JP4068538B2 - Cytokine release inhibitor - Google Patents
Cytokine release inhibitor Download PDFInfo
- Publication number
- JP4068538B2 JP4068538B2 JP2003321646A JP2003321646A JP4068538B2 JP 4068538 B2 JP4068538 B2 JP 4068538B2 JP 2003321646 A JP2003321646 A JP 2003321646A JP 2003321646 A JP2003321646 A JP 2003321646A JP 4068538 B2 JP4068538 B2 JP 4068538B2
- Authority
- JP
- Japan
- Prior art keywords
- chlorella
- cell wall
- ifn
- tnf
- cells
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000003112 inhibitor Substances 0.000 title claims description 24
- 102000004127 Cytokines Human genes 0.000 title description 25
- 108090000695 Cytokines Proteins 0.000 title description 25
- 241000195649 Chlorella <Chlorellales> Species 0.000 claims description 35
- 210000002421 cell wall Anatomy 0.000 claims description 28
- 108010074328 Interferon-gamma Proteins 0.000 claims description 24
- 102100037850 Interferon gamma Human genes 0.000 claims description 22
- 108010002350 Interleukin-2 Proteins 0.000 claims description 19
- 108090000978 Interleukin-4 Proteins 0.000 claims description 16
- 239000012634 fragment Substances 0.000 claims description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 24
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 24
- 102000004889 Interleukin-6 Human genes 0.000 description 23
- 108090001005 Interleukin-6 Proteins 0.000 description 23
- 102000000588 Interleukin-2 Human genes 0.000 description 18
- 102000004388 Interleukin-4 Human genes 0.000 description 15
- 230000002401 inhibitory effect Effects 0.000 description 14
- 239000000843 powder Substances 0.000 description 13
- 210000003719 b-lymphocyte Anatomy 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- -1 IL-1β Proteins 0.000 description 6
- 239000011324 bead Substances 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 6
- 244000249214 Chlorella pyrenoidosa Species 0.000 description 5
- 235000007091 Chlorella pyrenoidosa Nutrition 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 239000012190 activator Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- 206010012438 Dermatitis atopic Diseases 0.000 description 3
- 239000001856 Ethyl cellulose Substances 0.000 description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 201000009961 allergic asthma Diseases 0.000 description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 235000019325 ethyl cellulose Nutrition 0.000 description 3
- 229920001249 ethyl cellulose Polymers 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000002519 immonomodulatory effect Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229920006008 lipopolysaccharide Polymers 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 210000000822 natural killer cell Anatomy 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- 102000011767 Acute-Phase Proteins Human genes 0.000 description 2
- 108010062271 Acute-Phase Proteins Proteins 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 206010006895 Cachexia Diseases 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 101001002709 Homo sapiens Interleukin-4 Proteins 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003636 conditioned culture medium Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 102000055229 human IL4 Human genes 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 230000003832 immune regulation Effects 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000002433 mononuclear leukocyte Anatomy 0.000 description 2
- 210000002864 mononuclear phagocyte Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000003118 sandwich ELISA Methods 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- AICIYIDUYNFPRY-UHFFFAOYSA-N 1,3-dihydro-2H-imidazol-2-one Chemical class O=C1NC=CN1 AICIYIDUYNFPRY-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 206010048998 Acute phase reaction Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 241000832151 Chlorella regularis Species 0.000 description 1
- 240000009108 Chlorella vulgaris Species 0.000 description 1
- 235000007089 Chlorella vulgaris Nutrition 0.000 description 1
- 241000195628 Chlorophyta Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108010062580 Concanavalin A Proteins 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241001071795 Gentiana Species 0.000 description 1
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 1
- 244000303040 Glycyrrhiza glabra Species 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 1
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 208000019758 Hypergammaglobulinemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 208000007924 IgA Deficiency Diseases 0.000 description 1
- 208000011200 Kawasaki disease Diseases 0.000 description 1
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 1
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 1
- 102000043131 MHC class II family Human genes 0.000 description 1
- 108091054438 MHC class II family Proteins 0.000 description 1
- 101000686985 Mouse mammary tumor virus (strain C3H) Protein PR73 Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000195648 Pseudochlorella pringsheimii Species 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010039915 Selective IgA immunodeficiency Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 230000017274 T cell anergy Effects 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 208000005485 Thrombocytosis Diseases 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 231100000409 cytocidal Toxicity 0.000 description 1
- 230000000445 cytocidal effect Effects 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000000989 food dye Substances 0.000 description 1
- 208000024386 fungal infectious disease Diseases 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 210000002861 immature t-cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 201000007156 immunoglobulin alpha deficiency Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000017306 interleukin-6 production Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 229940010454 licorice Drugs 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 1
- 230000003525 myelopoietic effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 150000003022 phthalic acids Chemical class 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- 208000029138 selective IgA deficiency disease Diseases 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 231100000617 superantigen Toxicity 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
Landscapes
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines Containing Plant Substances (AREA)
Description
本発明は、ＩＬ−１β、ＩＬ−２、ＩＬ−４、ＩＬ−６、ＩＦＮ−γ及びＴＮＦ−α等のサイトカインを阻害するためのサイトカイン遊離阻害剤に関する。 The present invention relates to a cytokine release inhibitor for inhibiting cytokines such as IL-1β, IL-2, IL-4, IL-6, IFN-γ and TNF-α.
