The Science Behind Fucoidan & AHCC

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The Science Behind

FUCOIDAN & AHCC Clinical Evidence and Scientific Research proven by Scientists and Physicians

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영어버전.indd 1

2014-06-25 오전 8:38:55

Fucoidan

Important role of β1-integrin in fucoidan-induced apoptosis via caspase-8 activation.

Fucoidan induces apoptosis through activation of caspase-8 on human breast cancer MCF-7 cells.

01

02

Fucoidan induces apoptosis by activating caspase-8 in human MCF7 breast cancer cells, but the detailed mechanism for this is not understood. We demonstrate here that fucoidan interacted with the cell surface, and silencing the β1-integrin gene expression inhibited fucoidan-induced apoptosis accompanied by caspase-8 activation.

Caspase 8 initiates disassembly in response to extracellular apoptosisinducing ligands.

Caspase-8

Relative intensity (%)

Fucoidan induced formation of the β1-integrin-caspase-8 complex.

These data indicate that β1-integrin is an important factor for the cellsurface binding of fucoidan and plays an important role in fucoidan-induced apoptosis. Fucoidan also induced recruitment of caspase-8 to the β1-integrin intracellular domain, cleaved it into the activated protein by direct combination with β1-integrin, and induced apoptosis via the caspase Fucoidan cascade in MCF-7 cells.

Caspase-3

Other caspases

Cell Death

β-1 integrin regulate the attachment between a cell and its surroundings.

Fucoidan induces apoptosis by activating caspase-8 in human MCF-7 breast cancer cells by inducing the formation of the β1-integrin-caspase-8 complex.

Japan

Fucoidan is an active component of seaweed that has been shown to inhibit proliferation and induce apoptotic cell death in several tumor cells.

Results from the apoptosis assay demonstrated that fucoidan induced internucleosomal DNA fragmentation, chromatin condensation, activation of caspase-7, -8, and -9, and cleavage of poly(ADP ribose) polymerase. There was also a decline in cytosolic Bax and a striking increase of cytosolic cytochrome c. Caspase-8specific inhibitor, z-ITED-fmk, canceled the cytotoxicity of fucoidan, activation of caspase-7, -8, and -9, and a series of changes in Bax, Bid, and cytochrome c. These data indicated that fucoidan could induce apoptotic cell death through a caspase-8-dependent pathway in MCF-7 cells.

MCF-7 cells are breast cancer cells.

MCF stands for Michigan Cancer Foundation-7 referring to the institute where the cell line was established.

Caspase-7, -8 and -9 are a family of genes important for maintaining homeostasis through regulating cell death and inflammation.

Bid are pro-apoptotic proteins.

Bax is a protein that has a critical role in cancer cell apoptosis.

Cytochrome c– is a protein involved in the initiation of apoptosis.

DNA fragmentation is the separation or breaking of DNA strands into pieces.

Chromatin condensation begins during prophase (a stage of mitosis) chromosomes become visible.

Chromosomes remain condensed throughout the various stages of mitosis (nuclear division).

MCF-7 cells are breast cancer cells.

MCF stands for Michigan Cancer Foundation-7 referring to the institute where the cell line was established.

SUMMARY

Fukuoka,

Fucoidan

SUMMARY

Fucoidan is an active component of seaweed that has been shown to inhibit proliferation and induce apoptotic cell death in several tumor cells.

Authors: Yamsaki, Y., Yamasaki, M., Tachibana, H., Yamada, K.

Authors: Yamasaki-Miyamoto, Y., Yamasaki, M., Tachibana, H., Yamada, K.

Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University Bioscience, Biotechnology, and Biochemistry 2012, 76 (6):1163-1168.

PMID: 22790940 [PubMed - indexed for MEDLINE]

Laboratory of Food Chemistry, Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, 812-8581.

Article: J Agric Food Chem. 2009 Sep 23;57(18):8677-82.

PMID: 19754176 [PubMed - indexed for MEDLINE]

Fukuoka,

Japan

02|03

영어버전.indd 2-3

2014-06-25 오전 8:39:00

Fucoidan

Important role of β1-integrin in fucoidan-induced apoptosis via caspase-8 activation.

Fucoidan induces apoptosis through activation of caspase-8 on human breast cancer MCF-7 cells.

01

02

Fucoidan induces apoptosis by activating caspase-8 in human MCF7 breast cancer cells, but the detailed mechanism for this is not understood. We demonstrate here that fucoidan interacted with the cell surface, and silencing the β1-integrin gene expression inhibited fucoidan-induced apoptosis accompanied by caspase-8 activation.

Caspase 8 initiates disassembly in response to extracellular apoptosisinducing ligands.

Caspase-8

Relative intensity (%)

Fucoidan induced formation of the β1-integrin-caspase-8 complex.

These data indicate that β1-integrin is an important factor for the cellsurface binding of fucoidan and plays an important role in fucoidan-induced apoptosis. Fucoidan also induced recruitment of caspase-8 to the β1-integrin intracellular domain, cleaved it into the activated protein by direct combination with β1-integrin, and induced apoptosis via the caspase Fucoidan cascade in MCF-7 cells.

Caspase-3

Other caspases

Cell Death

β-1 integrin regulate the attachment between a cell and its surroundings.

Fucoidan induces apoptosis by activating caspase-8 in human MCF-7 breast cancer cells by inducing the formation of the β1-integrin-caspase-8 complex.

Japan

Fucoidan is an active component of seaweed that has been shown to inhibit proliferation and induce apoptotic cell death in several tumor cells.

Results from the apoptosis assay demonstrated that fucoidan induced internucleosomal DNA fragmentation, chromatin condensation, activation of caspase-7, -8, and -9, and cleavage of poly(ADP ribose) polymerase. There was also a decline in cytosolic Bax and a striking increase of cytosolic cytochrome c. Caspase-8specific inhibitor, z-ITED-fmk, canceled the cytotoxicity of fucoidan, activation of caspase-7, -8, and -9, and a series of changes in Bax, Bid, and cytochrome c. These data indicated that fucoidan could induce apoptotic cell death through a caspase-8-dependent pathway in MCF-7 cells.

MCF-7 cells are breast cancer cells.

MCF stands for Michigan Cancer Foundation-7 referring to the institute where the cell line was established.

Caspase-7, -8 and -9 are a family of genes important for maintaining homeostasis through regulating cell death and inflammation.

Bid are pro-apoptotic proteins.

Bax is a protein that has a critical role in cancer cell apoptosis.

Cytochrome c– is a protein involved in the initiation of apoptosis.

DNA fragmentation is the separation or breaking of DNA strands into pieces.

Chromatin condensation begins during prophase (a stage of mitosis) chromosomes become visible.

Chromosomes remain condensed throughout the various stages of mitosis (nuclear division).

MCF-7 cells are breast cancer cells.

MCF stands for Michigan Cancer Foundation-7 referring to the institute where the cell line was established.

SUMMARY

Fukuoka,

Fucoidan

SUMMARY

Fucoidan is an active component of seaweed that has been shown to inhibit proliferation and induce apoptotic cell death in several tumor cells.

Authors: Yamsaki, Y., Yamasaki, M., Tachibana, H., Yamada, K.

Authors: Yamasaki-Miyamoto, Y., Yamasaki, M., Tachibana, H., Yamada, K.

Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University Bioscience, Biotechnology, and Biochemistry 2012, 76 (6):1163-1168.

PMID: 22790940 [PubMed - indexed for MEDLINE]

Laboratory of Food Chemistry, Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, 812-8581.

Article: J Agric Food Chem. 2009 Sep 23;57(18):8677-82.

PMID: 19754176 [PubMed - indexed for MEDLINE]

Fukuoka,

Japan

02|03

영어버전.indd 2-3

2014-06-25 오전 8:39:00

Fucose-containing sulfated polysaccharides from brown seaweeds inhibit proliferation of melanoma cells and induce apoptosis by activation of caspase-3 in vitro.

Fucoidan

03

Caspase-3 Activity (% of control)

Fucose-containing sulfated polysaccharides (FCSPs) extracted from seaweeds, especially brown macro-algae, are known to possess essential bioactive properties, notably growth inhibitory effects on tumor cells.

The FCSPs-induced apoptosis was evidenced by loss of plasma membrane asymmetry and translocation of the cell membrane phospholipids and was accompanied by the activation of caspase-3. This study thus indicates that unfractionated FCSPs may exert bioactive effects on skin cancer cells via induction of apoptosis through cascades of reactions that involve activation of caspase-3.

Melanoma is a malignant tumor of melanocytes. Melanoma can originate from any part of the body , but predominantly occur in skin.

Melanocytes produce the dark pigment, melanin, which is responsible for the color of skin.

Caspase-3 is a protein that interacts with caspase 8 and caspase 9.

Pro Caspase 3

200 180

FSAR FVES

Caspase 9

160 140

Effects of oral administration of fucoidan extracted from Cladosiphon okamuranus on tumor growth and survival time in a tumor-bearing mouse model.

The anti-tumor activities of the oral administration of fucoidan extracted from Cladosiphon okamuranus using a tumor (colon 26)-bearing mouse model was evaluated. The materials used included low-molecular-weight fucoidan (LMWF: 6.5-40 kDa), intermediate-molecular-weight fucoidan (IMWF: 110-138 kDa) and high-molecular-weight fucoidan (HMWF: 300-330 kDa).

The LMWF and HMWF groups showed significantly increased survival times compared with that observed in the control group (mice fed a fucoidan-free diet). Furthermore, from the results of the experiment using Myd-88 knockout mice, it was found that these effects are related to gut immunity. These results suggest that fucoidan is a candidate anti-tumor functional food.

Caspase 8

Fucoidan

04

Colon-26 is a cell line that can be used as a model for testing immunotherapy protocols and in studies on the host immune system.

LMWF relates to a low molecular weight fucoidan.

HMWF relates to a high molecular weight fucoidan.

IMWF relates to an intermediatemolecular weight fucoidan.

Myd-88 is a protein that, in humans, is encoded by the MYD88 gene. Myd88 stands for Myeloid Differentiation Primary Response Gene (88).

120

Caspase 3

100 80

0

0.2

0.4

0.8

FCSPs dosage (mg/ml)

Activation of caspase-3 after treatment of melanoma B16 cells with different dosages of FCSPs from S. henslowianum (FSAR) and F. vesiculosus (FVES).

Cell Death

SUMMARY The fucose-containing sulfated polysaccharides (FCSPs)-induced apoptosis was evidenced by loss of plasma membrane of the cell membrane and was accompanied by the activation of caspase-3.

SUMMARY

Oral administration of fucoidan increased the population of natural killer cells in the spleen and it is a candidate anti-tumor functional food.

Authors: Azuma, K., Ishihara, T., Nakamoto, H., Amaha, T., Osaki, T., Tsuka, T., Imagawa, T., Minami, S., Takashima, O., Ifuku, S., Morimoto, M., Saimoto, H., Kawamoto, H., Okamoto, Y.

Authors: Ale, M. T., Maruyama, H., Tamauchi, H., Mikkelsen, J. D., Meyer A. S.

