KR102060227B1 - Pharmaceutical composition for preventing or treating colonic disease comprising caffeic acid phenethyl ester or pharmaceutically acceptable salts thereof as an active ingredient - Google Patents
Pharmaceutical composition for preventing or treating colonic disease comprising caffeic acid phenethyl ester or pharmaceutically acceptable salts thereof as an active ingredient Download PDFInfo
- Publication number
- KR102060227B1 KR102060227B1 KR1020170151787A KR20170151787A KR102060227B1 KR 102060227 B1 KR102060227 B1 KR 102060227B1 KR 1020170151787 A KR1020170151787 A KR 1020170151787A KR 20170151787 A KR20170151787 A KR 20170151787A KR 102060227 B1 KR102060227 B1 KR 102060227B1
- Authority
- KR
- South Korea
- Prior art keywords
- etbf
- pharmaceutically acceptable
- polyp
- caffeic acid
- phenethyl ester
- Prior art date
Links
- SWUARLUWKZWEBQ-VQHVLOKHSA-N phenethyl caffeate Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-VQHVLOKHSA-N 0.000 title claims abstract description 136
- WWVKQTNONPWVEL-UHFFFAOYSA-N caffeic acid phenethyl ester Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCC1=CC=CC=C1 WWVKQTNONPWVEL-UHFFFAOYSA-N 0.000 title claims abstract description 135
- SWUARLUWKZWEBQ-UHFFFAOYSA-N phenylethyl ester of caffeic acid Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-UHFFFAOYSA-N 0.000 title claims abstract description 135
- 150000003839 salts Chemical class 0.000 title claims abstract description 57
- 239000004480 active ingredient Substances 0.000 title claims abstract description 18
- 208000019399 Colonic disease Diseases 0.000 title claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 239000003540 gamma secretase inhibitor Substances 0.000 claims abstract description 35
- 229940125373 Gamma-Secretase Inhibitor Drugs 0.000 claims abstract description 34
- 230000000694 effects Effects 0.000 claims abstract description 34
- 201000010099 disease Diseases 0.000 claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 208000015181 infectious disease Diseases 0.000 claims abstract description 19
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 claims abstract description 16
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 206010009887 colitis Diseases 0.000 claims abstract description 12
- 230000000688 enterotoxigenic effect Effects 0.000 claims abstract description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 49
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 35
- 208000037062 Polyps Diseases 0.000 claims description 33
- 241000894006 Bacteria Species 0.000 claims description 14
- 206010020718 hyperplasia Diseases 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 241000606124 Bacteroides fragilis Species 0.000 claims description 8
- 230000036541 health Effects 0.000 claims description 8
- 230000000968 intestinal effect Effects 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 208000004804 Adenomatous Polyps Diseases 0.000 claims description 7
- 230000003211 malignant effect Effects 0.000 claims description 7
- 208000002458 carcinoid tumor Diseases 0.000 claims description 6
- 235000013376 functional food Nutrition 0.000 claims description 6
- 230000002757 inflammatory effect Effects 0.000 claims description 6
- 210000004877 mucosa Anatomy 0.000 claims description 6
- 206010024612 Lipoma Diseases 0.000 claims description 5
- 208000017819 hyperplastic polyp Diseases 0.000 claims description 5
- 208000004232 Enteritis Diseases 0.000 claims description 4
- 208000003243 intestinal obstruction Diseases 0.000 claims description 4
- 208000015768 polyposis Diseases 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 241000588921 Enterobacteriaceae Species 0.000 claims 6
- 208000035473 Communicable disease Diseases 0.000 claims 2
- 241000194033 Enterococcus Species 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 1
- 230000000069 prophylactic effect Effects 0.000 claims 1
- 208000014081 polyp of colon Diseases 0.000 abstract description 40
- 208000035143 Bacterial infection Diseases 0.000 abstract description 11
- 206010061218 Inflammation Diseases 0.000 abstract description 11
- 208000022362 bacterial infectious disease Diseases 0.000 abstract description 11
- 230000004054 inflammatory process Effects 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 241000606125 Bacteroides Species 0.000 abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 75
- 210000004027 cell Anatomy 0.000 description 71
- 108010007503 Bacteroides fragilis toxin Proteins 0.000 description 30
- 238000002360 preparation method Methods 0.000 description 28
- 102000000905 Cadherin Human genes 0.000 description 27
- 108050007957 Cadherin Proteins 0.000 description 27
- 239000002609 medium Substances 0.000 description 22