ＩＬ−１βはアデニール酸シクラーゼを活性化して、ｃＡＭＰレベルの上昇をもたらし、その結果、蛋白質キナーゼＡの活性化を誘発したり、あるいは細胞遺伝子転写活性化因子の役目を果たす核因子を誘発する。ＩＬ−１βは、プロスタグランジンを産生する酵素の合成を誘発する結果、発熱が生じる。低濃度では、ＩＬ−１βは主として免疫調整的に作用する。ＩＬ−１βはポリクローン活性因子と協同で作用し、ＣＤ４＋Ｔリンパ球増殖のみならず、Ｂリンパ球の成長と分化をも促進する。ＩＬ−１βは多数の細胞を刺激して、免疫または炎症反応エフェクター細胞として作用するとともに、単核食細胞や血管内皮によるＩＬ−６の合成以外に、自らの合成をも誘発する。ＩＬ−１βはその前炎症性特性の点で、腫瘍壊死因子 (TNF)と似ている。 IL-1β activates adenylate cyclase, leading to elevated cAMP levels, thereby inducing the activation of protein kinase A or a nuclear factor that acts as a cellular gene transcription activator. IL-1β induces the synthesis of an enzyme that produces prostaglandins, resulting in fever. At low concentrations, IL-1β acts primarily immunomodulating. IL-1β acts in concert with a polyclonal activator and promotes not only CD4 + T lymphocyte proliferation, but also B lymphocyte growth and differentiation. IL-1β stimulates many cells to act as an immune or inflammatory response effector cell and induces its own synthesis in addition to the synthesis of IL-6 by mononuclear phagocytes and vascular endothelium. IL-1β is similar to tumor necrosis factor (TNF) in its pro-inflammatory properties.
ＩＬ−２は、インターフェロンγやリンパトキシンを含むＴリンパ球によって産生されるその他のサイトカインの形成を促進する。ＩＬ−２合成が不適切な場合、抗原特異性Ｔリンパ球アネルギーにつながる可能性がある。ＩＬ−２によってＮＫ細胞の成長は促進され、リンフォカイン活性化キラー (LAK)細胞の産生を通して、ＮＫ細胞の細胞溶解作用は増強される。ＩＬ−２は、他のサイトカインに対する未成熟骨髄の反応性を促進する。胸腺では、ＩＬ−２は未成熟T細胞の成長を促進する可能性がある。また、ＩＬ−２は、免疫系因子の過剰産生又はそれらの因子に対する過剰反応により発症する自己免疫疾患の一因と考えられる。 IL-2 promotes the formation of other cytokines produced by T lymphocytes including interferon gamma and lymphotoxin. Inadequate IL-2 synthesis can lead to antigen-specific T lymphocyte anergy. IL-2 promotes the growth of NK cells and enhances the cytolytic effect of NK cells through the production of lymphokine-activated killer (LAK) cells. IL-2 promotes the response of immature bone marrow to other cytokines. In the thymus, IL-2 may promote the growth of immature T cells. In addition, IL-2 is considered to be a cause of autoimmune diseases that develop due to overproduction of immune system factors or excessive responses to those factors.
ＩＬ−４は、Ｂ細胞、マスト細胞、マクロファージの成長と分化に対して促進因子としての役割を果たし、マウスではＩｇＥ合成に対するスイッチ因子となる。そのほか、クローン化ＣＤ４＋Ｔ細胞の成長も促進し、ＭＨＣクラスII分子発現を増強し、Ｂリンパ球肥大を鎮静化する。ネズミとヒトのＩＬ−４はともに、Ｂリンパ球のスイッチングを誘発してＩｇＥを合成する。ヒトＩＬ−４はまた、ヒトにおいてＢリンパ球とマクロファージでのＣＤ２３発現も誘発する。ＩＬ−４は細胞仲介性免疫に何らかの役割を持つ可能性がある。 IL-4 serves as a promoter for the growth and differentiation of B cells, mast cells, and macrophages, and is a switch factor for IgE synthesis in mice. In addition, it also promotes the growth of cloned CD4 + T cells, enhances MHC class II molecule expression, and soothes B lymphocyte hypertrophy. Both murine and human IL-4 synthesize IgE by inducing B lymphocyte switching. Human IL-4 also induces CD23 expression on B lymphocytes and macrophages in humans. IL-4 may have some role in cell-mediated immunity.
