compared with placebo, there were a number of improvements in the curcumin group. The curcumin group had significantly better performance at 12 weeks on the virtual Morris Water Maze (p = .019). Curcumin was also associated with better performance on a pattern separation task (p = .025). Curcumin was also associated with number of significantly benefits to mood, including, from the Profile of Mood States (POMS), including, at 28 days only, total mood disturbance (p = .006), tension-anxiety (p = .028), confusion-bewilderment (p = .019), anger-Hostility (p = .009). There were also significant benefits to the POMS fatigue scores at both assessments (p ≤ .011). There were no group differences in biomarker levels. These results confirm that [lipidated] curcumin improves aspects of mood 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 populations at risk of pathological cognitive decline.
  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: Objectives: Curcumin (a flavonoid isolated from the spice turmeric) affects several processes involved in neurocognitive aging. We have previously reported that 4 weeks administration of a highly bioavailable curcumin extract ([lipidated curcumin]) improved working memory and reduced fatigue and stress reactivity in older Australians. This follow-up study (ACTRN12616000484448) was aimed at determining if similar effects were evident following 12 weeks administration of the same extract. Methods: A double-blind, placebo-controlled, parallel-groups trial was conducted. Eighty participants aged 50–80 years (mean = 68.1, SD 6.34) were randomised to receive administration of [lipidated curcumin] (400 mg daily containing 80 mg curcumin) or a matching placebo. Assessment took place at baseline then at 4 and 12 weeks. Outcomes included measures of cognitive performance focusing on memory processes relevant to hippocampal function. Participants also underwent neuroimaging and measures of mood, cardiovascular function and other blood biomarkers were collected. Results: Compared with placebo, there were a number of improvements in the curcumin group. The curcumin group had significantly better working memory performance at 12 weeks, as measured by Serial Threes, Serial Sevens and performance on a virtual Morris Water Maze. Curcumin was also associated with better performance on a pattern separation task. Curcumin was also associated with significantly lower fatigue scores on the Profile of Mood States (POMS) at both 4 and 12 weeks, and of tension, anger, confusion and total mood disturbance at 4 weeks only. There were no group differences in biomarker levels. Conclusions: These results confirm that [lipidated curcumin] improves aspects of mood 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.
  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: Purpose: Osteoarthritis is the single most common cause of disability in older adults with an estimated 10% to 15% prevalence in individuals above 60 years. The contemporary medications include nonsteroidal anti-inflammatory drugs acetaminophen, cyclooxygenase-2 inhibitors, and surgical interventions. In view of safety issues regarding their longterm use, necessitating search for effective and safe alternatives, we evaluated Capsule [lipidated curcumin] Optimized Curcumin prepared using solid lipid curcumin particles (SLCP) technology in patients with knee osteoarthritis. Patients and methods: Eligible patients fulfilling American College of Rheumatology Criteria were randomized to SLCP group (400 mg twice daily delivering 80 mg of curcumin per capsule) or Ibuprofen with placebo group (400 mg each once daily) for 90 days. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Visual Analog Scale (VAS) were used for clinical assessment of knee pain and function. Degree of knee flexion and swelling were also noted. Blood biochemistry included hemogram, blood urea, creatinine, Random blood sugar and inflammatory markers viz. PGE2, TNF α, IL6, IL1β and LTB4 while urine examination included degenerative marker CTX II. The parametric data was analyzed using unpaired t test while non-parametric data was analyzed using Friedman's test or Mann Whitney t test as applicable. A level of p < 0.05 was considered as statistically significant. Results: Out of 50 recruitments, 25 from the Ibuprofen group and 17 from the SLCP group completed the study with significant improvements in VAS and WOMAC scores indicating comparable efficacy of SLCP in alleviating pain with Ibuprofen. None of the markers displayed significant changes. Except one withdrawal in the study group due to rash and itching, the study drug was found safe. Conclusions: SLCP in a dose of 160 mg daily was found to be effective and safe in alleviating symptoms in patients suffering from knee osteoarthritis when administered for 90 days.
  25. Koronyo, Y et al. Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease. JCI Insight. 2017. 2(16). DOI: 10.1172/jci.insight.93621. ABSTRACT: Background: Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. Methods: Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. Results: Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). Conclusion: The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring.