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 21
- 241000699670 Mus sp. Species 0.000 description 20
- 208000029742 colonic neoplasm Diseases 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 102000003945 NF-kappa B Human genes 0.000 description 11
- 108010057466 NF-kappa B Proteins 0.000 description 11
- 241000241413 Propolis Species 0.000 description 10
- 210000001072 colon Anatomy 0.000 description 10
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 10
- 239000002953 phosphate buffered saline Substances 0.000 description 10
- 229940069949 propolis Drugs 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WHBMMWSBFZVSSR-GSVOUGTGSA-N (R)-3-hydroxybutyric acid Chemical compound C[C@@H](O)CC(O)=O WHBMMWSBFZVSSR-GSVOUGTGSA-N 0.000 description 9
- 208000035984 Colonic Polyps Diseases 0.000 description 9
- 206010051589 Large intestine polyp Diseases 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- -1 dioates Chemical class 0.000 description 9
- 239000012634 fragment Substances 0.000 description 9
- 230000037361 pathway Effects 0.000 description 9
- 101001055222 Homo sapiens Interleukin-8 Proteins 0.000 description 8
- 102100026236 Interleukin-8 Human genes 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 230000015556 catabolic process Effects 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 235000013305 food Nutrition 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- DGAKHGXRMXWHBX-ONEGZZNKSA-N Azoxymethane Chemical compound C\N=[N+](/C)[O-] DGAKHGXRMXWHBX-ONEGZZNKSA-N 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 238000012790 confirmation Methods 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 235000013365 dairy product Nutrition 0.000 description 5
- 238000013467 fragmentation Methods 0.000 description 5
- 238000006062 fragmentation reaction Methods 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229960005322 streptomycin Drugs 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 4
- 235000013361 beverage Nutrition 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 150000001720 carbohydrates Chemical class 0.000 description 4
- 235000014633 carbohydrates Nutrition 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 235000015203 fruit juice Nutrition 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000004017 serum-free culture medium Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 235000014347 soups Nutrition 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 239000003053 toxin Substances 0.000 description 4
- 231100000765 toxin Toxicity 0.000 description 4
- 108700012359 toxins Proteins 0.000 description 4
- RDEIXVOBVLKYNT-VQBXQJRRSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(1-aminoethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]o Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)C(C)N)N)[C@@H](N)C[C@H]1N.O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-VQBXQJRRSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 244000299461 Theobroma cacao Species 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 235000014121 butter Nutrition 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 229960002227 clindamycin Drugs 0.000 description 3
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 235000013882 gravy Nutrition 0.000 description 3
- 235000013402 health food Nutrition 0.000 description 3
- 210000000936 intestine Anatomy 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 235000012149 noodles Nutrition 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000011218 segmentation Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 description 2
- 208000007416 Aberrant Crypt Foci Diseases 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241000423333 Bacteroides fragilis NCTC 9343 Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 206010007275 Carcinoid tumour Diseases 0.000 description 2
- 241001107116 Castanospermum australe Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 208000034801 Enterobacteriaceae Infections Diseases 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 108010010803 Gelatin Proteins 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
- 240000005979 Hordeum vulgare Species 0.000 description 2
- 235000007340 Hordeum vulgare Nutrition 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 235000004347 Perilla Nutrition 0.000 description 2
- 244000124853 Perilla frutescens Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229940121773 Secretase inhibitor Drugs 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 235000021279 black bean Nutrition 0.000 description 2
- 235000007215 black sesame Nutrition 0.000 description 2
- 235000008429 bread Nutrition 0.000 description 2
- 235000021329 brown rice Nutrition 0.000 description 2