ＩＬ−６は多くのタイプの細胞に作用すると考えられ、一つの重要な機能として、Ｂリンパ球に作用して、抗体を合成する細胞に分化させる能力を持つ。ＩＬ−６は肝細胞に作用して、フィブリノーゲンを含む急性相蛋白質形成を誘発する。Ｂ細胞分化の晩期における活性化Ｂリンパ球にとって、主たる成長因子となっている。ＩＬ−６はまた、Ｔリンパ球と胸腺細胞の同時刺激因子としての役割も持つ。さらに、初期の骨髄造血性幹細胞の成長を促進する他のサイトカインと共同作用する。ＩＬ−６は、急性相蛋白質の転写レベルをコントロールすることによって、急性相反応誘発分子としても作用する。ＩＬ−６は、ポリクローナルＢ細胞活性化による高ガンマグロブリン血症やＣＲＰ陽性等の発症に関与していると考えられる他、自己免疫様症状を呈する疾患にＩＬ−６の関与が報告されている。またＩＬ−６は、癌の領域において増殖因子として機能している他、敗血症、炎症、外科手術後の回復遅延、骨粗鬆症、Ｉ型糖尿病、アルツハイマー病、アミロイドーシス、高脂血症、血小板増多症、心筋梗塞、川崎病、乾癬、メサンギウム細胞増殖性腎症にも関与しているものと考えられている。 IL-6 is thought to act on many types of cells, and one important function is the ability to act on B lymphocytes and differentiate them into cells that synthesize antibodies. IL-6 acts on hepatocytes and induces acute phase protein formation including fibrinogen. It is a major growth factor for activated B lymphocytes in the late stages of B cell differentiation. IL-6 also has a role as a costimulatory factor for T lymphocytes and thymocytes. In addition, it synergizes with other cytokines that promote early myelopoietic stem cell growth. IL-6 also acts as an acute phase reaction-inducing molecule by controlling the transcription level of the acute phase protein. IL-6 is thought to be involved in the development of hypergammaglobulinemia and CRP positivity due to polyclonal B cell activation, and IL-6 has been reported to be involved in diseases exhibiting autoimmune-like symptoms. . IL-6 functions as a growth factor in the area of cancer, sepsis, inflammation, delayed recovery after surgery, osteoporosis, type I diabetes, Alzheimer's disease, amyloidosis, hyperlipidemia, thrombocytosis It is thought to be involved in myocardial infarction, Kawasaki disease, psoriasis, and mesangial proliferative nephropathy.
インターフェロン-γ (ＩＦＮ−γ) には、抗細胞増殖、抗ウイルス特性がある。ＩＦＮ−γは強力な単核食細胞活性因子であり、細胞内微生物や腫瘍細胞に対するそれら食細胞の破壊能力を高める。ＩＦＮ−γ によって多くのタイプの細胞でＭＨＣクラスII分子の発現が誘発され、I 型の発現も多くなる。ＩＦＮ−γ は、Ｂリンパ球とＴリンパ球両者の分化を促進する。ＩＦＮ−γはＮＫ細胞の強力な活性因子であり、好中球や血管内皮細胞をも活性化する。ＩＦＮ−γは、慢性リンパ球性白血病、リンパ腫、ＩｇＡ欠乏のほか、風疹、Epstein-Barrウイルス、サイトメガロウイルスなどに感染した患者では減少する。組替えＩＦＮ−γはこれまでに慢性リンパ球性白血病、粘膜真菌症、ホジキン病、その他様々な疾患の治療に使用されてきた。ＩＦＮ−γはまた、線維芽細胞によるコラーゲン合成に対する減少作用もあり、結合組織障害の治療への応用が期待される。 Interferon-γ (IFN-γ) has anti-cell proliferation and anti-viral properties. IFN-γ is a powerful mononuclear phagocyte activator and enhances the ability of these phagocytes to destroy intracellular microorganisms and tumor cells. IFN-γ induces expression of MHC class II molecules in many types of cells and increases type I expression. IFN-γ promotes the differentiation of both B and T lymphocytes. IFN-γ is a powerful activator of NK cells and activates neutrophils and vascular endothelial cells. IFN-γ is decreased in patients infected with chronic lymphocytic leukemia, lymphoma, IgA deficiency, rubella, Epstein-Barr virus, cytomegalovirus and the like. Recombinant IFN-γ has been used to treat chronic lymphocytic leukemia, mucosal mycosis, Hodgkin's disease and various other diseases. IFN-γ also has a reducing effect on collagen synthesis by fibroblasts and is expected to be applied to the treatment of connective tissue disorders.
ＴＮＦ−α (腫瘍壊死因子-a) は殺細胞性モノカインであり、細菌性エンドトキシンによって刺激されたマクロファージによって産生される。ＴＮＦ−αは炎症、外傷の治癒、組織の再形成に加わる。ＴＮＦ−αはカケクチンの名前でも知られており、敗血性ショックや悪液質を誘発することがある。ＴＮＦ−αは白血球補充を促進し、血管形成を誘発し、線維芽細胞の増殖を促進する。ＴＮＦ−αは特定の腫瘍細胞上の受容器と結合し、細胞融解をもたらす。ＴＮＦ−αは天然のネズミ殺細胞性 (ＮＣ) 細胞の抗腫瘍作用に関与しており、その作用はナチュラルキラー (ＮＫ)細胞や細胞障害性Ｔ細胞のそれとは機能的に異なる。ＴＮＦ−αがカケクチンとも呼ばれるのは、実験動物に長期投与すると、体力消耗と貧血を誘発することができるためである。 TNF-α (tumor necrosis factor-a) is a cytocidal monokine produced by macrophages stimulated by bacterial endotoxins. TNF-α participates in inflammation, trauma healing, and tissue remodeling. TNF-α is also known as cachectin and may induce septic shock and cachexia. TNF-α promotes leukocyte recruitment, induces angiogenesis, and promotes fibroblast proliferation. TNF-α binds to a receptor on certain tumor cells and results in cell lysis. TNF-α is involved in the antitumor action of natural murine cell killing (NC) cells, and its action is functionally different from that of natural killer (NK) cells and cytotoxic T cells. TNF-α is also called cachectin because it can induce physical exhaustion and anemia when administered to experimental animals for a long time.