Lyngby,

Denmark

Center for Bioprocess Engineering, Department of Chemical and Biochemical Engineering, Technical University of Denmark, Kgs. Article: Mar Drugs. 2011 Dec;9(12):2605-21 PMID: : 22363242 [PubMed - indexed for MEDLINE] PMCID: PMC3280569

Tottori,

Japan

Department of Veterinary Clinical Medicine, School of Veterinary Medicine, Tottori University, 4-101 Koyama minami, Tottori-shi, 680-8553.

Article: Mar Drugs. 2012 Oct; 10(10):2337-48.

PMID: 23170088 [PubMed - indexed for MEDLINE] PMCID: PMC3497027

04|05

영어버전.indd 4-5

2014-06-25 오전 8:39:04

Fucose-containing sulfated polysaccharides from brown seaweeds inhibit proliferation of melanoma cells and induce apoptosis by activation of caspase-3 in vitro.

Fucoidan

03

Caspase-3 Activity (% of control)

Fucose-containing sulfated polysaccharides (FCSPs) extracted from seaweeds, especially brown macro-algae, are known to possess essential bioactive properties, notably growth inhibitory effects on tumor cells.

The FCSPs-induced apoptosis was evidenced by loss of plasma membrane asymmetry and translocation of the cell membrane phospholipids and was accompanied by the activation of caspase-3. This study thus indicates that unfractionated FCSPs may exert bioactive effects on skin cancer cells via induction of apoptosis through cascades of reactions that involve activation of caspase-3.

Melanoma is a malignant tumor of melanocytes. Melanoma can originate from any part of the body , but predominantly occur in skin.

Melanocytes produce the dark pigment, melanin, which is responsible for the color of skin.

Caspase-3 is a protein that interacts with caspase 8 and caspase 9.

Pro Caspase 3

200 180

FSAR FVES

Caspase 9

160 140

Effects of oral administration of fucoidan extracted from Cladosiphon okamuranus on tumor growth and survival time in a tumor-bearing mouse model.

The anti-tumor activities of the oral administration of fucoidan extracted from Cladosiphon okamuranus using a tumor (colon 26)-bearing mouse model was evaluated. The materials used included low-molecular-weight fucoidan (LMWF: 6.5-40 kDa), intermediate-molecular-weight fucoidan (IMWF: 110-138 kDa) and high-molecular-weight fucoidan (HMWF: 300-330 kDa).

The LMWF and HMWF groups showed significantly increased survival times compared with that observed in the control group (mice fed a fucoidan-free diet). Furthermore, from the results of the experiment using Myd-88 knockout mice, it was found that these effects are related to gut immunity. These results suggest that fucoidan is a candidate anti-tumor functional food.

Caspase 8

Fucoidan

04

Colon-26 is a cell line that can be used as a model for testing immunotherapy protocols and in studies on the host immune system.

LMWF relates to a low molecular weight fucoidan.

HMWF relates to a high molecular weight fucoidan.

IMWF relates to an intermediatemolecular weight fucoidan.

Myd-88 is a protein that, in humans, is encoded by the MYD88 gene. Myd88 stands for Myeloid Differentiation Primary Response Gene (88).

120

Caspase 3

100 80

0

0.2

0.4

0.8

FCSPs dosage (mg/ml)

Activation of caspase-3 after treatment of melanoma B16 cells with different dosages of FCSPs from S. henslowianum (FSAR) and F. vesiculosus (FVES).

Cell Death

SUMMARY The fucose-containing sulfated polysaccharides (FCSPs)-induced apoptosis was evidenced by loss of plasma membrane of the cell membrane and was accompanied by the activation of caspase-3.

SUMMARY

Oral administration of fucoidan increased the population of natural killer cells in the spleen and it is a candidate anti-tumor functional food.

Authors: Azuma, K., Ishihara, T., Nakamoto, H., Amaha, T., Osaki, T., Tsuka, T., Imagawa, T., Minami, S., Takashima, O., Ifuku, S., Morimoto, M., Saimoto, H., Kawamoto, H., Okamoto, Y.

Authors: Ale, M. T., Maruyama, H., Tamauchi, H., Mikkelsen, J. D., Meyer A. S.

Lyngby,

Denmark

Center for Bioprocess Engineering, Department of Chemical and Biochemical Engineering, Technical University of Denmark, Kgs. Article: Mar Drugs. 2011 Dec;9(12):2605-21 PMID: : 22363242 [PubMed - indexed for MEDLINE] PMCID: PMC3280569

Tottori,

Japan

Department of Veterinary Clinical Medicine, School of Veterinary Medicine, Tottori University, 4-101 Koyama minami, Tottori-shi, 680-8553.

Article: Mar Drugs. 2012 Oct; 10(10):2337-48.

PMID: 23170088 [PubMed - indexed for MEDLINE] PMCID: PMC3497027

04|05

영어버전.indd 4-5

2014-06-25 오전 8:39:04

05

Accumulating data clearly indicate that the induction of apoptosis by nontoxic natural compounds is a potent defense against the development and progression of many malignancies, including colon cancer.

The fucoidan enhanced the antiproliferative activity of resveratrol at nontoxic doses and facilitated resveratrol-induced apoptosis in the HCT 116 human colon cancer cell line. Apoptosis was realized by the activation of initiator caspase-9 and effector caspase-7 and -3, followed by the cleavage of PARP. Furthermore, significant inhibition of HCT 116 colony formation was associated with the sensitization of cells to resveratrol by the fucoidan.

Antiproliferative activity is term used to describe the inhibition of cell growth.

Resveratrol is a member of a group of plant compounds called polyphenols.

Polyphenols are antioxidants.

HCT 116 cell lines are used for human colon carcinoma.

PARP (Poly (ADP-ribose) polymerase) is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death.

Taken together, these results demonstrate that the combination of the algal fucoidan with resveratrol may provide a potential therapy against human colon cancer.

SUMMARY

Fucoidan enhanced the antiproliferative activity of resveratrol at nontoxic doses and facilitated resveratrol-induced apoptosis in the HCT 116 human colon cancer cell line.

Vladivostock,

Russian Federation

Fucoidan induces apoptosis of human HS-sultan cells accompanied by activation of caspase-3 and downregulation of ERK pathways.

Fucoidan

06

Fucoidan, a sulfated polysaccharide in brown seaweed, was found to inhibit proliferation and induce apoptosis in human lymphoma HS-Sultan cell lines. Fucoidan-induced apoptosis was accompanied by the activation of caspase-3.

HS-Sultan cells is a multiple myeloma plasmacytoma cell line.

It is possible fucoidan induced apoptosis though different receptors. These results demonstrate that fucoidan has direct anti-cancer effects on human HS-Sultan cells through caspase and ERK pathways.

ERK Pathways is a chain of proteins in the cell that communicate a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

Fucoidan-induced apoptosis in HS-Sultan cells. A) Arrows indicate the apoptotic bodies and nuclear condensation.

B) Detection of apoptosis by annexin-V staining.

Phosphatidylserine is a chemical.

When a cell undergoes apoptosis, phosphatidylserine becomes exposed on the surface of the cell.

Annexin positive cells (%)

Fucoidan

The effect of sulfated (1→3)-α-l-fucan from the brown alga Saccharina cichorioides Miyabe on resveratrolinduced apoptosis in colon carcinoma cells.

Control

Fucoidan

Caspase-3 is a protein that interacts with caspase -8 and caspase -9.

Annexin-V provides quick and reliable detection methods for studying the externalization of phosphatidylserine.

Fucoidan+zVAD

SUMMARY

Fucoidan has a direct anti-cancer effects on human HS-Sultan (myeloma) cells through caspase and ERK pathways.

Authors: Vishchuk, O.S., Ermakova, S.P., Zvyagintseva, T.N.

Authors: Aisa, Y., Miyakawa, Y., Nakazato, T., Shibata, H., Saito, K., Ikeda, Y., Kizaki, M.

Laboratory of Enzyme Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159 100-Let Vladivostoku Ave., 690022.

Article: Marine Drugs, 2013 Jan 21; 11(1):194-212.

PMID: 23337253 [PubMed - indexed for MEDLINE] PMCID: PMC3564167

Department of Internal Medicine, Keio University School of Medicine.

Article: Am J Hematol. 2005 Jan; 78(1):7-14.

PMID: 15609279 [PubMed - indexed for MEDLINE]

Tokyo,

Japan 06|07

영어버전.indd 6-7

2014-06-25 오전 8:39:08

05

Accumulating data clearly indicate that the induction of apoptosis by nontoxic natural compounds is a potent defense against the development and progression of many malignancies, including colon cancer.

The fucoidan enhanced the antiproliferative activity of resveratrol at nontoxic doses and facilitated resveratrol-induced apoptosis in the HCT 116 human colon cancer cell line. Apoptosis was realized by the activation of initiator caspase-9 and effector caspase-7 and -3, followed by the cleavage of PARP. Furthermore, significant inhibition of HCT 116 colony formation was associated with the sensitization of cells to resveratrol by the fucoidan.

Antiproliferative activity is term used to describe the inhibition of cell growth.

Resveratrol is a member of a group of plant compounds called polyphenols.

Polyphenols are antioxidants.

HCT 116 cell lines are used for human colon carcinoma.

PARP (Poly (ADP-ribose) polymerase) is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death.

Taken together, these results demonstrate that the combination of the algal fucoidan with resveratrol may provide a potential therapy against human colon cancer.

SUMMARY

Fucoidan enhanced the antiproliferative activity of resveratrol at nontoxic doses and facilitated resveratrol-induced apoptosis in the HCT 116 human colon cancer cell line.

Vladivostock,

Russian Federation

Fucoidan induces apoptosis of human HS-sultan cells accompanied by activation of caspase-3 and downregulation of ERK pathways.

Fucoidan

06

Fucoidan, a sulfated polysaccharide in brown seaweed, was found to inhibit proliferation and induce apoptosis in human lymphoma HS-Sultan cell lines. Fucoidan-induced apoptosis was accompanied by the activation of caspase-3.

HS-Sultan cells is a multiple myeloma plasmacytoma cell line.

It is possible fucoidan induced apoptosis though different receptors. These results demonstrate that fucoidan has direct anti-cancer effects on human HS-Sultan cells through caspase and ERK pathways.

ERK Pathways is a chain of proteins in the cell that communicate a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

Fucoidan-induced apoptosis in HS-Sultan cells. A) Arrows indicate the apoptotic bodies and nuclear condensation.

B) Detection of apoptosis by annexin-V staining.

Phosphatidylserine is a chemical.

When a cell undergoes apoptosis, phosphatidylserine becomes exposed on the surface of the cell.

Annexin positive cells (%)

Fucoidan

The effect of sulfated (1→3)-α-l-fucan from the brown alga Saccharina cichorioides Miyabe on resveratrolinduced apoptosis in colon carcinoma cells.

Control

Fucoidan

Caspase-3 is a protein that interacts with caspase -8 and caspase -9.

Annexin-V provides quick and reliable detection methods for studying the externalization of phosphatidylserine.

Fucoidan+zVAD

SUMMARY

Fucoidan has a direct anti-cancer effects on human HS-Sultan (myeloma) cells through caspase and ERK pathways.

Authors: Vishchuk, O.S., Ermakova, S.P., Zvyagintseva, T.N.

Authors: Aisa, Y., Miyakawa, Y., Nakazato, T., Shibata, H., Saito, K., Ikeda, Y., Kizaki, M.

Laboratory of Enzyme Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159 100-Let Vladivostoku Ave., 690022.