- 235000004883 caffeic acid Nutrition 0.000 description 2
- 229940074360 caffeic acid Drugs 0.000 description 2
- QAIPRVGONGVQAS-DUXPYHPUSA-N caffeic acid Natural products OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 description 2
- 235000012970 cakes Nutrition 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 235000014171 carbonated beverage Nutrition 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000019219 chocolate Nutrition 0.000 description 2
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 210000004922 colonic epithelial cell Anatomy 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 210000004921 distal colon Anatomy 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229940025294 hemin Drugs 0.000 description 2
- BTIJJDXEELBZFS-QDUVMHSLSA-K hemin Chemical compound CC1=C(CCC(O)=O)C(C=C2C(CCC(O)=O)=C(C)\C(N2[Fe](Cl)N23)=C\4)=N\C1=C/C2=C(C)C(C=C)=C3\C=C/1C(C)=C(C=C)C/4=N\1 BTIJJDXEELBZFS-QDUVMHSLSA-K 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 235000015243 ice cream Nutrition 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940041476 lactose 100 mg Drugs 0.000 description 2
- 210000002429 large intestine Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- 235000015192 vegetable juice Nutrition 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- AMOYMEBHYUTMKJ-UHFFFAOYSA-N 2-(2-phenylethoxy)ethylbenzene Chemical compound C=1C=CC=CC=1CCOCCC1=CC=CC=C1 AMOYMEBHYUTMKJ-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical compound OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 235000019737 Animal fat Nutrition 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 101150090693 BFT gene Proteins 0.000 description 1
- 241001135228 Bacteroides ovatus Species 0.000 description 1
- 241000606123 Bacteroides thetaiotaomicron Species 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 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
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 240000001879 Digitalis lutea Species 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 239000001512 FEMA 4601 Substances 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 108090000717 Fragilysin Proteins 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 240000008397 Ganoderma lucidum Species 0.000 description 1
- 235000001637 Ganoderma lucidum Nutrition 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 239000004378 Glycyrrhizin Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 241001071861 Lethrinus genivittatus Species 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 238000001190 Q-PCR Methods 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- HELXLJCILKEWJH-SEAGSNCFSA-N Rebaudioside A Natural products O=C(O[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)[C@@]1(C)[C@@H]2[C@](C)([C@H]3[C@@]4(CC(=C)[C@@](O[C@H]5[C@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)[C@H](O)[C@@H](CO)O5)(C4)CC3)CC2)CCC1 HELXLJCILKEWJH-SEAGSNCFSA-N 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- 102000013814 Wnt Human genes 0.000 description 1
- 108050003627 Wnt Proteins 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- YTIVTFGABIZHHX-UHFFFAOYSA-L acetylenedicarboxylate(2-) Chemical compound [O-]C(=O)C#CC([O-])=O YTIVTFGABIZHHX-UHFFFAOYSA-L 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 210000002867 adherens junction Anatomy 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 235000013334 alcoholic beverage Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000015197 apple juice Nutrition 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- 235000015895 biscuits Nutrition 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 235000010633 broth Nutrition 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000002045 capillary electrochromatography Methods 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 235000015190 carrot juice Nutrition 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 208000015636 celiac disease-epilepsy-cerebral calcification syndrome Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000004715 cellular signal transduction Effects 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 230000008951 colonic inflammation Effects 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 235000014510 cooky Nutrition 0.000 description 1
- 235000012495 crackers Nutrition 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- HELXLJCILKEWJH-UHFFFAOYSA-N entered according to Sigma 01432 Natural products C1CC2C3(C)CCCC(C)(C(=O)OC4C(C(O)C(O)C(CO)O4)O)C3CCC2(C2)CC(=C)C21OC(C1OC2C(C(O)C(O)C(CO)O2)O)OC(CO)C(O)C1OC1OC(CO)C(O)C(O)C1O HELXLJCILKEWJH-UHFFFAOYSA-N 0.000 description 1
- 239000000147 enterotoxin Substances 0.000 description 1