以上のような反応は、生理学的過程を調整するのに必要である。しかしながら、そうしたサイトカイン（ＴＮＦ−α、ＩＦＮ−γ、ＩＬ−１β、ＩＬ−６、ＩＬ−２等）の濃度がスーパー抗原又は感染中に突然上昇すると、大規模な全身反応が生じ、それは別名"サイトカイン発作"とも呼ばれて、宿主の全身性ショックをもたらす。ＩＬ−４を過度に活性化すると、アレルギー性喘息やアトピー性皮膚炎につながることもある。いくつかのタイプの癌は、高レベルのＩＬ−６産生との関連性が指摘されている。さらに、炎症が動脈硬化につながることもあり、より多くのヒトでの病変と密接に相関しているものと考えられる。従って、前記のようなサイトカインの合成が抑制され又はそれらの活性が調整されることは、ＴＮＦ−α、ＩＦＮ−γ、ＩＬ−１β、ＩＬ−６についてはそれらの濃度増大による全身性ショック及び悪液質を防ぎ、ＩＬ−４についてはアレルギー性喘息やアトピー性皮膚炎を防ぎ、ＩＬ−６については癌及び動脈硬化を防ぐ効果をもたらすものと考えられる。また、これらのサイトカインは、低濃度で免疫調節作用を有していることから、それらの阻害により、免疫調節異常による各種疾患の予防・治療に有用と考えられる。 Such reactions are necessary to regulate physiological processes. However, when the concentration of such cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-2, etc.) suddenly rises during superantigen or infection, a massive systemic reaction occurs, also known as “ Also called “cytokine seizures”, it causes systemic shock in the host. Excessive activation of IL-4 may lead to allergic asthma and atopic dermatitis. Several types of cancer have been linked to high levels of IL-6 production. In addition, inflammation can lead to arteriosclerosis and is thought to correlate closely with more human lesions. Therefore, suppression of cytokine synthesis as described above or regulation of their activities means that systemic shock and adverse effects due to increased concentrations of TNF-α, IFN-γ, IL-1β, and IL-6. It is considered that liquid quality is prevented, IL-4 prevents allergic asthma and atopic dermatitis, and IL-6 has an effect of preventing cancer and arteriosclerosis. In addition, since these cytokines have an immunomodulatory action at low concentrations, their inhibition is considered to be useful for the prevention and treatment of various diseases caused by abnormal immune regulation.
サイトカイン阻害作用を有する化合物としては、特許文献１記載の置換イミダゾール化合物のほか、特許文献２記載の１，３−ジヒドロ−２ Ｈ−イミダゾール−２−オン誘導体、及び特許文献３記載のヒドロキシアルキルアンモニウム−ピリミジン等が知られているが、多様な局面で、サイトカインを阻害する上で、更なるＩＬ−１β、ＩＬ−２、ＩＬ−４、ＩＬ−６、ＩＦＮ−γ及びＴＮＦ−α等のサイトカインを阻害するサイトカイン遊離阻害剤に対する要望は強い。
本発明は、従来技術に存した上記のような課題に鑑み行われたものであって、その目的とするところは、ＩＬ−１β、ＩＬ−２、ＩＬ−４、ＩＬ−６、ＩＦＮ−γ及びＴＮＦ−α等のサイトカインを阻害する新規サイトカイン遊離阻害剤を提供することにある。 The present invention has been made in view of the above-mentioned problems existing in the prior art, and the object thereof is IL-1β, IL-2, IL-4, IL-6, IFN-γ. And a novel cytokine release inhibitor that inhibits cytokines such as TNF-α.
本発明者は、ＩＬ−１β、ＩＬ−２、ＩＬ−４、ＩＬ−６、ＩＦＮ−γ及びＴＮＦ−α等のサイトカインの遊離を阻害する上で有用な物質について研究を行った結果、本発明を完成したものである。 The present inventor conducted research on substances useful for inhibiting the release of cytokines such as IL-1β, IL-2, IL-4, IL-6, IFN-γ and TNF-α. Is completed.
すなわち、本発明のサイトカイン遊離阻害剤は、クロレラの細胞壁破砕物を含有してなるものである。また本発明は、細胞壁破砕クロレラを使用してサイトカインの遊離を阻害する方法を提供するものである。 That is, the cytokine release inhibitor of the present invention contains chlorella cell wall crushed material. The present invention also provides a method of inhibiting the release of cytokines using cell wall disrupted chlorella.
また本発明のＩＬ−１β遊離阻害剤は、クロレラの細胞壁破砕物を含有してなるものである。また本発明は、細胞壁破砕クロレラを使用してＩＬ−１βの遊離を阻害する方法を提供するものである。 In addition, the IL-1β release inhibitor of the present invention contains a chlorella cell wall crushed material. The present invention also provides a method for inhibiting the release of IL-1β using cell wall disrupted chlorella.
また本発明のＩＬ−２遊離阻害剤は、クロレラの細胞壁破砕物を含有してなるものである。また本発明は、細胞壁破砕クロレラを使用してＩＬ−２の遊離を阻害する方法を提供するものである。 Moreover, the IL-2 release inhibitor of the present invention comprises a chlorella cell wall crushed material. The present invention also provides a method of inhibiting IL-2 release using cell wall disrupted chlorella.
更に、本発明のＩＬ−４遊離阻害剤は、クロレラの細胞壁破砕物を含有してなるものである。また本発明は、細胞壁破砕クロレラを使用してＩＬ−４の遊離を阻害する方法を提供するものである。 Furthermore, the IL-4 release inhibitor of the present invention contains a chlorella cell wall crushed material. The present invention also provides a method of inhibiting IL-4 release using cell wall disrupted chlorella.