Article: Marine Drugs, 2013 Jan 21; 11(1):194-212.

PMID: 23337253 [PubMed - indexed for MEDLINE] PMCID: PMC3564167

Department of Internal Medicine, Keio University School of Medicine.

Article: Am J Hematol. 2005 Jan; 78(1):7-14.

PMID: 15609279 [PubMed - indexed for MEDLINE]

Tokyo,

Japan 06|07

영어버전.indd 6-7

2014-06-25 오전 8:39:08

Fucoidan

07

Fucoidan reduces secretion and expression of vascular endothelial growth factor in the retinal pigment epithelium and reduces angiogenesis in vitro.

Fucoidan is a polysaccharide isolated from brown algae which is of current interest for anti-tumor therapy. In this study, we investigated the effect of fucoidan on the retinal pigment epithelium (RPE), looking at physiology, vascular endothelial growth factor (VEGF) secretion, and angiogenesis, thus investigating a potential use of fucoidan for the treatment of exudative age-related macular degeneration.

Fucoidan decreases VEGF secretion in RPE/choroid explants and RPE cells.

Furthermore, fucoidan reduces RPE-supernatantand VEGF-induced angiogenesis of peripheral endothelial cells.

Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates angiogenesis.

Angiogenesis is a physiological process through which new blood vessels form from pre-existing vessels.

Retinal pigment epithelium (RPE) is the pigmented cell layer just outside the neurosensory retina.

Supernatant is the liquid that lies above a sediment or precipitate. It floats on the surface of a liquid.

Fucoidan ingestion increases the expression of CXCR4 on human CD34+ cells.

Fucoidan

08 Transplantation of hematopoietic progenitor stem cells (HPC) is an important treatment modality for a variety of neoplastic diseases. Methods to improve mobilization of HPCs are required.

Disruption of the interaction between the cell surface receptor CXCR4 and its ligand stromal derived factor-1 (SDF-1) is a mechanism for HPC release from the bone marrow into the peripheral blood (PB).

Oral fucoidan significantly amplified the CXCR4(+) HPC population. The ability to mobilize HPC using sulfated polysaccharides and mobilize more HPC with high levels of CXCR4 could be clinically valuable.

Hematopoietic progenitor stem cells (HPC) are blood cells that give rise to all other blood cells and are derived from mesoderm.

Neoplastic diseases are diseases in which there is the formation of an abnormally large amount of tissue mass.

Cell surface receptor CXCR4 is a cell surface receptor for extracellular ubiquitin.

Peripheral blood cells are the cellular components of blood, consisting of red blood cells, white blood cells, and platelets, which are found within the circulating pool of blood.

Primary RPE cells (A) and ARPE-19 cells (B) were treated with 100 µg/ml fucoidan for 24 hours. Cells treated with fucoidan exhibited a substantial decrease in intracellular VEGF expression.

SUMMARY

Fucoidan reduces VEGF expression and angiogenesis in vitro and may be of interest for further studies as a potential therapy against exudative agerelated macular degeneration.

Essenheim,

Germany

SUMMARY

Fucoidan significantly amplified the CXCR4(+) HPC population. Fucoidan has the ability to mobilize HPC (hematopoietic progenitor stem cells) with high levels of CXCR4.

Authors: Dithmer, M., Fuchs, S., Shi, Y., Schmidt, H., Richert, E., Roider, J., Klettner, A.

Authors: Mohammad R. Irhimeh, J. Helen Fitton, Raymond M. Lowenthal

INSERM University of Kiel, University Medical Center, Department of Ophthalmology, Kiel, Germany. University of Kiel, University Medical Center, Experimental Trauma Surgery, Kiel, Germany. MetaPhysiol.

Article: PLoS One, 2014 Feb 18;9(2):e89150.

PMID: 24558482 [PubMed - in process] PMCID: PMC3928431

Discipline of Medicine, Clinical School, University of Tasmania, Hobart, Australia. Clinical Haematology and Medical Oncology Unit, Royal Hobart Hospital.

Article: Experimental Hematology Volume 35, Issue 6, Pages 989-994, June 2007.

PMID: 17533053 [PubMed - indexed for MEDLINE]

Hobart,

Australia

08|09

영어버전.indd 8-9

2014-06-25 오전 8:39:12

Fucoidan

07

Fucoidan reduces secretion and expression of vascular endothelial growth factor in the retinal pigment epithelium and reduces angiogenesis in vitro.

Fucoidan is a polysaccharide isolated from brown algae which is of current interest for anti-tumor therapy. In this study, we investigated the effect of fucoidan on the retinal pigment epithelium (RPE), looking at physiology, vascular endothelial growth factor (VEGF) secretion, and angiogenesis, thus investigating a potential use of fucoidan for the treatment of exudative age-related macular degeneration.

Fucoidan decreases VEGF secretion in RPE/choroid explants and RPE cells.

Furthermore, fucoidan reduces RPE-supernatantand VEGF-induced angiogenesis of peripheral endothelial cells.

Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates angiogenesis.

Angiogenesis is a physiological process through which new blood vessels form from pre-existing vessels.

Retinal pigment epithelium (RPE) is the pigmented cell layer just outside the neurosensory retina.

Supernatant is the liquid that lies above a sediment or precipitate. It floats on the surface of a liquid.

Fucoidan ingestion increases the expression of CXCR4 on human CD34+ cells.

Fucoidan

08 Transplantation of hematopoietic progenitor stem cells (HPC) is an important treatment modality for a variety of neoplastic diseases. Methods to improve mobilization of HPCs are required.

Disruption of the interaction between the cell surface receptor CXCR4 and its ligand stromal derived factor-1 (SDF-1) is a mechanism for HPC release from the bone marrow into the peripheral blood (PB).

Oral fucoidan significantly amplified the CXCR4(+) HPC population. The ability to mobilize HPC using sulfated polysaccharides and mobilize more HPC with high levels of CXCR4 could be clinically valuable.

Hematopoietic progenitor stem cells (HPC) are blood cells that give rise to all other blood cells and are derived from mesoderm.

Neoplastic diseases are diseases in which there is the formation of an abnormally large amount of tissue mass.

Cell surface receptor CXCR4 is a cell surface receptor for extracellular ubiquitin.

Peripheral blood cells are the cellular components of blood, consisting of red blood cells, white blood cells, and platelets, which are found within the circulating pool of blood.

Primary RPE cells (A) and ARPE-19 cells (B) were treated with 100 µg/ml fucoidan for 24 hours. Cells treated with fucoidan exhibited a substantial decrease in intracellular VEGF expression.

SUMMARY

Fucoidan reduces VEGF expression and angiogenesis in vitro and may be of interest for further studies as a potential therapy against exudative agerelated macular degeneration.

Essenheim,

Germany

SUMMARY

Fucoidan significantly amplified the CXCR4(+) HPC population. Fucoidan has the ability to mobilize HPC (hematopoietic progenitor stem cells) with high levels of CXCR4.

Authors: Dithmer, M., Fuchs, S., Shi, Y., Schmidt, H., Richert, E., Roider, J., Klettner, A.

Authors: Mohammad R. Irhimeh, J. Helen Fitton, Raymond M. Lowenthal

INSERM University of Kiel, University Medical Center, Department of Ophthalmology, Kiel, Germany. University of Kiel, University Medical Center, Experimental Trauma Surgery, Kiel, Germany. MetaPhysiol.

Article: PLoS One, 2014 Feb 18;9(2):e89150.

PMID: 24558482 [PubMed - in process] PMCID: PMC3928431

Discipline of Medicine, Clinical School, University of Tasmania, Hobart, Australia. Clinical Haematology and Medical Oncology Unit, Royal Hobart Hospital.

Article: Experimental Hematology Volume 35, Issue 6, Pages 989-994, June 2007.

PMID: 17533053 [PubMed - indexed for MEDLINE]

Hobart,

Australia

08|09

영어버전.indd 8-9

2014-06-25 오전 8:39:12

Fucoidan

A sulfated polysaccharide, fucoidan, enhances the immunomodulatory effects of lactic acid bacteria.

Beneficial effects of fucoidan in patients with chronic hepatitis C virus infection.

09

10

Fucoidan, a sulfated polysaccharide contained in brown algae, has a variety of immunomodulatory effects, including antitumor and antiviral effects. On the other hand, lactic acid bacteria (LAB) also have immunomodulatory effects such as anti-allergic effects.

In this study, we demonstrated that fucoidan enhances the probiotic effects of LAB on immune functions. By using Peyer's patch cells and spleen cells in vitro, fucoidan amplified interferon (IFN)-γ production in response to a strain of LAB, Tetragenococcus halophilus KK221, and this activity was abolished by desulfation of fucoidan.

These results indicate that fucoidan enhanced IL-12 production in response to KK221, resulting in promoting IFN-γ production.

These findings suggest that fucoidan can enhance a variety of beneficial effects of LAB on immune functions.

Lactic acid bacteria (LAB) has been used to ferment or culture foods for at least 4000 years.

METHODS: HCV-1b replicon-expressing cells were cultured in the presence of fucoidan obtained from Cladosiphon okamuranus. In an open-label uncontrolled study, 15 patients with chronic hepatitis C, and HCV-related cirrhosis and hepatocellular carcinoma were treated with fucoidan (0.83 g/d) for 12 mo.

Interferon (IFN)-γ is involved in the regulation of nearly all phases of immune and inflammatory responses, including the activation of T cells, B cells , macrophages and NK cells.

RESULTS: HCV RNA levels were significantly lower relative to the baseline. Fucoidan had no serious adverse effects.

IL-2 is a type of cytokine signaling molecule in the immune system.

Fucoidan enhances the probiotic effects of LAB on immune functions.

Fucoidan enhanced IL-12 production in response to KK221, resulting in promoting IFN-γ production.

Chiba,

AIM: To evaluate the effects of fucoidan on hepatitis C virus (HCV) RNA load both in vitro and in vivo.

Peyer’s patch, any of the nodules of lymphatic cells that aggregate to form bundles or patches and occur usually only in the lower portion of the small intestine.

SUMMARY

Japan

Fucoidan

CONCLUSION: Our findings suggest that fucoidan is safe and useful in the treatment of patients with HCV-related chronic liver diseases. Further controlled clinical trials are needed to confirm the present findings.

Hepatitis C Virus (HCV) is an infectious disease affecting primarily the liver.

HCV-1b is one of the genotypes accounting for one third of genotype 1 infections.

Cirrhosis is a result of advanced liver disease that results in scarring of the liver.

Hepatocellular carcinoma is the most common type of liver cancer. Most cases are secondary to either a viral hepatitis infection (hepatitis B or C) or cirrhosis.

SUMMARY

Fucoidan dose-dependently inhibited the expression of HCV (hepatitis C virus) replicon. Fucoidan is safe and useful in the treatment of patients with HCV-related chronic liver diseases.

Authors: Kawashima, T., Murakami, K., Nishimura, I., Nakano, T., Obata, A.

Authors: Mori, N., Nakasone, K., Tomimori, K., Ishikawa, C.

Research and Development Division, Kikkoman Corporation, 399 Noda, Noda City, 278-0037.

Article: International Journal of Molecular Medicine, Volume 29, Number 3, 2012, pp. 447-453 (7).

PMID: 22160132 [PubMed - indexed for MEDLINE]

Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, 903-0215.