  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 (Albany NY). 2017 Jan 3;9(1):187-208. doi: 10.18632/aging.101149. ABSTRACT: We hypothesized that curcumin would improve resistance and conduit artery endothelial function and large elastic artery stiffness in healthy middle-aged and older adults. Thirty-nine healthy men and postmenopausal women (45-74 yrs) were randomized to 12 weeks of curcumin (2000 mg/day [lipidated curcumin]; n=20) or placebo (n=19) supplementation. Forearm blood flow response to acetylcholine infusions (FBFACh; resistance artery endothelial function) increased 37% following curcumin supplementation (107±13 vs. 84±11 AUC at baseline, P=0.03), but not placebo (P=0.2). Curcumin treatment augmented the acute reduction in FBFACh induced by the nitric oxide synthase inhibitor NG monomethyl-L-arginine (L-NMMA; P=0.03), and reduced the acute increase in FBFACh to the antioxidant vitamin C (P=0.02), whereas placebo had no effect (both P>0.6). Similarly, brachial artery flow-mediated dilation (conduit artery endothelial function) increased 36% in the curcumin group (5.7±0.4 vs. 4.4±0.4% at baseline, P=0.001), with no change in placebo (P=0.1). Neither curcumin nor placebo influenced large elastic artery stiffness (aortic pulse wave velocity or carotid artery compliance) or circulating biomarkers of oxidative stress and inflammation (all P>0.1). In healthy middle-aged and older adults, 12 weeks of curcumin supplementation improves resistance artery endothelial function by increasing vascular nitric oxide bioavailability and reducing oxidative stress, while also improving conduit artery endothelial function.
  27. McFarlin B et al. Reduced inflammatory and muscle damage biomarkers following oral supplementation with bioavailable curcumin. University of North Texas. BBA Clin. 2016 Feb 18;5:72-8. doi: 10.1016/j.bbacli.2016.02.003. ABSTRACT: Background: Exercise-Induced Muscle Damage (EIMD) and delayed onset muscle soreness (DOMS) impact subsequent training sessions and activities of daily living (ADL) even in active individuals. In sedentary or diseased individuals, EIMD and DOMS may be even more pronounced and present even in the absence of structured exercise. Methods: The purpose of this study was to determine the effects of oral curcumin supplementation ([lipidated curcumin] 400 mg/days) on muscle & ADL soreness, creatine kinase (CK), and inflammatory cytokines (TNF-α, IL-6, IL-8, IL-10) following EMID (eccentric-only dual-leg press exercise). Subjects (N = 28) were randomly assigned to either curcumin (400 mg/day) or placebo (rice flour) and supplemented 2 days before to 4 days after EMID. Blood samples were collected prior to (PRE), and 1, 2, 3, and 4 days after EIMD to measure CK and inflammatory cytokines. Data were analyzed by ANOVA with P < 0.05. Results: Curcumin supplementation resulted in significantly smaller increases in CK (- 48%), TNF-α (- 25%), and IL-8 (- 21%) following EIMD compared to placebo. We observed no significant differences in IL-6, IL-10, or quadriceps muscle soreness between conditions for this sample size. Conclusions: Collectively, the findings demonstrated that consumption of curcumin reduced biological inflammation, but not quadriceps muscle soreness, during recovery after EIMD. The observed improvements in biological inflammation may translate to faster recovery and improved functional capacity during subsequent exercise sessions. General significance: These findings support the use of oral curcumin supplementation to reduce the symptoms of EIMD. The next logical step is to evaluate further the efficacy of an inflammatory clinical disease model.
  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: Mounting evidence suggests that curcumin, an anti-inflammatory ingredient in the Indian spice tumeric, has vascular protective effects in aging animals and humans. We tested the hypothesis that curcumin improves vascular endothelial function, as assessed by endothelium-dependent dilation (EDD), in middle-aged and older (MA/O) adults (45-74 yrs) by enhancing bioavailability of the vasodilatory and vascular protective molecule, nitric oxide (NO). Conduit and resistance artery EDD were assessed by brachial artery flow-mediated dilation (FMDba) and forearm blood flow in response to incremental brachial artery infusions of acetylcholine (FBFach), respectively, before and after 12 weeks of curcumin (2000 mg/day-[lipidated curcumin]; n=16) or placebo (n=13) supplementation. FMDba was increased by 34% (P < 0.01 vs. placebo; 5.6±0.5 compared to 4.6±0.4% at baseline, P < 0.001) in the curcumin group, whereas no change was observed with placebo (P>0.05). Similarly, FBFach increased by 44% following curcumin (P < 0.05 vs. placebo; 222±74 vs. 170±57 AUC at baseline, P=0.06) and this improvement was mediated in part by an increase in NO bioavailability as indicated by a greater deltaFBFach AUC during co-infusion of the NO synthase inhibitor, NG monomethyl-L-arginine (-34 vs. -5%; P=0.08). In contrast, there was no change in either FBFach or NO bioavailability in the placebo group (both P>0.05). Conduit (sublingual nitroglycerin) and resistance artery (incremental brachial artery infusions of sodium nitroprusside) endothelium-independent dilation were unchanged in both groups (all P>0.05), suggesting an endothelium-specific effect of curcumin. Our findings indicate that 12 weeks of curcumin supplementation improves EDD in MA/O adults and this is mediated, in part, by an increase in NO bioavailability.