また本発明のＩＬ−６遊離阻害剤は、クロレラの細胞壁破砕物を含有してなるものである。また本発明は、細胞壁破砕クロレラを使用してＩＬ−６の遊離を阻害する方法を提供するものである。 Moreover, the IL-6 release inhibitor of the present invention comprises a chlorella cell wall crushed material. The present invention also provides a method of inhibiting IL-6 release using cell wall disrupted chlorella.
また更に本発明のＩＦＮ−γ遊離阻害剤は、クロレラの細胞壁破砕物を含有してなるものである。また本発明は、細胞壁破砕クロレラを使用してＩＦＮ−γの遊離を阻害する方法を提供するものである。 Furthermore, the IFN-γ release inhibitor of the present invention contains chlorella cell wall crushed material. The present invention also provides a method for inhibiting the release of IFN-γ using cell wall disrupted chlorella.
また本発明のＴＮＦ−α遊離阻害剤は、クロレラの細胞壁破砕物を含有してなるものである。また本発明は、細胞壁破砕クロレラを使用してＴＮＦ−αの遊離を阻害する方法を提供するものである。 The TNF-α release inhibitor of the present invention contains chlorella cell wall crushed material. The present invention also provides a method for inhibiting the release of TNF-α using a cell wall disrupted chlorella.
本発明のサイトカイン遊離阻害剤は、低濃度で免疫調節作用を果している各サイトカインの遊離を阻害するため、免疫調節異常による各種疾患の予防・治療に有用と考えられ、ＴＮＦ−α、ＩＦＮ−γ、ＩＬ−１β、ＩＬ−６、IL−２についてはそれらの濃度増大による全身性ショック及び悪液質を防ぎ、ＩＬ−４についてはアレルギー性喘息やアトピー性皮膚炎を防ぎ、ＩＬ−６については癌及び動脈硬化を防ぐ効果をもたらす。 Since the cytokine release inhibitor of the present invention inhibits the release of each cytokine that exerts immunomodulatory action at a low concentration, it is considered useful for the prevention and treatment of various diseases caused by abnormal immune regulation. TNF-α, IFN-γ , IL-1β, IL-6, IL-2 prevent systemic shock and cachexia due to their increased concentration, IL-4 prevents allergic asthma and atopic dermatitis, and IL-6 It has the effect of preventing cancer and arteriosclerosis.
本発明におけるクロレラとは、クロレラ属(Chlorella) に属する単細胞緑藻類であって、例えば、Chlorella pyrenoidosa、Chlorella ellipsoidea 、Chlorella vulgaris 、Chlorella regularis 等を挙げることができる。本発明に最も適しているのは、クロレラ・ピレノイドサ（Chlorella pyrenoidosa）である。 The chlorella in the present invention is a unicellular green algae belonging to the genus Chlorella, and examples thereof include Chlorella pyrenoidosa, Chlorella ellipsoidea, Chlorella vulgaris, and Chlorella regularis. Most suitable for the present invention is Chlorella pyrenoidosa.
本発明のサイトカイン遊離阻害剤（ＩＬ−１β遊離阻害剤、ＩＬ−２遊離阻害剤、ＩＬ−４遊離阻害剤、ＩＬ−６遊離阻害剤、ＩＦＮ−γ遊離阻害剤、及びＴＮＦ−α遊離阻害剤を含む。以下同じ。）におけるクロレラの細胞壁破砕物は、例えば次のようにして得ることができる。すなわち、先ずクロレラ濃度１０乃至２５重量％のクロレラ粉体・水懸濁液を１０℃以下に調整する。次にこの懸濁液を、下記のような連続湿式微粉砕機に送入し、破砕直後のスラリーが４０℃以下になるよう微粉砕する。次いで、このようにして得られたクロレラスラリーを、直ちに１０℃以下に冷却することにより、細胞壁が破砕されたクロレラを、品質劣化を生じさせることなく得ることができる。 Cytokine release inhibitor (IL-1β release inhibitor, IL-2 release inhibitor, IL-4 release inhibitor, IL-6 release inhibitor, IFN-γ release inhibitor, and TNF-α release inhibitor of the present invention For example, the chlorella cell wall fragment in the following can be obtained as follows. That is, first, a chlorella powder / water suspension having a chlorella concentration of 10 to 25% by weight is adjusted to 10 ° C. or lower. Next, this suspension is fed into a continuous wet pulverizer as described below, and pulverized so that the slurry immediately after crushing becomes 40 ° C. or lower. Subsequently, the chlorella slurry thus obtained is immediately cooled to 10 ° C. or lower, so that a chlorella having a crushed cell wall can be obtained without causing quality deterioration.
上記連続湿式微粉砕機は、冷却外套を持つ密閉シリンダー中に多数の直径０．５乃至１．５mmのグラスビーズが封入されたものである。そのグラスビーズ容量は密閉シリンダー容量の８０乃至８５％であり、グラスビーズを流入液体と混和・回転することにより、流入液体中の物質を摩砕するものである。 In the continuous wet pulverizer, a large number of glass beads having a diameter of 0.5 to 1.5 mm are enclosed in a closed cylinder having a cooling mantle. The capacity of the glass beads is 80 to 85% of the capacity of the sealed cylinder, and the glass beads are mixed and rotated with the inflowing liquid to grind the substance in the inflowing liquid.
このようにして細胞壁が破砕されたクロレラは、そのまま用いることもできるが、例えば、真空乾燥後粉砕を行う等の適宜の処理を施した後に使用してもよい。 The chlorella in which the cell wall is crushed in this way can be used as it is, but it may be used after an appropriate treatment such as pulverization after vacuum drying.