- 231100000655 enterotoxin Toxicity 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 235000012041 food component Nutrition 0.000 description 1
- 239000005417 food ingredient Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 235000020510 functional beverage Nutrition 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 235000019674 grape juice Nutrition 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 235000021098 high calorie intake Nutrition 0.000 description 1
- 238000010842 high-capacity cDNA reverse transcription kit Methods 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000005027 intestinal barrier Anatomy 0.000 description 1
- 230000007358 intestinal barrier function Effects 0.000 description 1
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N lauric acid triglyceride Natural products CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000003468 luciferase reporter gene assay Methods 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 235000013622 meat product Nutrition 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical class O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 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
- 235000013550 pizza Nutrition 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 208000022131 polyp of large intestine Diseases 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 235000019203 rebaudioside A Nutrition 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 235000015193 tomato juice Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 239000000225 tumor suppressor protein Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/32—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the digestive tract
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Mycology (AREA)
- Medicinal Chemistry (AREA)
- Nutrition Science (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
본 발명은 카페인산 페네틸 에스테르(caffeic acid phenethyl ester) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 대장성 질환 예방 또는 치료용 약학적 조성물에 관한 것으로, 보다 구체적으로 카페인산 페네틸 에스테르가 감마-세크레타제 활성을 저해하는 감마-세크레타제 저해제(gamma-secretase inhibitor)로 작용하여, ETBF(Enterotoxigenic Bacteroides fragilis) 세균 감염에 의한 염증을 완화하고, ETBF 세균 감염에 의해 유발되는 대장염 및 대장 용종 형성을 억제하는 것을 확인하였으므로, 상기 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용가능한 염은 ETBF 감염증에 의해 유발된 대장성 질환 예방 또는 치료용 조성물의 유효성분으로 이용할 수 있다.The present invention relates to a pharmaceutical composition for preventing or treating colorectal diseases containing caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof as an active ingredient, and more specifically, caffeic acid phenethyl ester Acts as a gamma-secretase inhibitor that inhibits gamma-secretase activity, resulting in Enterotoxigenic Bacteroides (ETBF). fragilis ) has been shown to relieve inflammation caused by bacterial infections and to inhibit colitis and colon polyp formation caused by ETBF bacterial infections, so the caffeic acid phenethyl ester or its pharmaceutically acceptable salts is caused by ETBF infection It can be used as an active ingredient of the composition for preventing or treating colon disease.
Description
본 발명은 카페인산 페네틸 에스테르(caffeic acid phenethyl ester) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는, 대장성 질환 예방 또는 치료용 약학적 조성물에 관한 것이다.
The present invention relates to a pharmaceutical composition for preventing or treating colorectal diseases, containing caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof as an active ingredient.
인간의 장내 상재균(intestinal bacteria)은 사람의 장관 내에 생후부터 형성된 세균총에 속하는 균주를 말하는 것으로, 균속으로는 박테로이데스, 유박테륨, 혐기성렌서균, 대장균, 유산간균 등이 있다. Human intestinal bacteria (intestinal bacteria) refers to a strain belonging to the bacterial flora formed after birth in the human intestine, the bacteria include bacteroides, yubacterium, anaerobic lancer bacteria, E. coli, lactic acid bacteria.
특히, 박테로이데스 균속은 무산소성 그람음성 막대균으로서 탄수화물을 분해하고, 담즙에 내성이 있으며 주로 장에서 분리된다. 20종 이상의 균종이 있으며, 이 중에서 B. fragilis, B. thetaiotaomicron 및 B. ovatus는 사람에서 주로 감염을 일으킨다. B. fragilis 중에는 장독(Bacteroides fragilis toxin, BFT)를 생성하는 세균(enterotoxigenic Bacteroides fragilis, ETBF)이 있으며, 이들은 설사질환 환자의 변에서 처음 분리되었다. ETBF는 염증성 대장질환(inflammatory bowel disease, IBD) 환자의 변에서 정상인보다 더 높은 빈도로 검출됨이 보고된 바 있다. 세포 수준에서, ETBF에 의해 생성된 BFT는 대장암 세포주에 존재하는 E-cadherin을 분절을 유도하여 33 kDa 및 28 kDa의 E-cadherin 절편이 생성되도록 한다. BFT는 20 kDa의 아연 의존성 메탈로프로테아제(metalloprotease) 독소로서 대장 상피 세포 (colonic epithelial cells, CEC)에 결합하고, 종양 억제 단백질인 E-cadherin의 절단화(cleavage)를 촉진하는 것으로 알려져 있다. E-cadherin 절단화는 장내 장벽 투과성을 증가시키고 대장암에서 지속적으로 활성화되는 β-catenin/Wnt 경로를 통한 세포 신호 전달을 증가시키므로, 결과적으로 BFT가 인간 대장암 세포의 증식과 이동을 자극한다. 또한, 최근 연구를 통해 BFT가 CEC에서 전염증성 사이토카인 분비를 유도하는 NF-κB 경로를 추가로 활성화시키고, NF-κB 경로에 의해 상피 종양 형성의 개시 및 촉진이 야기되는 것이 알려지면서, ETBF가 대장염, 대장 용종, 대장암 등을 유발하는 세균임이 입증되었다. 그러나, 아직까지 ETBF 감염에 의해 유발되는 대장성 질환 치료를 위한 분자생물학적 기전, 조직병리학 및 치료제 관련 연구는 부족한 실정이다.