Article: World J Gastroenterol. 2012 May 14; 18(18):2225-30 PMID: 22611316 [PubMed - indexed for MEDLINE] PMCID: PMC3351773

Okinawa,

Japan

10|11

영어버전.indd 10-11

2014-06-25 오전 8:39:15

Fucoidan

A sulfated polysaccharide, fucoidan, enhances the immunomodulatory effects of lactic acid bacteria.

Beneficial effects of fucoidan in patients with chronic hepatitis C virus infection.

09

10

Fucoidan, a sulfated polysaccharide contained in brown algae, has a variety of immunomodulatory effects, including antitumor and antiviral effects. On the other hand, lactic acid bacteria (LAB) also have immunomodulatory effects such as anti-allergic effects.

In this study, we demonstrated that fucoidan enhances the probiotic effects of LAB on immune functions. By using Peyer's patch cells and spleen cells in vitro, fucoidan amplified interferon (IFN)-γ production in response to a strain of LAB, Tetragenococcus halophilus KK221, and this activity was abolished by desulfation of fucoidan.

These results indicate that fucoidan enhanced IL-12 production in response to KK221, resulting in promoting IFN-γ production.

These findings suggest that fucoidan can enhance a variety of beneficial effects of LAB on immune functions.

Lactic acid bacteria (LAB) has been used to ferment or culture foods for at least 4000 years.

METHODS: HCV-1b replicon-expressing cells were cultured in the presence of fucoidan obtained from Cladosiphon okamuranus. In an open-label uncontrolled study, 15 patients with chronic hepatitis C, and HCV-related cirrhosis and hepatocellular carcinoma were treated with fucoidan (0.83 g/d) for 12 mo.

Interferon (IFN)-γ is involved in the regulation of nearly all phases of immune and inflammatory responses, including the activation of T cells, B cells , macrophages and NK cells.

RESULTS: HCV RNA levels were significantly lower relative to the baseline. Fucoidan had no serious adverse effects.

IL-2 is a type of cytokine signaling molecule in the immune system.

Fucoidan enhances the probiotic effects of LAB on immune functions.

Fucoidan enhanced IL-12 production in response to KK221, resulting in promoting IFN-γ production.

Chiba,

AIM: To evaluate the effects of fucoidan on hepatitis C virus (HCV) RNA load both in vitro and in vivo.

Peyer’s patch, any of the nodules of lymphatic cells that aggregate to form bundles or patches and occur usually only in the lower portion of the small intestine.

SUMMARY

Japan

Fucoidan

CONCLUSION: Our findings suggest that fucoidan is safe and useful in the treatment of patients with HCV-related chronic liver diseases. Further controlled clinical trials are needed to confirm the present findings.

Hepatitis C Virus (HCV) is an infectious disease affecting primarily the liver.

HCV-1b is one of the genotypes accounting for one third of genotype 1 infections.

Cirrhosis is a result of advanced liver disease that results in scarring of the liver.

Hepatocellular carcinoma is the most common type of liver cancer. Most cases are secondary to either a viral hepatitis infection (hepatitis B or C) or cirrhosis.

SUMMARY

Fucoidan dose-dependently inhibited the expression of HCV (hepatitis C virus) replicon. Fucoidan is safe and useful in the treatment of patients with HCV-related chronic liver diseases.

Authors: Kawashima, T., Murakami, K., Nishimura, I., Nakano, T., Obata, A.

Authors: Mori, N., Nakasone, K., Tomimori, K., Ishikawa, C.

Research and Development Division, Kikkoman Corporation, 399 Noda, Noda City, 278-0037.

Article: International Journal of Molecular Medicine, Volume 29, Number 3, 2012, pp. 447-453 (7).

PMID: 22160132 [PubMed - indexed for MEDLINE]

Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, 903-0215.

Article: World J Gastroenterol. 2012 May 14; 18(18):2225-30 PMID: 22611316 [PubMed - indexed for MEDLINE] PMCID: PMC3351773

Okinawa,

Japan

10|11

영어버전.indd 10-11

2014-06-25 오전 8:39:15

The inhibitory effect of Cladosiphon fucoidan on the attachment of Helicobacter pylori (H. pylori), a gastroduodenal pathogen, to human gastric cell lines was studied.

The bacterial binding in these cell lines was inhibited more

by Cladosiphon fucoidan (IC50 = 16-30 mg/mL), than by the fucoidan from Fucus (IC50 > 30 mg/mL).

It was also shown that this fucoidan blocks both Leb- and sulfatide-mediated attachment of H. pylori to gastric cells.

Furthermore, fucoidan-binding proteins were found on the H. pylori cell surface by Western blot analysis.

Thus, the inhibitory effect exerted by Cladosiphon fucoidan on binding between H. pylori and gastric cells might result from the coating with this component of the bacterial surface.

Helicobacter pylori (H. pylori) is a Gram-negative, microaerophilic bacterium found in the stomach.

Western blot is a widely used analytical technique used to detect specific proteins in a sample of tissue homogenate or extract.

Leb- The Lewis (b) (Le(b)) blood group antigen mediates H. pylori attachment to human gastric mucosa.

Sulfitides are a class of sulfated galactosylceramides synthesized primarily in the oligodendrocytes in the central nervous system.

SUMMARY

Cladosiphon fucoidan has an inhibitory effect on the attachment of Helicobacter pylori (H. pylori), a gastroduodenal pathogen, to human gastric cell lines.

Active hexose correlated compound (AHCC) is a natural compound with the potential to be used as an immuno-enhancer in cases in which the immune system is compromised.

Tokyo,

Japan

CD4+

*

5.0

**

4.0 3.0

*

*

* p<0.01 ** p<0.05 P values compared With baseline

*

2.0 1.0 0.0

12.0

Visit 1 n=30 CD8+

10.0

Visit 2 n=28

Visit 3 n=25

**

8.0

** *

*

6.0 4.0

IFN- γ TNF-α IFN- γ and TNF-α

*

2.0 0.0

Visit 4 n=26

Visit 1

Visit 2

Visit 3

Visit 4

Flg.2 Changes in the frequency of CD4(+) and CD8(+) T cells producing cytokines before and after active hexose correlated compound(AHCC). As described in Fig.1. the frequency of CD4(+) and CD8(+) T cells producing IFN- γ, TNF-α or both cytokines was determined before and after AHCC intake. Visits 1,2,3 and 4 indicate before AHCC. 30 and 60 days on AHCC. And 30 day after discontinuing AHCC, respectively.

The frequency of CD4(+) and CD8(+) T cells producing IFN-γ alone, TNF-α alone, or both increased during AHCC intake compared with baseline values. Overall, these findings suggest that AHCC enhances CD4(+) and CD8(+) T cell immune responses in healthy elderly persons taking at least 30 days to obtain such effect, which remained up to 30 days after discontinuing treatment with this compound.

AHCC

01

IFN-γ belongs to a group of proteins, known as cytokines. They are involved in the regulation of the immune system and inflammatory response.

TNF-α is involved in the systemic inflammation. Its primary role is the regulation of immune cells.

CD4+ is a glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages and dendritic cells.

CD8+ is expressed on the surface of cytotoxic T cells, but also on natural killer (NK) cells and dendritic cells.

SUMMARY

AHCC is a natural compound that can enhance cell immune response.

Authors: Shibata, H., Kimura, T., Nagaoka, M., Hashimoto, S., Sawada, H., Ueyama, S., Yokokura, T. Yakult Central Institute for Microbiological Research.

Article: J Nutr Sci Vitaminol (Tokyo). 1999 Jun;45 (3):325-36.

PMID: 10524351 [PubMed - indexed for MEDLINE]

6.0

% of Cells

11

% of Cells

Fucoidan

Inhibitory effect of Cladosiphon fucoidan on the adhesion of Helicobacter pylori to human gastric cells.

Effects of Active Hexose Correlated Compound (AHCC) on frequency of CD4+ and CD8+ T cells producing interferon-γ and/or tumor necrosis factor-α in healthy adults.

Authors: Yin, Z., Fujii, H., Walshe, T.

Massachusetts,

USA

Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA. Amino Up Chemical Co., Ltd., Sapporo, Japan. Academic Research Associates, Boston, Massachusetts, USA. Brigham and Women’s Hospital and Harvard Medical School, Boston.

Article: Human Immunology 71 (2010) 1187-1190.

PMID: 20732368 [PubMed - indexed for MEDLINE]

12|13

영어버전.indd 12-13

2014-06-25 오전 8:39:19

The inhibitory effect of Cladosiphon fucoidan on the attachment of Helicobacter pylori (H. pylori), a gastroduodenal pathogen, to human gastric cell lines was studied.

The bacterial binding in these cell lines was inhibited more

by Cladosiphon fucoidan (IC50 = 16-30 mg/mL), than by the fucoidan from Fucus (IC50 > 30 mg/mL).

It was also shown that this fucoidan blocks both Leb- and sulfatide-mediated attachment of H. pylori to gastric cells.

Furthermore, fucoidan-binding proteins were found on the H. pylori cell surface by Western blot analysis.

Thus, the inhibitory effect exerted by Cladosiphon fucoidan on binding between H. pylori and gastric cells might result from the coating with this component of the bacterial surface.

Helicobacter pylori (H. pylori) is a Gram-negative, microaerophilic bacterium found in the stomach.

Western blot is a widely used analytical technique used to detect specific proteins in a sample of tissue homogenate or extract.

Leb- The Lewis (b) (Le(b)) blood group antigen mediates H. pylori attachment to human gastric mucosa.

Sulfitides are a class of sulfated galactosylceramides synthesized primarily in the oligodendrocytes in the central nervous system.

SUMMARY

Cladosiphon fucoidan has an inhibitory effect on the attachment of Helicobacter pylori (H. pylori), a gastroduodenal pathogen, to human gastric cell lines.

Active hexose correlated compound (AHCC) is a natural compound with the potential to be used as an immuno-enhancer in cases in which the immune system is compromised.

Tokyo,

Japan

CD4+

*

5.0

**

4.0 3.0

*

*

* p<0.01 ** p<0.05 P values compared With baseline

*

2.0 1.0 0.0

12.0

Visit 1 n=30 CD8+

10.0

Visit 2 n=28

Visit 3 n=25

**

8.0

** *

*

6.0 4.0

IFN- γ TNF-α IFN- γ and TNF-α

*

2.0 0.0

Visit 4 n=26

Visit 1

Visit 2

Visit 3

Visit 4

Flg.2 Changes in the frequency of CD4(+) and CD8(+) T cells producing cytokines before and after active hexose correlated compound(AHCC). As described in Fig.1. the frequency of CD4(+) and CD8(+) T cells producing IFN- γ, TNF-α or both cytokines was determined before and after AHCC intake. Visits 1,2,3 and 4 indicate before AHCC. 30 and 60 days on AHCC. And 30 day after discontinuing AHCC, respectively.

The frequency of CD4(+) and CD8(+) T cells producing IFN-γ alone, TNF-α alone, or both increased during AHCC intake compared with baseline values. Overall, these findings suggest that AHCC enhances CD4(+) and CD8(+) T cell immune responses in healthy elderly persons taking at least 30 days to obtain such effect, which remained up to 30 days after discontinuing treatment with this compound.

AHCC

01

IFN-γ belongs to a group of proteins, known as cytokines. They are involved in the regulation of the immune system and inflammatory response.