本発明のサイトカイン遊離阻害剤は、経口適用が望ましい。経口適用の形態に特に限定はないが、好ましくは、栄養食品、栄養補助食品、粉末、錠剤、硬カプセル剤、軟カプセル剤、又は飲料用液体の形態である。 The cytokine release inhibitor of the present invention is preferably applied orally. The form for oral application is not particularly limited, but is preferably a nutritional food, a dietary supplement, a powder, a tablet, a hard capsule, a soft capsule, or a beverage liquid.
また種々の形態を形成する上で、各種賦形剤、結合剤、崩壊剤、滑沢剤、コーティング剤、着色剤、矯味剤、矯臭剤、可塑剤等を適宜用いることができる。 In forming various forms, various excipients, binders, disintegrants, lubricants, coating agents, coloring agents, flavoring agents, flavoring agents, plasticizers, and the like can be appropriately used.
賦形剤の例としては、糖類（乳糖，白糖，ブドウ糖，マンニトール），デンプン（バレイショ，コムギ，トウモロコシ），無機物（炭酸カルシウム，硫酸カルシウム，炭酸水素ナトリウム，塩化ナトリウム），結晶セルロース，植物末（カンゾウ末，ゲンチアナ末）等を挙げることができる。 Examples of excipients include sugars (lactose, sucrose, glucose, mannitol), starch (potato, wheat, corn), inorganic substances (calcium carbonate, calcium sulfate, sodium bicarbonate, sodium chloride), crystalline cellulose, plant powder ( Licorice powder, gentian powder) and the like.
結合剤の例としては、デンプンのり液，アラビアゴム，ゼラチン，アルギン酸ナトリウム，メチ／レセルロース（ＭＣ），エチルセルロース（ＥＣ），ポリビニルピロリドン（ＰＶＰ），ポリビニルアルコール（ＰＶＡ），ヒドロキシプロピルセルロース（ＨＰＣ），カルポキシメチルセルロース（ＣＭＣ）等を挙げることができる。 Examples of binders include starch paste, gum arabic, gelatin, sodium alginate, meth / recellulose (MC), ethylcellulose (EC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC). , Carboxymethylcellulose (CMC) and the like.
崩壊剤の例としては、デンプン，寒天，ゼラチン末，結晶セルロース，ＣＭＣ・Ｎａ，ＣＭＣ・Ｃａ，炭酸カルシウム，炭酸水素ナトリウム，アルギン酸ナトリウム等を挙げることができる。 Examples of the disintegrant include starch, agar, gelatin powder, crystalline cellulose, CMC / Na, CMC / Ca, calcium carbonate, sodium hydrogen carbonate, sodium alginate and the like.
滑沢剤の例としては、ステアリン酸マグネシウム，タルク，水素添加植物油，マクロゴール，シリコーン油等を挙げることができる。 Examples of lubricants include magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil and the like.
コーティング剤の例としては、糖衣（白糖，ＨＰＣ，セラック），膠衣（ゼラチン，グリセリン，ソルビトール），フイルムコーティング〔ヒドロキシプロピルメチルセルロース（ＨＰＭＣ），ＥＣ，ＨＰＣ，ＰＶＰ〕，腸溶性コーティング〔ヒドロキシプロビルメチルセルロースフタレート（ＨＰＭＣＰ），セルロースアセテートフタレート（ＣＡＰ）〕等を挙げることができる。 Examples of coating agents include sugar coating (sucrose, HPC, shellac), glue (gelatin, glycerin, sorbitol), film coating [hydroxypropyl methylcellulose (HPMC), EC, HPC, PVP], enteric coating [hydroxyprovir Methyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP)] and the like.
着色剤の例としては、水溶性食用色素，レーキ色素）等を挙げることができる。矯味剤の例としては、乳糖，白糖，ブドウ糖，マンニトール）等を挙げることができる。矯臭剤の例としては、芳香性精油類），光線遮断剤（酸化チタン）等を挙げることができる。可塑剤の例としては、フタル酸エステル類，植物油，ポリエチレングリコール）等を挙げることができる。 Examples of the colorant include water-soluble food dyes and lake dyes. Examples of the corrigent include lactose, sucrose, glucose, mannitol) and the like. Examples of flavoring agents include aromatic essential oils) and light blocking agents (titanium oxide). Examples of the plasticizer include phthalic acid esters, vegetable oils, polyethylene glycol) and the like.