In particular, Bacteroides is an anoxic Gram-negative rod that breaks down carbohydrates, is resistant to bile and is primarily isolated from the intestine. There are more than 20 species of fungi, of which B. fragilis , B. thetaiotaomicron and B. ovatus mainly cause infection in humans. B. fragilis bacteria while generating the enterotoxins (Bacteroides fragilis toxin, BFT) ( enterotoxigenic Bacteroides fragilis , ETBF), which were first isolated from the stools of patients with diarrhea. ETBF has been reported to be detected at a higher frequency than normal in stool in patients with inflammatory bowel disease (IBD). At the cellular level, the BFT produced by ETBF induces fragmentation of E-cadherin present in colorectal cancer cell lines, resulting in the production of 33 kDa and 28 kDa E-cadherin fragments. BFT is a 20 kDa zinc dependent metalloprotease toxin that binds to colonic epithelial cells (CEC) and is known to promote cleavage of the tumor suppressor protein E-cadherin. E-cadherin cleavage increases intestinal barrier permeability and increases cellular signal transduction through the β-catenin / Wnt pathway, which is continuously activated in colorectal cancer, and consequently BFT stimulates the proliferation and migration of human colorectal cancer cells. In addition, recent studies have shown that BFT further activates the NF-κB pathway, which induces proinflammatory cytokine secretion in CECs, and that the NF-κB pathway causes the initiation and promotion of epithelial tumor formation. It has proven to be a bacterium that causes colitis, colon polyps, and colon cancer. However, studies on molecular biological mechanisms, histopathology and therapeutic agents for treating colorectal diseases caused by ETBF infections are still insufficient.
한편, 대장 용종(Colonic polyp)은 대장 점막이 비정상적으로 자라 사마귀 모양의 혹으로 보이는 조직이 되어 장의 안쪽으로 돌출되어 있는 상태로서, 흔히 암으로 발전할 가능성이 있는 종양성 용종과 암으로 발전할 가능성이 없는 비종양성 용종으로 나뉜다. 종양성 용종에는 선종성 용종, 유암종, 악성용종 등이 있고, 대부분이 대장암과 아무 관련이 없는 비종양성 용종에는 과형성 용종, 용종양 점막, 과오종, 염증성 용종, 지방종 등이 있다.On the other hand, colonic polyp is a condition in which the colonic mucosa grows abnormally and becomes a wart-shaped nodule and protrudes into the intestine, which can often develop into cancerous polyps and cancers that may develop into cancer. It is divided into non-tumor polyps. Tumorous polyps include adenomatous polyps, carcinoid tumors, and malignant polyps. Most of the non-tumor polyps that have nothing to do with colorectal cancer include hyperplastic polyps, polyps of mucosa, hyperplasia, inflammatory polyps, and lipomas.
그 중 선종성 용종은 시간이 지나면 암으로 진행할 가능성이 높아 반드시 제거해야 한다. 선종성 용종의 위험한 정도는 그 크기와 현미경적 조직 소견에 따라 차이가 있는데 크기가 1 cm 이상이거나, 현미경 소견에서 융모형태의 세포를 많이 포함하는 경우, 세포가 덜 분화된 경우는 진행성 선종이라 부르고, 암으로 발전할 가능성이 매우 높다.Among them, adenomatous polyps are more likely to develop cancer over time and must be removed. The degree of risk of adenomatous polyps varies according to their size and microscopic findings. If the size is greater than 1 cm or if the microscopic findings include a large number of villoidal cells, less differentiated cells are called advanced adenoma. It is very likely to develop cancer.
유암종은 주로 직장에서 발견되며 크기가 커지면 다른 장기로 전이될 수 있어 악성종양으로 분류된다. 이러한 용종의 경우 제거하지 않으면 결국 악성으로 변할 수 있고, 결장과 직장의 벽을 뚫고 다른 곳으로 전이될 수 있다.Carcinoid tumors are mainly found in the rectum and are classified as malignant because they can spread to other organs as they grow in size. If not removed, these polyps can eventually become malignant and penetrate the walls of the colon and rectum and spread elsewhere.