TNF-α is involved in the systemic inflammation. Its primary role is the regulation of immune cells.

CD4+ is a glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages and dendritic cells.

CD8+ is expressed on the surface of cytotoxic T cells, but also on natural killer (NK) cells and dendritic cells.

SUMMARY

AHCC is a natural compound that can enhance cell immune response.

Authors: Shibata, H., Kimura, T., Nagaoka, M., Hashimoto, S., Sawada, H., Ueyama, S., Yokokura, T. Yakult Central Institute for Microbiological Research.

Article: J Nutr Sci Vitaminol (Tokyo). 1999 Jun;45 (3):325-36.

PMID: 10524351 [PubMed - indexed for MEDLINE]

6.0

% of Cells

11

% of Cells

Fucoidan

Inhibitory effect of Cladosiphon fucoidan on the adhesion of Helicobacter pylori to human gastric cells.

Effects of Active Hexose Correlated Compound (AHCC) on frequency of CD4+ and CD8+ T cells producing interferon-γ and/or tumor necrosis factor-α in healthy adults.

Authors: Yin, Z., Fujii, H., Walshe, T.

Massachusetts,

USA

Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA. Amino Up Chemical Co., Ltd., Sapporo, Japan. Academic Research Associates, Boston, Massachusetts, USA. Brigham and Women’s Hospital and Harvard Medical School, Boston.

Article: Human Immunology 71 (2010) 1187-1190.

PMID: 20732368 [PubMed - indexed for MEDLINE]

12|13

영어버전.indd 12-13

2014-06-25 오전 8:39:19

AHCC

02

Active Hexose Correlated Compounds (AHCC) promotes T helper (Th) 17 and 1 cell responses via inducing Il-1β production from monocytes in humans.

The differentiation of T helper (Th) cells is critically dependent on cytokine milieu. The innate immune monocytes produce IL1β which can affect the development of Th17 and Th1 cells that predominantly produce IL-17 and IFN-γ, respectively. Active Hexose Correlated Compound (AHCC) that contains a large amount of oligosaccharides is a natural extract prepared from the mycelium of the edible Basidiomycete fungus.

This compound is reported to modulate immune responses against pathogens although the mechanisms for this effect are largely unknown. Here we show that AHCC could induce high levels of IL-1β production from human monocytes. Furthermore, AHCC-treated monocytes increased the production of IL-17 and IFN-γ from autologous CD4(+) T cells, which was blocked by adding IL-1 receptor antagonist. These finding provide new insight into how food supplements like AHCC could enhance human immunity by modulating monocytes and Th cells.

Th1 helper cells are the host immunity effectors against intracellular bacteria and protozoa.

Th17 helper cells promote inflammation and attract neutrophils, Th17 cells may help to remove microbes from the body.

IL-1β is also known as catabolin, is a cytokine protein that in humans is encoded by the IL1B gene.

IFN-γ or interferon gamma is a cytokine that is critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control.

CD4+ T cells are white blood cells that are an essential part of the human immune system.

SUMMARY

AHCC can stimulate innate immune cells and can induce high levels of human cytokines for tumor control.

Connecticut,

USA

영어버전.indd 14-15

Evaluation of Active Hexose Correlated Compound (AHCC) hepatic metabolism and potential drug interactions with chemotherapy agents.

Active hexose correlated compound (AHCC), a Basidiomycotina extract, is a well-tolerated nutritional supplement with no reported adverse effects. It has demonstrated potential antitumor activity and immune modulator activity. However, there is no current information regarding its metabolism and the potential for drugdrug interactions for AHCC in combination with chemotherapy.

The objective of this study was to characterize AHCC hepatic metabolism, specifically involving the potential for drug interactions with selected chemotherapy agents. High-throughput cytochrome P-450 (CYP450) metabolism inhibition experiments were conducted in vitro evaluating CYP450 3A4, 2C8, 2C9, and 2D6 followed by an evaluation of AHCC as a substrate of these same isoenzymes.

AHCC does have the potential for drug-drug interactions involving CYP450 2D6, such as doxorubicin or ondansetron; however, the overall data suggest that AHCC would be safe to administer with most other chemotherapy agents that are not metabolized via the CYP450 2D6 pathway.

AHCC

03

Cytochrome P-450 is a large and diverse group of enzymes that catalyze the oxidation of organic substances.

Isoenzymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction.

CYP450 3A4 is an important enzyme in the body, mainly found in the liver and in the intestine.

CYP450 2D6 is an enzyme that in humans is encoded by the CYP2D6 gene.

Doxorubicin is a drug used in cancer chemotherapy.

Ondansetron is used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, and surgery.

SUMMARY

AHCC has demonstrated potential antitumor activity and immune modulator activity. AHCC is safe to administer with most other chemotherapy agents.

Authors: Lee, W. W., Lee, N., Fujii, H., Kang, I.

Authors: Mach, C.M., Fugii, H., Wakame, K. and Smith, J.

Department of Internal Medicine, Yale University School of Medicine, New Haven CT 06520, USA. Department of Microbiology and Immunology, College of Medicine, Seoul National University, 103 Daehak-no, Chongnogu, 110-799, Seoul, Republic of Korea. Research and Development Division, Amino Up Chemical Co. Ltd., 0040839 Sapporo, Japan.

Article: Cellular Immunology 275 (2012) 19-23 PMID: 22531483 [PubMed - indexed for MEDLINE] PMCID: PMC3348379

Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center, Houston 77230.

Article: Journal for the Society of Integrative Oncology 2008 Summer; 6 (3): 105-9.

PMID: 19087767 [PubMed - indexed for MEDLINE]

Texas,

USA 14|15

2014-06-25 오전 8:39:23

AHCC

02

Active Hexose Correlated Compounds (AHCC) promotes T helper (Th) 17 and 1 cell responses via inducing Il-1β production from monocytes in humans.

The differentiation of T helper (Th) cells is critically dependent on cytokine milieu. The innate immune monocytes produce IL1β which can affect the development of Th17 and Th1 cells that predominantly produce IL-17 and IFN-γ, respectively. Active Hexose Correlated Compound (AHCC) that contains a large amount of oligosaccharides is a natural extract prepared from the mycelium of the edible Basidiomycete fungus.

This compound is reported to modulate immune responses against pathogens although the mechanisms for this effect are largely unknown. Here we show that AHCC could induce high levels of IL-1β production from human monocytes. Furthermore, AHCC-treated monocytes increased the production of IL-17 and IFN-γ from autologous CD4(+) T cells, which was blocked by adding IL-1 receptor antagonist. These finding provide new insight into how food supplements like AHCC could enhance human immunity by modulating monocytes and Th cells.

Th1 helper cells are the host immunity effectors against intracellular bacteria and protozoa.

Th17 helper cells promote inflammation and attract neutrophils, Th17 cells may help to remove microbes from the body.

IL-1β is also known as catabolin, is a cytokine protein that in humans is encoded by the IL1B gene.

IFN-γ or interferon gamma is a cytokine that is critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control.

CD4+ T cells are white blood cells that are an essential part of the human immune system.

SUMMARY

AHCC can stimulate innate immune cells and can induce high levels of human cytokines for tumor control.

Connecticut,

USA

영어버전.indd 14-15

Evaluation of Active Hexose Correlated Compound (AHCC) hepatic metabolism and potential drug interactions with chemotherapy agents.

Active hexose correlated compound (AHCC), a Basidiomycotina extract, is a well-tolerated nutritional supplement with no reported adverse effects. It has demonstrated potential antitumor activity and immune modulator activity. However, there is no current information regarding its metabolism and the potential for drugdrug interactions for AHCC in combination with chemotherapy.

The objective of this study was to characterize AHCC hepatic metabolism, specifically involving the potential for drug interactions with selected chemotherapy agents. High-throughput cytochrome P-450 (CYP450) metabolism inhibition experiments were conducted in vitro evaluating CYP450 3A4, 2C8, 2C9, and 2D6 followed by an evaluation of AHCC as a substrate of these same isoenzymes.

AHCC does have the potential for drug-drug interactions involving CYP450 2D6, such as doxorubicin or ondansetron; however, the overall data suggest that AHCC would be safe to administer with most other chemotherapy agents that are not metabolized via the CYP450 2D6 pathway.

AHCC

03

Cytochrome P-450 is a large and diverse group of enzymes that catalyze the oxidation of organic substances.

Isoenzymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction.

CYP450 3A4 is an important enzyme in the body, mainly found in the liver and in the intestine.

CYP450 2D6 is an enzyme that in humans is encoded by the CYP2D6 gene.

Doxorubicin is a drug used in cancer chemotherapy.

Ondansetron is used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, and surgery.

SUMMARY

AHCC has demonstrated potential antitumor activity and immune modulator activity. AHCC is safe to administer with most other chemotherapy agents.

Authors: Lee, W. W., Lee, N., Fujii, H., Kang, I.

Authors: Mach, C.M., Fugii, H., Wakame, K. and Smith, J.

Department of Internal Medicine, Yale University School of Medicine, New Haven CT 06520, USA. Department of Microbiology and Immunology, College of Medicine, Seoul National University, 103 Daehak-no, Chongnogu, 110-799, Seoul, Republic of Korea. Research and Development Division, Amino Up Chemical Co. Ltd., 0040839 Sapporo, Japan.

Article: Cellular Immunology 275 (2012) 19-23 PMID: 22531483 [PubMed - indexed for MEDLINE] PMCID: PMC3348379

Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center, Houston 77230.

Article: Journal for the Society of Integrative Oncology 2008 Summer; 6 (3): 105-9.

PMID: 19087767 [PubMed - indexed for MEDLINE]

Texas,

USA 14|15

2014-06-25 오전 8:39:23

AHCC

Disruption of endothelial adherens junction by invasive breast cancer cells is mediated by reactive oxygen species and is attenuated by AHCC

04 The effect of antioxidants on treatment of cancer is still controversial. Previously, we demonstrated that interaction of breast cancer cells with endothelial cells leads to tyrosine phosphorylation of VE-cadherin and disruption of endothelial adherens junction (EAJ).

Interaction of breast cancer cells (MDA-MB-231 cells) with human umbilical vein endothelial cells (HUVECs) leads to an increase in generation of reactive oxygen species (ROS). Treatment of HUVECs with H2O2 or phorbol myristate acetate (PMA) led to tyrosine phosphorylation of VE-cadherin, dissociation of β-catenin from VE-cadherin complex and increased transendothelial migration (TEM) of MDA-MB-231 cells.

Disruption of EAJ and phosphorylation of VE-cadherin induced by interaction of MDA-MB-231 cells with HUVECs were attenuated when HUVECs were pretreated with an antioxidant, N-acetylcysteine (NAC) or AHCC. AHCC inhibited TEM of MDAMB-231 cells and generation of ROS induced by interaction of MDA-MB-231 cells with HUVECs.

Tyrosine phosphorylation of VEcadherin affects endothelial junction integrity.

Endothelial adherens junction (EAJ), an interaction of breast cancer cells with endothelial cells leads to the destruction of this junction.

MDA-MB-231 cells is a cell line of human breast adenocarcinoma.

HUVECs or human umbilical vein endothelial cells are also derived from the endothelium of veins from the umbilical cord.