クロレラ・ピレノイドサ（Chlorella pyrenoidosa）乾燥粉末の製造
冷却外套を持つ密閉シリンダー中にその密閉シリンダー容量の８０乃至８５％の容量の多数の直径０．５乃至１．５mmのグラスビーズが封入されており、そのグラスビーズを流入液体と混和・回転することにより流入液体中の物質を摩砕する連続湿式微粉砕機（商品名：ダイノーミル［KD型］ WAB, Inc.製）に、１０℃以下に調整されたクロレラ・ピレノイドサ濃度１０乃至２５重量％のクロレラ・ピレノイドサ粉体・水懸濁液を送入して、破砕直後のスラリーが４０℃以下になるよう微粉砕し、次いで、このようにして得られたクロレラ・ピレノイドサスラリーを、直ちに１０℃以下に冷却し、真空乾燥後、粉砕することにより、細胞壁破砕クロレラ・ピレノイドサ乾燥粉末（株式会社サン・クロレラ製の細胞壁破砕クロレラ粉末）が得られた。
Production of Chlorella pyrenoidosa dry powder In a closed cylinder with a cooling mantle, a large number of glass beads having a diameter of 80 to 85% of the closed cylinder capacity and having a diameter of 0.5 to 1.5 mm are encapsulated. The glass beads are adjusted to 10 ° C or lower by a continuous wet pulverizer (trade name: DYNOMILL [KD type] manufactured by WAB, Inc.) that mixes and rotates the glass beads with the influent liquid to grind the substances in the inflow liquid. The chlorella pyrenoidosa powder / water suspension having a concentration of 10 to 25% by weight was fed and finely pulverized so that the slurry immediately after crushing was 40 ° C. or less, and then obtained in this way. The chlorella / pyrenoid suspension was immediately cooled to 10 ° C. or lower, dried in vacuum, and then pulverized to obtain a cell wall-crushed chlorella / pyrenoid suspension (powdered) Sun Chlorella made of cell wall disruption chlorella powder) was obtained.
ヒト末梢血液単核細胞内のＩＬ−１β、ＩＬ−６、ＴＮＦ−α放出阻害の測定
細胞壁破砕クロレラ・ピレノイドサ乾燥粉末および／または溶媒を、２５ｎｇ／ｍｌ（ナノグラム／ミリリットル）のリポ多糖 (LPS)-刺激ヒト末梢血単核白血球（リポ多糖：Ｓｉｇｍａ［米国］から入手。ヒト末梢血単核細胞[PBML]：中国血液サービス財団［台湾］から入手。）と共に、培地ｐＨ７．４内で、３７℃にて一夜インキュベートした。
Measurement of IL-1β, IL-6, TNF-α release inhibition in human peripheral blood mononuclear cells Cell wall disrupted chlorella pyrenoids dry powder and / or solvent, 25 ng / ml (nanogram / milliliter) lipopolysaccharide (LPS) -Stimulated human peripheral blood mononuclear leukocytes (Lipopolysaccharide: obtained from Sigma [USA]. Human peripheral blood mononuclear cells [PBML]: obtained from China Blood Service Foundation [Taiwan]), 37 in medium pH 7.4 Incubate overnight at ° C.
その後、サンドイッチＥＬＩＳＡキット（Ｒ＆Ｄ Ｓｙｓｔｅｍｓ［米国］から入手）を用いて、コンディションドメディウム内のサイトカインレベルを定量したところ、細胞壁破砕クロレラ・ピレノイドサ（乾燥粉末）による５０％阻害濃度は、ＩＬ−１βが４４．９μｇ／ｍｌ（マイクログラム／ミリリットル）、ＩＬ−６が３４．７μｇ／ｍｌ、ＴＮＦ−αが１１μｇ／ｍｌであった。すなわち、細胞壁破砕クロレラ・ピレノイドサはＩＬ−１β、ＩＬ−６、及びＴＮＦ−αの阻害作用を有していた。 Then, when the cytokine level in the conditioned medium was quantified using a sandwich ELISA kit (obtained from R & D Systems [USA]), the 50% inhibitory concentration by cell wall disrupted chlorella pyrenoids (dry powder) It was 44.9 μg / ml (microgram / milliliter), IL-6 was 34.7 μg / ml, and TNF-α was 11 μg / ml. That is, cell wall disrupted chlorella pyrenoids had an inhibitory action on IL-1β, IL-6, and TNF-α.
ヒト末梢血液単核細胞内のＩＦＮ−γ、ＩＬ−２、ＩＬ−４放出阻害の測定
細胞壁破砕クロレラ・ピレノイドサ乾燥粉末および／または溶媒を、２０ｎｇ／ｍｌのコンカバナリンＡ(Concanavalin A)-刺激ヒト末梢血単核白血球（コンカバナリンＡ：Ｓｉｇｍａ［米国］から入手。ヒト末梢血単核細胞[PBML]：中国血液サービス財団［台湾］から入手）と共に、培地ｐＨ７．４内で、３７℃にて一夜インキュベートした。
Measurement of IFN-γ, IL-2, IL-4 release inhibition in human peripheral blood mononuclear cells Cell wall disrupted chlorella pyrenoids dry powder and / or solvent, 20 ng / ml Concanavalin A-stimulated human peripheral Incubate overnight at 37 ° C. in medium pH 7.4 with blood mononuclear leukocytes (concavanaline A: obtained from Sigma [USA]. Human peripheral blood mononuclear cells [PBML]: obtained from China Blood Service Foundation [Taiwan]) did.