  29. Cox KH et al. Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population. J Psychopharmacol. 2015 May;29(5):642-51. doi: 10.1177/0269881114552744. ABSTRACT: Curcumin possesses many properties which may prevent or ameliorate pathological processes underlying age-related cognitive decline, dementia or mood disorders. These benefits in preclinical studies have not been established in humans. This randomized, double-blind, placebo-controlled trial examined the acute (1 and 3 h after a single dose), chronic (4 weeks) and acute-on-chronic (1 and 3 h after single dose following chronic treatment) effects of solid lipid curcumin formulation (400 mg as [lipidated curcumin]) on cognitive function, mood and blood biomarkers in 60 healthy adults aged 60-85. One hour after administration curcumin significantly improved performance on sustained attention and working memory tasks, compared with placebo. Working memory and mood (general fatigue and change in state calmness, contentedness and fatigue induced by psychological stress) were significantly better following chronic treatment. A significant acute-on-chronic treatment effect on alertness and contentedness was also observed. Curcumin was associated with significantly reduced total and LDL cholesterol and had no effect on hematological safety measures. To our knowledge this is the first study to examine the effects of curcumin on cognition and mood in a healthy older population or to examine any acute behavioral effects in humans. Results highlight the need for further investigation of the potential psychological and cognitive benefits of curcumin in an older population.
  30. Hazarey VK et al. Efficacy of curcumin in the treatment for oral health – A randomized clinical trial. J Oral Maxillofac Pathol. May-Aug 2015;19(2):145-52. doi: 10.4103/0973-029X.164524. ABSTRACT: Introduction: Oral submucous fibrosis (OSF) is a chronic, insidious disease that is associated with significant functional morbidity and an increased risk for malignancy. Turmeric and its active ingredient "curcumin" are being studied upon as chemopreventive agents in various diseases. The present study aims to determine the efficacy of curcumin in the treatment of OSF. Materials and methods: Thirty clinically diagnosed OSF patients were divided into two groups, 15 patients in each group from the Outpatient Department. Test group patients were treated with [lipidated curcumin] (curcumin) lozenges and control group with Tenovate ointment (clobetasol propionate (0.05%). The treatment was given for 3 months duration and follow-up was done for 6 months. Both the groups were advised for physiotherapy exercises by mouth exercise device. The baseline and follow-up results were compared for IIO (interincisal distance on maximum mouth opening), Visual Analogue Scale (VAS) for normal food and VAS for spicy food. Results: The test group showed 5.93 (±2.37) mm increase in mouth opening compared to 2.66 (±1.76) mm of the control group. In relation to VAS scale with spicy and normal food the average reduction was 64 (42-73) and 77 (70.5-82) as compared to 34 (14.5-64.5) and 64 (46-75.5) respectively in control group. The test group results achieved in the treatment span was sustained in the follow-up (P < 0.05) compared to control group which showed statistically significant (P < 0.05) relapse. Conclusion: It can be concluded that combination strategies for the management of OSF which include the stoppage of causative ill habits, appropriate medicinal and physiotherapy management is more efficient than single therapeutic modality. It is evident from the study that curcumin holds good promise in the treatment of OSF in future.