ROS or Reactive Oxygen Species are chemically reactive molecules containing oxygen. β-catenin regulates cell-cell adhesion and gene transcription.

SUMMARY

Japan

Active hexose correlated compound (AHCC) (a mixture of polysaccharides, amino acids, lipids and minerals derived from cultured mycelia of a Basidiomycete mushroom, Lentinula edodes) was used to assess amelioration of alopecia (hair loss) caused by cytosine arabinoside (Ara-C) and modulation of liver injury caused by single doses 6-mercaptopurine (6-MP) plus methotrexate (MTX).

Of the Ara-C treated rats 71.4% showed severe alopecia and 28.6% showed moderate alopecia. However, the AHCC (p.o.)-treated Ara-C group was significantly protected from alopecia. Ara-C treated rats had profound loss of hair follicles but the Ara-C plus AHCCtreated group had mild losses of follicles. AHCC supplementation to the 6-MP- and MTX-treated mice significantly increased body weight, erythrocytes, leukocytes and serum albumin, improved liver hypertrophy and degeneration, normalized the activities of serum glutamic oxaloacetic transaminase (sGOT) and serum glutamic pyruvic transaminase (sGPT), and enhanced liver drug-metabolizing enzymes. Co-administration of AHCC significantly reduced the side effects associated with Ara-C, 6-MP and MTX. However, the molecular mechanism for AHCC activity and its clinical integrity for use needs defining.

AHCC

05

Arabinoside (Ara-C) is a gene sequence encoding enzymes needed for catabolism of arabinose to xylulose5-phosphate.

6-mercaptopurine is an immunosuppressive drug.

Methotrexate (MTX) is an antimetabolite and antifolate drug.

Erythrocytes or red blood cells, are the most common type of blood cell.

Leukocytes or white blood cells are the cells of the immune system that are involved in defending the body against infections.

Serum albumin is a globular protein that in humans is encoded by the ALB gene.

SUMMARY

Interaction of breast cancer cells (MDA-MB-231 cells) with human umbilical vein endothelial cells (HUVECs) leads to an increase in generation of reactive oxygen species (ROS). AHCC has shown to reduce this alteration.

Sapporo,

The effect of Active Hexose Correlated Compound (AHCC) in modulating cytosine arabinoside-induced hair loss, and 6-mercaptopurine-and methotrexateinduced liver injury in rodents

Co-administration of AHCC has shown to reduce hair loss in patients.

AHCC supplementation significantly increased body weight, erythrocytes, leukocytes and improved and enhanced liver function.

Authors: Haidari, M., Zhang, W., Wakame, K.

Authors: Sun, B., Wakame, K., Sato, E., Nishioka, H., Aruoma, O. I., Fujii, H.

Department of Internal Medicine, Division of Cardiology, The University of Texas Health Science Center at Houston, USA. Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, TX, USA. Research and Development Division, Amino Up Chemical Co., Ltd., Sapporo, Japan.

Article: Life Sciences 93 (2013) 994-1003.

PMID: 24211779 [PubMed - indexed for MEDLINE]

Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, 230 West 125th, New York, NY 10027, USA. Research and Development Division, Amino Up Chemical Co., Ltd. Article: Cancer Epidemiology 33 (2009) 293-299.

PMID: 19699163 [PubMed - indexed for MEDLINE]

Sapporo,

Japan

16|17

영어버전.indd 16-17

2014-06-25 오전 8:39:27

AHCC

Disruption of endothelial adherens junction by invasive breast cancer cells is mediated by reactive oxygen species and is attenuated by AHCC

04 The effect of antioxidants on treatment of cancer is still controversial. Previously, we demonstrated that interaction of breast cancer cells with endothelial cells leads to tyrosine phosphorylation of VE-cadherin and disruption of endothelial adherens junction (EAJ).

Interaction of breast cancer cells (MDA-MB-231 cells) with human umbilical vein endothelial cells (HUVECs) leads to an increase in generation of reactive oxygen species (ROS). Treatment of HUVECs with H2O2 or phorbol myristate acetate (PMA) led to tyrosine phosphorylation of VE-cadherin, dissociation of β-catenin from VE-cadherin complex and increased transendothelial migration (TEM) of MDA-MB-231 cells.

Disruption of EAJ and phosphorylation of VE-cadherin induced by interaction of MDA-MB-231 cells with HUVECs were attenuated when HUVECs were pretreated with an antioxidant, N-acetylcysteine (NAC) or AHCC. AHCC inhibited TEM of MDAMB-231 cells and generation of ROS induced by interaction of MDA-MB-231 cells with HUVECs.

Tyrosine phosphorylation of VEcadherin affects endothelial junction integrity.

Endothelial adherens junction (EAJ), an interaction of breast cancer cells with endothelial cells leads to the destruction of this junction.

MDA-MB-231 cells is a cell line of human breast adenocarcinoma.

HUVECs or human umbilical vein endothelial cells are also derived from the endothelium of veins from the umbilical cord.

ROS or Reactive Oxygen Species are chemically reactive molecules containing oxygen. β-catenin regulates cell-cell adhesion and gene transcription.

SUMMARY

Japan

Active hexose correlated compound (AHCC) (a mixture of polysaccharides, amino acids, lipids and minerals derived from cultured mycelia of a Basidiomycete mushroom, Lentinula edodes) was used to assess amelioration of alopecia (hair loss) caused by cytosine arabinoside (Ara-C) and modulation of liver injury caused by single doses 6-mercaptopurine (6-MP) plus methotrexate (MTX).

Of the Ara-C treated rats 71.4% showed severe alopecia and 28.6% showed moderate alopecia. However, the AHCC (p.o.)-treated Ara-C group was significantly protected from alopecia. Ara-C treated rats had profound loss of hair follicles but the Ara-C plus AHCCtreated group had mild losses of follicles. AHCC supplementation to the 6-MP- and MTX-treated mice significantly increased body weight, erythrocytes, leukocytes and serum albumin, improved liver hypertrophy and degeneration, normalized the activities of serum glutamic oxaloacetic transaminase (sGOT) and serum glutamic pyruvic transaminase (sGPT), and enhanced liver drug-metabolizing enzymes. Co-administration of AHCC significantly reduced the side effects associated with Ara-C, 6-MP and MTX. However, the molecular mechanism for AHCC activity and its clinical integrity for use needs defining.

AHCC

05

Arabinoside (Ara-C) is a gene sequence encoding enzymes needed for catabolism of arabinose to xylulose5-phosphate.

6-mercaptopurine is an immunosuppressive drug.

Methotrexate (MTX) is an antimetabolite and antifolate drug.

Erythrocytes or red blood cells, are the most common type of blood cell.

Leukocytes or white blood cells are the cells of the immune system that are involved in defending the body against infections.

Serum albumin is a globular protein that in humans is encoded by the ALB gene.

SUMMARY

Interaction of breast cancer cells (MDA-MB-231 cells) with human umbilical vein endothelial cells (HUVECs) leads to an increase in generation of reactive oxygen species (ROS). AHCC has shown to reduce this alteration.

Sapporo,

The effect of Active Hexose Correlated Compound (AHCC) in modulating cytosine arabinoside-induced hair loss, and 6-mercaptopurine-and methotrexateinduced liver injury in rodents

Co-administration of AHCC has shown to reduce hair loss in patients.

AHCC supplementation significantly increased body weight, erythrocytes, leukocytes and improved and enhanced liver function.

Authors: Haidari, M., Zhang, W., Wakame, K.

Authors: Sun, B., Wakame, K., Sato, E., Nishioka, H., Aruoma, O. I., Fujii, H.

Department of Internal Medicine, Division of Cardiology, The University of Texas Health Science Center at Houston, USA. Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, TX, USA. Research and Development Division, Amino Up Chemical Co., Ltd., Sapporo, Japan.

Article: Life Sciences 93 (2013) 994-1003.

PMID: 24211779 [PubMed - indexed for MEDLINE]

Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, 230 West 125th, New York, NY 10027, USA. Research and Development Division, Amino Up Chemical Co., Ltd. Article: Cancer Epidemiology 33 (2009) 293-299.

PMID: 19699163 [PubMed - indexed for MEDLINE]

Sapporo,

Japan

16|17

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2014-06-25 오전 8:39:27

AHCC

06

Effect of Active Hexose Correlated Compound (AHCC) in women receiving adjuvant chemotherapy for breast cancer: a retrospective study.

Anthracyclines and taxanes are often used as first-line chemotherapy treatments in patients with breast cancer. There are, however, significant toxicity and side effects associated with these therapies. Previous studies have demonstrated that active hexose-correlated compound (AHCC) reduces such side effects.

The present study explored the beneficial effects of AHCC on adverse events in patients receiving adjuvant chemotherapy for breast cancer.

Forty-one women who were treated with anthracyclines and taxanes at Nagumo Clinic in Tokyo from October 2004 to March 2011 were selected for this study. We found that, compared to the control group, the AHCC group had significantly fewer neutrophilrelated events (odds ratio, 0.30; p=0.016), significantly lower use of granulocyte colony-stimulating factor, and a higher (although not significant) rate of adverse events associated with γ-glutamyl transpeptidase.

Anthracyclines are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium.

Taxanes are diterpenes produced by the plants of the genus Taxus (yews), and are widely used as chemotherapy agents.

Granulocyte colony stimulating factor is a glycoprotein that stimulates bone marrow to produce granulocytes and stem cells and release them into the bloodstream.

Neutrophils are the most abundant type of white blood cells and form essential part of the innate immune system.

Gamma-glutamyl transpeptidase is an enzyme that transfers gammaglutamyl functional groups.

Active Hexose Correlated Compound (AHCC) downregulates HSP27 of pancreatic cells, and helps the cytotoxic effect of gemcitabine.

Active hexose-correlated compound (AHCC), an extract of basidiomycete mushroom, is used as health food to enhance the therapeutic effects and reduce the adverse effects of chemotherapy. Our previous proteomic analysis revealed that upregulation of heat-shock protein 27 (HSP27) was responsible for gemcitabine resistance of pancreatic cancer cells.

KLM1-R cells were treated with AHCC, and the expression of HSP27 as well as the cytotoxic effects of combinatorial treatment of AHCC and gemcitabine were investigated with western blotting and MTS assay, respectively. AHCC down-regulated HSP27 and exhibited a cytotoxic effect on KLM1-R cells. Furthermore, the cytotoxic effect of the combinatorial treatment of AHCC and gemcitabine was synergistic.

This study supports the potential therapeutic benefits of combinatorial treatment of AHCC and gemcitabine for patients with pancreatic cancer.

AHCC has the potential to reduce the severity of neutropenia induced by breast cancer chemotherapy and the use of G-CSF during chemotherapy.

Heat-shock protein 27 (HSP27) is a protein that in humans is encoded by the HSPB1 gene.

Gemcitabine is a nucleoside analog used as chemotherapy.

KLM1-R are pancreatic cancer cells.

Western blotting is a widely used analytical technique used to detect specific proteins in a sample of tissue homogenate or extract.

MTS assay is often described as a 'one-step' MTT assay, which offers the convenience of adding the reagent straight to the cell culture without the intermittent steps required in the MTT assay.

AHCC reduces the adverse effects of chemotherapy. AHCC has potential therapeutic benefits of combinatorial treatment of AHCC and gemcitabine for patients with pancreatic cancer.