その後、サンドイッチＥＬＩＳＡキット（Ｒ＆Ｄ Ｓｙｓｔｅｍｓ［米国］から入手）を用いて、コンディションドメディウム内のサイトカインレベルを定量したところ、細胞壁破砕クロレラ・ピレノイドサ（乾燥粉末）による５０％阻害濃度は、ＩＦＮ−γが３１．６μｇ／ｍｌ、ＩＬ−２が１４．８μｇ／ｍｌ、ＩＬ−４が４９．２μｇ／ｍｌであった。すなわち、細胞壁破砕クロレラ・ピレノイドサはＩＦＮ−γ、ＩＬ−２、及びＩＬ−４の阻害作用を有していた。 Then, when the cytokine level in the conditioned medium was quantified using a sandwich ELISA kit (obtained from R & D Systems [USA]), the 50% inhibitory concentration by cell wall disrupted chlorella pyrenoids (dry powder) was determined by IFN-γ. It was 31.6 μg / ml, IL-2 was 14.8 μg / ml, and IL-4 was 49.2 μg / ml. That is, the cell wall disrupted chlorella pyrenoidosa had an inhibitory action on IFN-γ, IL-2, and IL-4.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003321646A JP4068538B2 (en) | 2003-09-12 | 2003-09-12 | Cytokine release inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003321646A JP4068538B2 (en) | 2003-09-12 | 2003-09-12 | Cytokine release inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2005089325A JP2005089325A (en) | 2005-04-07 |
| JP4068538B2 true JP4068538B2 (en) | 2008-03-26 |
Family
ID=34453271
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2003321646A Expired - Lifetime JP4068538B2 (en) | 2003-09-12 | 2003-09-12 | Cytokine release inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4068538B2 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003232872A1 (en) | 2002-05-27 | 2003-12-12 | Ostergotlands Lans Landsting | Method for determining immune system affecting compounds |
| SE0402536D0 (en) | 2004-10-20 | 2004-10-20 | Therim Diagnostica Ab | Immunoregulation in cancer, chronic inflammatory and autoimmune diseases |
| WO2006110091A1 (en) * | 2005-04-15 | 2006-10-19 | Therim Diagnostica Ab | Diagnostic method for detecting cancer by measuring amount of a cytokine like il-6 |
| JP5175479B2 (en) * | 2007-03-23 | 2013-04-03 | 株式会社サン・クロレラ | Cyclooxygenase-2 inhibitor |
| ES2747363T3 (en) | 2007-05-08 | 2020-03-10 | Canimguide Therapeutics Ab | Normally found protein immunoregulatory structures |
| JP5877773B2 (en) * | 2011-11-09 | 2016-03-08 | 株式会社サン・クロレラ | Sympathetic nerve inhibitor |
| SG11201403567TA (en) * | 2012-01-11 | 2014-09-26 | Sun Chlorella Corp | Use of cell wall disrupted product of chlorella for reducing serum resistin level |
| JP2013014618A (en) * | 2012-10-05 | 2013-01-24 | Sun Chlorella Corp | Gaba pentine receptor binding inhibitor |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6444654B1 (en) * | 1997-01-21 | 2002-09-03 | Board Of Regents Of University Of Nebraska | Isolated asgal lipopolysaccharides and use of same to inhibit innate immune response |
| JPH1160484A (en) * | 1997-08-25 | 1999-03-02 | Akira Kanematsu | Tnf production inhibitor |
| JP3295779B2 (en) * | 2000-04-05 | 2002-06-24 | 株式会社日健総本社 | Anticancer substance |
| JPWO2002074298A1 (en) * | 2001-03-21 | 2004-07-08 | 小野薬品工業株式会社 | IL-6 production inhibitor |
-
2003
- 2003-09-12 JP JP2003321646A patent/JP4068538B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2005089325A (en) | 2005-04-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4068538B2 (en) | Cytokine release inhibitor | |
| WO2009128523A1 (en) | Immunostimulating agent | |
| Ganeshpurkar et al. | In silico interaction of hesperidin with some immunomodulatory targets: A docking analysis | |
| Quintiliani et al. | Relationship of blood transfusion, post-operative infections and immunoreactivity in patients undergoing surgery for gastrointestinal cancer | |
| CA2637590C (en) | Treatment of inflammatory disorders with triazole compounds | |
| US20020128317A1 (en) | Treatment of pathological conditions characterized by an increased IL-1 level | |
| KR20120032530A (en) | New crystalline form of pemirolast | |
| JP4380951B2 (en) | Garlic fermentation composition | |
| KR20130078147A (en) | Pharmaceutical composition comprising 4,5-diaryl-3(2h)-furanone derivative having a constant grain size | |
| TWI435727B (en) | Use of modulating secretion of cytokines | |
| JP4018610B2 (en) | Tyrosine phosphatase inhibitor | |
| EP1419777A1 (en) | Use of glycyrrhizin and its derivatives as MCP-1 production inhibitors | |
| JP4068539B2 (en) | B / T cell growth inhibitor | |
| JP2005089321A (en) | Phorbol ester receptor bonding inhibitor | |
| JP2005089324A (en) | Caspase inhibitor | |
| KR0185226B1 (en) | Rejection inhibitor for transplant and il-1 production inhibitor | |
| JP4018611B2 (en) | Matrix metalloproteinase inhibitor | |
| WO2020234833A1 (en) | Method for treating, preventing, inhibiting or reducing cytokine release | |
| AU757489B2 (en) | Method for inhibiting cytokine production by cells | |
| JP2006232751A (en) | Endothelial cell damage inhibitor and its use | |
| JPWO2013105617A1 (en) | Use of chlorella cell wall debris to lower serum resistin levels | |
| CN113329732B (en) | Composition containing thymus vulgaris extract fermented by lactic acid bacteria as effective component for improving atopic dermatitis and skin wrinkle | |
| JP6820246B2 (en) | Manufacturing method of immunostimulatory agent and manufacturing method of food and drink for immune activation | |
| TWI659749B (en) | Composition for Anti-Senescence | |
| KR20220074559A (en) | Anti-inflammatory active composition containing Lutonarine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20070703 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20070812 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20080108 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20080110 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110118 Year of fee payment: 3 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 4068538 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20240118 Year of fee payment: 16 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| EXPY | Cancellation because of completion of term |