β-GLUCANS ® Lentinan, a β-glucan is the main biologically active substance found within medicinal Shiitake LENTINEX mushrooms (Letinus edodes). It is characterized as a high molecular weight polysaccharide organized in a triple helix structure. These mushrooms have long traditional uses within Asian INTRODUCTION cultures for their various medicinal properties, which include its anti-thrombotic activity and its LENTINEX® by Xediton Pharmaceuticals is a natural ability to reduce blood cholesterol levels. ß-glucans are able to directly activate leukocytes to health product containing 100% concentrated, stimulate phagocytic, cytotoxic and antimicrobial activity as well as the production of pro- natural β-glucan from Lentinula edodes. Inflammatory mediators, which are necessary to effectively eliminate pathogens from the body. Lentinan, the bioactive β-glucan in LENTINEX® has been shown to elicit positive immune system When injected or given orally, Lentinan is generally considered safe. Animal studies have been enhancement, effects that are associated with an used to evaluate the safety and immune-enhancing effects of LENTINEX® in mice, rats, chickens improved ability to fight infections. These include: and pigs. A significant increase in white blood cells and immune cell signaling proteins were ✓ Activation of Natural Killer-Cells observed in rats. No signs of toxicity were observed. ✓ Increased production of B-cells (CD19+) AND Lymphokine-Activated Killer Cells HOW LENTINEX® WORKS ✓ Increased production of cytokines such as Cellular experimental models and animal studies have demonstrated that the extracts of interleukins (IL-1α and IL-1β) and interferon-y Shiitake mushroom have anti-viral and anti-tumor properties. These properties occur through (IFN-y) the stimulation of immune cell maturation, differentiation or proliferation in host defence ✓ Suppression of prostaglandins leading to mechanisms against cancer or infection. increased T-cell differentiation and suppressor T-cell activity. THE IMMUNE SYSTEM Lentinan is able to improve The immune system is viewed as a network of cells, proteins and tissues, which protects immune cell function through individuals from millions of foreign microorganisms such as viruses, bacteria and fungi. Its diverse the activation of natural killer and intelligent mechanisms allows it to distinguish pathogenic agents from healthy self-cells. cells an the stimulation of helper T cells. Natural killer cells There are two main parts of the immune system: the innate system and the adaptive immune are a type of white blood cell, system. The innate system provides a general defence against pathogens1 through specific which protect against viral proteins, phagocytes (such as macrophages) and natural killer cells2. The adaptive immune system infections as well as the has particular agents called antibodies that target certain pathogens which the body has already formation of tumors within come in contact with1. B-cells and T-cells are important components of the adaptive immune cells. system2. B-cells work to secrete antibodies while T-cells regulate immune response and attack infected cells 3. Helper T cells support the immune activity of other cells ABOUT LENTINEX® by releasing cell signalling LENTINEX® is a liquid product obtained from the fermentation of Lentinula edodes, which is more proteins that modulate activity commonly known as the Shiitake mushroom. This clear, light brown liquid contains free glucose, between the cell based and protein and the β-glucan polysaccharide Lentinan, which has an extensive history of use as a humoral immune responses. medical aid in Asia, Europe and North America. Additionally, Lentinan inhibits the synthesis of prostaglandins, which are normally responsible Produced using a proprietary, patented process, LENTINEX® generates completely soluble β- for slowing T cell glucans with high molecular weight to aid in absorption while preserving the natural triple helix configuration. Due to its highly efficacious ingredients, only a small daily dose of differentiation, and affects suppressor T cell activity. Lentinan stimulates peripheral blood LENTINEX® is necessary to initiate enhancement of the immune system. It’s signature lymphocytes in vitro to increase IL-2-mediated lymphokine-activated killer cell and natural combination of a triple helix structure, high molecular weight, completely soluble β-glucan killer cell activity. Increased production of interleukins have also been observed with lentinan and 100% natural ingredients all work in concert to produce a high immune stimulating effect. supplementation. These cells are responsible for promoting the development and differentiation of T and B-cells. Lentinan is able to act as a T-cell immune adjuvant, to restore and potentiate helper T-cell functions. Currently there are no other β-glucan products like LENTINEX® on the market that provide the same profound immune stimulating effect due to its triple helix structure. SAFETY The production of LENTINEX® is carried out according to current Good Manufacturing Practices REFERENECES 1How does the immune system work? (2016, September 21). https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072548/ (cGMP) regulations. 2 Sompayrac, L. (2012). How the immune system works. 4th Edition 3 Understanding the immune system: how it works. Volume 3 (2003). Research and Clinical Trials: Supplementation with a soluble β-glucan exported from Shiitake Research and Clinical Trials: Animal Studies medicinal mushroom, Lentinus edodes – A double-blind, cross-over, placebo-controlled study in An increase in B-cells were observed in early safety and efficacy studies in mice and rats. B- 4 healthy elderly subjects cells almost doubled in mice from 16% in controls to 25% after an oral intake of This study investigated the effect and safety of β-glucan from L.edodes mycelium, LENTINEX®, in LENTINEX®. A similar effect was observed in a rat safety study conducted in Bergen, healthy, elderly subjects. Norway, which also evaluated LENTINEX®. A total of forty-two healthy subjects (both male and female) aged 65 and over participated in a placebo-controlled, randomized, double-blind trial and were randomly allocated to two groups The author of the study suggested that the increase in B-cell and monocytic populations given either 2.5mg/day LENTINEX® or a cellulose placebo orally for six weeks. could be related to the decrease in the immunosuppressive Interleukin-10 (IL-10). Increases observed in B-cell and monocyte populations as well increased interferon- gamma (IFN-y) levels may suggest that LENTINEX® induces an immune-stimulatory Change from Untreated PP-Population, B-cells (CD19+) response. 0.6 Changes in Titer 0.4 0.2 Placebo CELLS 100000 - 0 LENTINEX -0.2 10000 -0.4 1000 DIFF IN % B % IN DIFF -0.6 100 -0.8