Authors: Hangai, S., Iwase, S., Kawaguchi, T., Kogue, Y., Miyaji, T., Matsunaga, T., Nagumo, T., Yamaguchi, T. Tokyo,

07

SUMMARY

SUMMARY

Japan

AHCC

Department of Hematology and Oncology, The University of Tokyo Hospital , Bunkyo-ku.

Article: Journal of Alternative and Complementary Medicine 2013 Nov; 19 (11): 905-10.

PMID: 23829813 [PubMed - in process] PMCID: PMC3842887

Authors: Suenaga, S., Kuramitsu, Y., Kaino, S., Maehara, S., Sakaida, I., Nakamura, K.

Yamaguchi,

Japan

Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, 755-8505.

Article: Anticancer Research 2014 Jan; 34 (1): 141:6.

PMID: 24403454 [PubMed - in process]

18|19

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2014-06-25 오전 8:39:32

AHCC

06

Effect of Active Hexose Correlated Compound (AHCC) in women receiving adjuvant chemotherapy for breast cancer: a retrospective study.

Anthracyclines and taxanes are often used as first-line chemotherapy treatments in patients with breast cancer. There are, however, significant toxicity and side effects associated with these therapies. Previous studies have demonstrated that active hexose-correlated compound (AHCC) reduces such side effects.

The present study explored the beneficial effects of AHCC on adverse events in patients receiving adjuvant chemotherapy for breast cancer.

Forty-one women who were treated with anthracyclines and taxanes at Nagumo Clinic in Tokyo from October 2004 to March 2011 were selected for this study. We found that, compared to the control group, the AHCC group had significantly fewer neutrophilrelated events (odds ratio, 0.30; p=0.016), significantly lower use of granulocyte colony-stimulating factor, and a higher (although not significant) rate of adverse events associated with γ-glutamyl transpeptidase.

Anthracyclines are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium.

Taxanes are diterpenes produced by the plants of the genus Taxus (yews), and are widely used as chemotherapy agents.

Granulocyte colony stimulating factor is a glycoprotein that stimulates bone marrow to produce granulocytes and stem cells and release them into the bloodstream.

Neutrophils are the most abundant type of white blood cells and form essential part of the innate immune system.

Gamma-glutamyl transpeptidase is an enzyme that transfers gammaglutamyl functional groups.

Active Hexose Correlated Compound (AHCC) downregulates HSP27 of pancreatic cells, and helps the cytotoxic effect of gemcitabine.

Active hexose-correlated compound (AHCC), an extract of basidiomycete mushroom, is used as health food to enhance the therapeutic effects and reduce the adverse effects of chemotherapy. Our previous proteomic analysis revealed that upregulation of heat-shock protein 27 (HSP27) was responsible for gemcitabine resistance of pancreatic cancer cells.

KLM1-R cells were treated with AHCC, and the expression of HSP27 as well as the cytotoxic effects of combinatorial treatment of AHCC and gemcitabine were investigated with western blotting and MTS assay, respectively. AHCC down-regulated HSP27 and exhibited a cytotoxic effect on KLM1-R cells. Furthermore, the cytotoxic effect of the combinatorial treatment of AHCC and gemcitabine was synergistic.

This study supports the potential therapeutic benefits of combinatorial treatment of AHCC and gemcitabine for patients with pancreatic cancer.

AHCC has the potential to reduce the severity of neutropenia induced by breast cancer chemotherapy and the use of G-CSF during chemotherapy.

Heat-shock protein 27 (HSP27) is a protein that in humans is encoded by the HSPB1 gene.

Gemcitabine is a nucleoside analog used as chemotherapy.

KLM1-R are pancreatic cancer cells.

Western blotting is a widely used analytical technique used to detect specific proteins in a sample of tissue homogenate or extract.

MTS assay is often described as a 'one-step' MTT assay, which offers the convenience of adding the reagent straight to the cell culture without the intermittent steps required in the MTT assay.

AHCC reduces the adverse effects of chemotherapy. AHCC has potential therapeutic benefits of combinatorial treatment of AHCC and gemcitabine for patients with pancreatic cancer.

Authors: Hangai, S., Iwase, S., Kawaguchi, T., Kogue, Y., Miyaji, T., Matsunaga, T., Nagumo, T., Yamaguchi, T. Tokyo,

07

SUMMARY

SUMMARY

Japan

AHCC

Department of Hematology and Oncology, The University of Tokyo Hospital , Bunkyo-ku.

Article: Journal of Alternative and Complementary Medicine 2013 Nov; 19 (11): 905-10.

PMID: 23829813 [PubMed - in process] PMCID: PMC3842887

Authors: Suenaga, S., Kuramitsu, Y., Kaino, S., Maehara, S., Sakaida, I., Nakamura, K.

Yamaguchi,

Japan

Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, 755-8505.

Article: Anticancer Research 2014 Jan; 34 (1): 141:6.

PMID: 24403454 [PubMed - in process]

18|19

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2014-06-25 오전 8:39:32

AHCC

In vitro and in vivo evaluation of Active Hexose Correlated Compound (AHCC) for the Eradication of HPV

08 Objectives: Evaluate if Active Hexose Correlated Compound (AHCC) will eradicate HPV expression in vitro and in vivo cervical cancer models. Define the mechanism of AHCC eradication of HPV infections.

Methods: Cervical cancer cells, SiHa (HPV16/18+) and C-33A (HPV), were treated with AHCC and incubated for 72 hours with sampling every 24 hours. Study was then repeated with AHCC once daily x 7 days then observed x 7 days. Samples were collected every 24 hours for 14 days. Tumors were measured 3 times a week and blood samples collected at baseline and once weekly. After 90 days of treatment, there was a 30 days of observation to evaluate the potential recurrence of HPV infections. Tumors were then extracted and PCR was used to evaluate the HPV expression.

HPV is the Human Papillomavirus.

SiHa is a HPV16 positive cervical carcinoma cell line.

C-33A is a cervical cancer cell line that does not contain any HPV copies.

PCR is the polymerase chain reaction.

Eradication is the complete destruction of something.

Combination therapy of Active Hexose Correlated Compound (AHCC) plus UFT significantly reduces the metastasis of rat mammary adenocarcinoma.

Synergistic effects of active hexose correlated compound (AHCC) extracted from mushroom on the treatment with UFT against mammary adenocarcinoma, SST-2 cells, in congenitally T celldepressed spontaneously hypertensive rats (SHR) were observed.

AHCC plus UFT had slight but significant effects on the growth of primary tumors. Pulmonary metastases were not inhibited by the treatment with AHCC plus UFT, whereas metastases to axillary lymph nodes (LN) were obviously inhibited. Combination of AHCC plus UFT showed similar synergistic anti-metastatic effects in SHR rats with accelerated pulmonary metastases following the surgical removal of the primary tumors. In vitro studies demonstrated that AHCC plus UFT enhanced the NK cell activity in tumor-bearing rats, whereas UFT alone depressed the NK cell activity. In addition, AHCC restored the suppressed mRNA expression of interleukin-1alpha and tumor necrosis factor-alpha induced by the chemotherapy.

Results: There was in vitro suppression of HPV expression after a single dose at 24 hours, but suppression was not sustained; HPV was detected again at 48 hours. With dosing every 24 hours for 7 days followed by 7 days of no treatment, HPV eradication was achieved.

Taken together, the combination of AHCC plus UFT brought about good therapeutic effects not only on primary tumor growth but also on reducing metastasis and these effects were mediated by host immunity which was restored or activated by AHCC. AHCC may be a good candidate for a biological response modifier.

SUMMARY

SUMMARY

These data suggest AHCC will eradicate HPV 16/18+ infections attributed to the modulation of the expression and signaling of IFNα/β/γ and may have a role in the prevention of HPV-related cervical cancer.

AHCC

09

UFT or Tegafur-uracil is a chemotherapy drug used in the treatment of cancer, primarily bowel cancer. It is also called UFUR. Spontaneously hypertensive rats (SHR) is an animal model of essential (or primary) hypertension, used to study cardiovascular disease.

Metastasis, or metastatic disease, is the spread of a cancer from one organ or part to another non-adjacent organ or part.

AHCC plus UFT brought about good therapeutic effects not only on primary tumor growth but also on reducing metastasis and these effects were mediated by host immunity which was restored or activated by AHCC.

Authors: Judith A. Smith, Pharm.D., Lata Mathew B.S., Anjali Gaikwad, M.S., Jonathan P. Faro, M.D.,2,3, Larissa Meyer, M.D., John L. Dalrymple, M.D.

Authors: Matsushita, K., Kuramitsu, Y., Ohiro, Y., Obara, M., Kobayashi, M., Li, Y.Q., Hosokawa, M.

Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center, Houston 77230.

Laboratory of Pathology, Cancer Institute, Hokkaido University School of Medicine.

Article: Anticancer Drugs, 1998 Apr; 9 (4): 343-50.

PMID: 9635925 [PubMed - indexed for MEDLINE]

Texas,

Sapporo,

USA

Japan

20|21

영어버전.indd 20-21

2014-06-25 오전 8:39:36

AHCC

In vitro and in vivo evaluation of Active Hexose Correlated Compound (AHCC) for the Eradication of HPV

08 Objectives: Evaluate if Active Hexose Correlated Compound (AHCC) will eradicate HPV expression in vitro and in vivo cervical cancer models. Define the mechanism of AHCC eradication of HPV infections.

Methods: Cervical cancer cells, SiHa (HPV16/18+) and C-33A (HPV), were treated with AHCC and incubated for 72 hours with sampling every 24 hours. Study was then repeated with AHCC once daily x 7 days then observed x 7 days. Samples were collected every 24 hours for 14 days. Tumors were measured 3 times a week and blood samples collected at baseline and once weekly. After 90 days of treatment, there was a 30 days of observation to evaluate the potential recurrence of HPV infections. Tumors were then extracted and PCR was used to evaluate the HPV expression.

HPV is the Human Papillomavirus.

SiHa is a HPV16 positive cervical carcinoma cell line.

C-33A is a cervical cancer cell line that does not contain any HPV copies.

PCR is the polymerase chain reaction.

Eradication is the complete destruction of something.

Combination therapy of Active Hexose Correlated Compound (AHCC) plus UFT significantly reduces the metastasis of rat mammary adenocarcinoma.

Synergistic effects of active hexose correlated compound (AHCC) extracted from mushroom on the treatment with UFT against mammary adenocarcinoma, SST-2 cells, in congenitally T celldepressed spontaneously hypertensive rats (SHR) were observed.

AHCC plus UFT had slight but significant effects on the growth of primary tumors. Pulmonary metastases were not inhibited by the treatment with AHCC plus UFT, whereas metastases to axillary lymph nodes (LN) were obviously inhibited. Combination of AHCC plus UFT showed similar synergistic anti-metastatic effects in SHR rats with accelerated pulmonary metastases following the surgical removal of the primary tumors. In vitro studies demonstrated that AHCC plus UFT enhanced the NK cell activity in tumor-bearing rats, whereas UFT alone depressed the NK cell activity. In addition, AHCC restored the suppressed mRNA expression of interleukin-1alpha and tumor necrosis factor-alpha induced by the chemotherapy.

Results: There was in vitro suppression of HPV expression after a single dose at 24 hours, but suppression was not sustained; HPV was detected again at 48 hours. With dosing every 24 hours for 7 days followed by 7 days of no treatment, HPV eradication was achieved.