  31. DiSilvestro et al. Diverse effects of a low-dose supplement of lipidated curcumin in healthy middle-aged people. Nutr J. 2012 Sep 26;11:79. doi: 10.1186/1475-2891-11-79. ABSTRACT: Background: Curcumin extracts of turmeric are proposed to produce health benefits. To date, human intervention studies have focused mainly on people with existing health problems given high doses of poorly absorbed curcumin. The purpose of the current study was to check whether in healthy people, a low dose of a lipidated curcumin extract could alter wellness-related measures. Methods: The present study was conducted in healthy middle aged people (40-60 years old) with a low dose of curcumin (80 mg/day) in a lipidated form expected to have good absorption. Subjects were given either curcumin (N = 19) or placebo (N = 19) for 4 wk. Blood and saliva samples were taken before and after the 4 weeks and analyzed for a variety of blood and saliva measures relevant to health promotion. Results: Curcumin, but not placebo, produced the following statistically significant changes: lowering of plasma triglyceride values, lowering of salivary amylase levels, raising of salivary radical scavenging capacities, raising of plasma catalase activities, lowering of plasma beta amyloid protein concentrations, lowering of plasma sICAM readings, increased plasma myeloperoxidase without increased c-reactive protein levels, increased plasma nitric oxide, and decreased plasma alanine amino transferase activities. Conclusion: Collectively, these results demonstrate that a low dose of a curcumin-lipid preparation can produce a variety of potentially health promoting effects in healthy middle aged people.
  32. Shah et al. Acute human pharmacokinetics of a lipid-dissolved turmeric extract. PPlanta Med. 2012; 78 - PH5. doi: 10.1055/s-0032-1320664. ABSTRACT: Curcumin is a lipophilic compound found in the rhizome of turmeric (Curcuma longa Linn.) that targets several inflammatory and neurological pathways. Dosing of turmeric extract is associated with safety and tolerability in humans, yet literature on its efficacy is limited, possibly due to its low bioavailability in plasma and high rate of metabolism, mainly to glucuronide conjugate. The primary aim of this study was to quantify plasma and red blood cell levels of curcumin by HPLC after ingestion of 40mg curcumin from a lipid-dissolved turmeric extract formulation (SLCP-1) at a dosage of 200mg in healthy human volunteers. The secondary aim of this study was to determine the relationship between plasma and red blood cell (RBC) curcumin in blood samples treated with and without glucuronidase enzyme. An HPLC system (Shimadzu 1100) with PDA detector and C18 column using mobile phase gradient of 0.1% phosphoric acid and acetonitrile was used, as previously published. The mean peak concentration (Cmax) of free curcumin in blood prepared with and without glucuronidase was 48.3 and 39.2ng/mL, respectively, with time of maximum concentration (Tmax) occurring at 6 hours. Most of the curcumin from dosing of the formulation was detected in blood in free form in plasma and RBC fractions. The concentrations of curcumin detected are in the range offering therapeutic impact in various models.
  33. Gota et al. Safety and pharmacokinetics of a solid lipid curcumin particle formulation in 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.
  34. Vitamin D3 References

  35. Aranow C. Vitamin D and the Immune System. J Investigative Medicine, 2011 Aug;59(6):881-886. Abstract: 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.
  36. Autier P et al. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007 Sep 10;167(16):1730-7. doi: 10.1001/archinte.167.16.1730. ABSTRACT: Background: Ecological and observational studies suggest that low vitamin D status could be associated with higher mortality from life-threatening conditions including cancer, cardiovascular disease, and diabetes mellitus that account for 60% to 70% of total mortality in high-income countries. We examined the risk of dying from any cause in subjects who participated in randomized trials testing the impact of vitamin D supplementation (ergocalciferol [vitamin D(2)] or cholecalciferol [vitamin D(3)]) on any health condition. Methods: The literature up to November 2006 was searched without language restriction using the following databases: PubMed, ISI Web of Science (Science Citation Index Expanded), EMBASE, and the Cochrane Library. Results: We 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. The summary relative risk for mortality from any cause was 0.93 (95% confidence interval, 0.87-0.99). There was neither indication for heterogeneity nor indication for publication biases. The summary relative risk did not change according to the addition of calcium supplements in the intervention. Conclusions: Intake of ordinary doses of vitamin D supplements seems to be associated with decreases in total mortality rates. The relationship between baseline vitamin D status, dose of vitamin D supplements, and total mortality rates remains to be investigated. Population-based, placebo-controlled randomized trials with total mortality as the main end point should be organized for confirming these findings.
  37. 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.
  38. 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.
  39. 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.
  40. 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.
  41. Epigallocatechin-3-gallate (EGCG) References

  42. 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.
  43. 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.
  44. 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-κB (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).
  45. 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.
  46. 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 < 0.05 for all comparisons). EGCG may exert at least part of its anticancer effect by inhibiting angiogenesis through blocking the induction of VEGF.
  47. 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.
  48. 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.
  49. 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.
  50. 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 beta-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 beta-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 μl of sterile saline or water containing 2 nmol/μl beta-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 beta-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 beta-amyloid-induced behavioral derangements in rats regarding coordination and memory abilities.