Figure 1: LENTINEX® was able to prevent the fall in B-cells observed in an elderly population. The difference between the Titer Calculated 10 treatments were significant, p=0.038 When a subgroup with pre-treatment values below the group median at entry was analyzed, a 1 highly statistically difference in response in B-cells was observed (Figure 2) Lentinan Untreated Figure 2 shows the increase in B-cells from zero-time (pre-treated) to after 6 weeks of treatment Treatment with LENTINEX®. The differences between the B-cells in the LENTINEX® group compared to those Figure 3: Difference in antibody titer after treatment with LENTINEX® compared to controls. number of B-cells in the control (placebo) group was statistically significant, p=0.017. Apart from showing this one critical immune marker responding to LENTINEX® supplementation, The School of Veterinary Medicine at Louisiana State University used a mouse model to the results from the study indicated that beta-glucans are most effective when the immune system determine the effect of oral LENTINEX® treatment on the colonization load of Helicobacter is not optimal. Therefore, the intake of supplements like LENTINEX® will probably work like pylori. LENTINEX® treatment resulted in a statistically significant increase in antibody prophylactics, keeping the immune system alert (i.e. “immune surveillance”). response compared to the non-treated mice (p=0.033). An average 256-fold increase in antibody production was observed in LENTINEX® treatment animals compared to non- Change from Untreated Subgroups (< median), B-cells treated (Figure 3). The increase in antibodies is an expression of increased matured B-cells, which in the presence of antigens produce specific antibodies directed against the + (CD19 ) antigens. 2 RECOMMENDED USE: 1.5 Helps support and boost immune function. Intended for adults 18 years of age or older. Dose is

2.5ml (half a teaspoon) with a meal, once daily. Pregnant and breastfeeding women are advised CELLS - 1 Placebo to consult with their healthcare practitioner prior to using this product. 0.5 LENTINEX For more information, please visit www.xediton.com/product/lentinex or call +1-905-286-9111. XEDITON PHARMACEUTICALS INC 0 2000 ARGENTIA ROAD DIFF IN % B % IN DIFF MISSISSAUGA, ON -0.5 L5N 1W1 CANADA Figure 2: Change from untreated in a subgroup of subjects Email: [email protected]

4Gaullier, J. et al. (2011). Supplementation with a Soluble Beta-Glucan Exported from Shiitake Medicinal Mushroom, Lentinus edodes (Berk.) Singer Mycelium: a Crossover, Placebo-Controlled Study in Healthy Elderly. International Journal of Medicinal Mushrooms, 13(4), 319-326. Health Canada LENTINEX® NPN number is 80049210 LTSS01