Taken together, the combination of AHCC plus UFT brought about good therapeutic effects not only on primary tumor growth but also on reducing metastasis and these effects were mediated by host immunity which was restored or activated by AHCC. AHCC may be a good candidate for a biological response modifier.

SUMMARY

SUMMARY

These data suggest AHCC will eradicate HPV 16/18+ infections attributed to the modulation of the expression and signaling of IFNα/β/γ and may have a role in the prevention of HPV-related cervical cancer.

AHCC

09

UFT or Tegafur-uracil is a chemotherapy drug used in the treatment of cancer, primarily bowel cancer. It is also called UFUR. Spontaneously hypertensive rats (SHR) is an animal model of essential (or primary) hypertension, used to study cardiovascular disease.

Metastasis, or metastatic disease, is the spread of a cancer from one organ or part to another non-adjacent organ or part.

AHCC plus UFT brought about good therapeutic effects not only on primary tumor growth but also on reducing metastasis and these effects were mediated by host immunity which was restored or activated by AHCC.

Authors: Judith A. Smith, Pharm.D., Lata Mathew B.S., Anjali Gaikwad, M.S., Jonathan P. Faro, M.D.,2,3, Larissa Meyer, M.D., John L. Dalrymple, M.D.

Authors: Matsushita, K., Kuramitsu, Y., Ohiro, Y., Obara, M., Kobayashi, M., Li, Y.Q., Hosokawa, M.

Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center, Houston 77230.

Laboratory of Pathology, Cancer Institute, Hokkaido University School of Medicine.

Article: Anticancer Drugs, 1998 Apr; 9 (4): 343-50.

PMID: 9635925 [PubMed - indexed for MEDLINE]

Texas,

Sapporo,

USA

Japan

20|21

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2014-06-25 오전 8:39:36

AHCC

10

Immunological Effect of Active Hexose Correlated Compound (AHCC) in Healthy Volunteers: A DoubleBlind, Placebo-Controlled Trial.

The aim of this study was to evaluate the effects of active hexose correlated compound (AHCC) intake on immune responses by investigating the number and function of circulating dendritic cells (DCs) in healthy volunteers. Allogeneic mixed-leukocyte reaction (MLR) was performed. Natural killer (NK) cell activity and the proliferative response of T lymphocytes toward mitogen (phytohemagglutinin [PHA]) were measured. We also measured cytokine production stimulated by lipopolysaccharide [interleukin (IL)-2, IL-4, IL-6, IL-10, interferon gamma-gamma, tumor necrosis factor-alpha).

The number of DC1s in the AHCC group after intake was significantly higher than at baseline. DC2s in the AHCC group were significantly increased in comparison with controls. The MLR in the AHCC group was significantly increased compared to controls. No significant differences in PHA, NK cell activity, and cytokine production were found between groups. AHCC intake resulted in the increased number of DCs and function of DC1s, which have a role in specific immunity.

Dendritic cells are antigen-presenting cells of the mammalian immune system.

Allogeneic mixed-leukocyte reaction (MLR) – expression of the T-cell receptor gamma-chain gene products on the surface of peripheral T cells and T-cell blasts generated by this reaction.

T-lymphocytes represent a small subset of T cells that possess a distinct T cell receptor (TCR) on the surface.

Phytohemagglutinin (PHA) is a lectin found in plants, especially legumes.

Cytokines are a broad and loose category of small proteins that are important in cell signaling.

Interleukins are a group of cytokines that were fist seen to be expressed by white blood cells.

H-2 haplotype-dependent serum IL-12 production in tumor-bearing mice treated with various mycelial extracts (AHCC).

IL-12 is considered to be one of the most important cytokines in anti-cancer therapy. We have demonstrated that substances derived from Basidiomycetes, such as active hexose-correlated compound (AHCC) and PSK induce the production of IL-12. In this study, the MHC dependency of IL-12 production induced by various mycelial extracts, PSK, AHCC and IL-X, was examined.

During tumor-bearing, higher serum IL-12 levels were observed in H-2a and H-2b mice as compared to H-2d mice. Concerning the effect of genetic background of mice on response to mycelial extracts, AHCC administration enhanced the serum IL-12 level in H-2b mice but not in H-2d mice, while PSK administration increased the serum IL-12 level in H-2d mice but not in H-2b mice.

So we propose that the suitable combinations of various mycelial extracts may be effective methods of endogenous IL-12 induction for cancer patients of all stages, which is important as a cancer therapy that is relatively free from adverse reactions and which emphasizes the QOL in individual patients.

AHCC intake resulted in the increased number of DCs (dendritic cells) and function of DC1s, which have a role in specific immunity.

IL-12 is an interleukin that is naturally produced by dendritic cells, macrophages and human B-lymphoblastoid cells.

Macrophage/ Monocyte

IL-12

IL-10 IL-12 and IL-10 work to inhibit each other

IL-12 stimulates Th 1 development

IFN- γ release stimulates monocytes leading to further IL-12 release

IFN-γ

Immature T cell

Th 1 cell

PSK or polysaccharide K is a proteinbound polysaccharide, which is used as an anticancer immunologic adjuvant in some countries.

IL-12 (interleukin-12) is considered to be one of the most important cytokines in anti-cancer therapy. AHCC administration enhanced the serum IL-12 level in H-2b mice

Authors: Naoyoshi, T., Yoichi, M., Sohei, S., Hiroaki, Y., Kanji, T., Tomohisa, Y., Jun, Y., Soichiro, T., A-Hon, K., Yasuo, K. Osaka,

11

SUMMARY

SUMMARY

Japan

AHCC

Department of Surgery, Kansai Medical University.

Article: Nutrition and Cancer 2008, 60(5), 643–651 PMID: 18791928 [PubMed - indexed for MEDLINE]

Authors: Yagita, A., Maruyama, S., Wakasugi, S., Sukegawa, Y.

Osaka,

Japan

Institute of Immunotherapy for Cancer, Kinki University Hospital, 377-2, Ohnohigashi, Osakasayama-city, 5898511.

Article: In Vivo, 2002, Jan-Feb; 16 (1): 9-54.

PMID: 11980361 [PubMed - indexed for MEDLINE]

22|23

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2014-06-25 오전 8:39:40

AHCC

10

Immunological Effect of Active Hexose Correlated Compound (AHCC) in Healthy Volunteers: A DoubleBlind, Placebo-Controlled Trial.

The aim of this study was to evaluate the effects of active hexose correlated compound (AHCC) intake on immune responses by investigating the number and function of circulating dendritic cells (DCs) in healthy volunteers. Allogeneic mixed-leukocyte reaction (MLR) was performed. Natural killer (NK) cell activity and the proliferative response of T lymphocytes toward mitogen (phytohemagglutinin [PHA]) were measured. We also measured cytokine production stimulated by lipopolysaccharide [interleukin (IL)-2, IL-4, IL-6, IL-10, interferon gamma-gamma, tumor necrosis factor-alpha).

The number of DC1s in the AHCC group after intake was significantly higher than at baseline. DC2s in the AHCC group were significantly increased in comparison with controls. The MLR in the AHCC group was significantly increased compared to controls. No significant differences in PHA, NK cell activity, and cytokine production were found between groups. AHCC intake resulted in the increased number of DCs and function of DC1s, which have a role in specific immunity.

Dendritic cells are antigen-presenting cells of the mammalian immune system.

Allogeneic mixed-leukocyte reaction (MLR) – expression of the T-cell receptor gamma-chain gene products on the surface of peripheral T cells and T-cell blasts generated by this reaction.

T-lymphocytes represent a small subset of T cells that possess a distinct T cell receptor (TCR) on the surface.

Phytohemagglutinin (PHA) is a lectin found in plants, especially legumes.

Cytokines are a broad and loose category of small proteins that are important in cell signaling.

Interleukins are a group of cytokines that were fist seen to be expressed by white blood cells.

H-2 haplotype-dependent serum IL-12 production in tumor-bearing mice treated with various mycelial extracts (AHCC).

IL-12 is considered to be one of the most important cytokines in anti-cancer therapy. We have demonstrated that substances derived from Basidiomycetes, such as active hexose-correlated compound (AHCC) and PSK induce the production of IL-12. In this study, the MHC dependency of IL-12 production induced by various mycelial extracts, PSK, AHCC and IL-X, was examined.

During tumor-bearing, higher serum IL-12 levels were observed in H-2a and H-2b mice as compared to H-2d mice. Concerning the effect of genetic background of mice on response to mycelial extracts, AHCC administration enhanced the serum IL-12 level in H-2b mice but not in H-2d mice, while PSK administration increased the serum IL-12 level in H-2d mice but not in H-2b mice.

So we propose that the suitable combinations of various mycelial extracts may be effective methods of endogenous IL-12 induction for cancer patients of all stages, which is important as a cancer therapy that is relatively free from adverse reactions and which emphasizes the QOL in individual patients.

AHCC intake resulted in the increased number of DCs (dendritic cells) and function of DC1s, which have a role in specific immunity.

IL-12 is an interleukin that is naturally produced by dendritic cells, macrophages and human B-lymphoblastoid cells.

Macrophage/ Monocyte

IL-12

IL-10 IL-12 and IL-10 work to inhibit each other

IL-12 stimulates Th 1 development

IFN- γ release stimulates monocytes leading to further IL-12 release

IFN-γ

Immature T cell

Th 1 cell

PSK or polysaccharide K is a proteinbound polysaccharide, which is used as an anticancer immunologic adjuvant in some countries.

IL-12 (interleukin-12) is considered to be one of the most important cytokines in anti-cancer therapy. AHCC administration enhanced the serum IL-12 level in H-2b mice

Authors: Naoyoshi, T., Yoichi, M., Sohei, S., Hiroaki, Y., Kanji, T., Tomohisa, Y., Jun, Y., Soichiro, T., A-Hon, K., Yasuo, K. Osaka,

11

SUMMARY

SUMMARY

Japan

AHCC

Department of Surgery, Kansai Medical University.

Article: Nutrition and Cancer 2008, 60(5), 643–651 PMID: 18791928 [PubMed - indexed for MEDLINE]

Authors: Yagita, A., Maruyama, S., Wakasugi, S., Sukegawa, Y.

Osaka,

Japan

Institute of Immunotherapy for Cancer, Kinki University Hospital, 377-2, Ohnohigashi, Osakasayama-city, 5898511.

Article: In Vivo, 2002, Jan-Feb; 16 (1): 9-54.

PMID: 11980361 [PubMed - indexed for MEDLINE]

22|23

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2014-06-25 오전 8:39:40

FOR INTERNAL USE ONLY Disclaimer This catalog is watermarked because certain important information in this document has not been evaluated by the U.S. Food and Drug Administration. This catalog should only be used for internal purposes and it is intended to help the reader round out their understanding of some of the complexities and difficulties involved in the research of complex carbohydrates as is the case of polysaccharides. This catalog is designed for educational purposes only and does not render medical advice or professional services. The information provided should not be used for diagnosing or treating a health problem or disease. It is not a substitute for professional care. If you have -- or suspect you may have – a health problem, you should consult your health care provider. *These statements have not been evaluated by the Food and Drug Administration.

The information on this catalog is not intended to diagnose, treat, cure or prevent any disease.

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