이와 같이 대부분의 대장암은 이미 존재하고 있던 대장 안의 조직인 용종(Polyp)에서 발생된다고 할 수 있어, 대장 용종과 매우 밀접한 관련이 있다. 일반적으로 결장암과 직장암을 통틀어 대장암(Colorectal cancer, CRC)이라고 일컫는데, 대장암은 전 세계적으로 가장 흔한 암들 중 하나이면서 악성종양에 의한 주요 사망원인 4위에 해당하는 암이다. 대장암은 높은 열량의 섭취, 동물성 지방 섭취, 섬유소 섭취 부족, 비만 등이 원인이 되어 발생하는 것으로 알려져 있다.
As described above, most colon cancers are caused by polyps, which are tissues in the colon, which are already present, and are closely related to colon polyps. Colon cancer and colorectal cancer are commonly referred to as colorectal cancer (CRC), which is one of the most common cancers in the world and ranks fourth in cancer, the leading cause of death from malignant tumors. Colorectal cancer is known to be caused by high calorie intake, animal fat intake, lack of fiber, and obesity.
이에, 본 발명자들은 ETBF에 감염에 의해 유발되는 대장성 질환 치료제를 개발하기 위해 노력한 결과, 카페인산 페네틸 에스테르(caffeic acid phenethyl ester) 농도가 40 ~ 80 μM일 경우에 감마-세크레타제 활성을 저해하는 감마-세크레타제 저해제(gamma-secretase inhibitor)로 작용하여, ETBF 세균 감염에 의한 염증을 완화하고, ETBF 세균 감염에 의해 유발되는 대장염 및 대장 용종 형성을 억제하는 것을 확인하여, 상기 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용가능한 염을 ETBF 감염증에 의해 유발된 대장성 질환 예방 또는 치료용 조성물의 유효성분으로 이용할 수 있음을 밝힘으로써, 본 발명을 완성하였다.
Therefore, the present inventors have tried to develop a therapeutic agent for colorectal diseases caused by infection with ETBF, and as a result, when the concentration of caffeic acid phenethyl ester is 40 to 80 μM, gamma-secretase activity is reduced. It acts as an inhibitory gamma-secretase inhibitor to mitigate inflammation caused by ETBF bacterial infection and to inhibit colitis and colon polyp formation caused by ETBF bacterial infection. The present invention has been completed by revealing that phenethyl ester or a pharmaceutically acceptable salt thereof can be used as an active ingredient for preventing or treating colorectal diseases caused by ETBF infection.
본 발명의 목적은 카페인산 페네틸 에스테르(caffeic acid phenethyl ester) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, 대장성 질환 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for preventing or treating colorectal disease, which contains caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 다른 목적은 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, 대장성 질환 예방 또는 개선용 건강기능식품을 제공하는 것이다.
Another object of the present invention is to provide a functional food for preventing or improving colon disease, containing caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 카페인산 페네틸 에스테르(caffeic acid phenethyl ester) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, 대장성 질환 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating colorectal diseases, containing caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, 대장성 질환 예방 또는 개선용 건강기능식품을 제공한다.
In addition, the present invention provides a functional food for preventing or improving colorectal disease, containing caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명은 카페인산 페네틸 에스테르(caffeic acid phenethyl ester)가 감마-세크레타제 활성을 저해하는 감마-세크레타제 저해제(gamma-secretase inhibitor)로 작용하여, ETBF(Enterotoxigenic Bacteroides fragilis) 세균 감염에 의한 염증을 완화하고, ETBF 세균 감염에 의해 유발되는 대장염 및 대장 용종 형성을 억제하는 것을 확인하였으므로, 상기 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용가능한 염은 ETBF 감염증에 의해 유발된 대장성 질환 예방 또는 치료용 조성물의 유효성분으로 이용할 수 있다.
In the present invention, caffeic acid phenethyl ester acts as a gamma-secretase inhibitor that inhibits gamma-secretase activity, thereby causing ETBF (Enterotoxigenic Bacteroides fragilis ) bacterial infection. Since it has been shown to alleviate inflammation and inhibit colitis and colon polyp formation caused by ETBF bacterial infection, the caffeic acid phenethyl ester or its pharmaceutically acceptable salts can be used to prevent or prevent colonic disease caused by ETBF infection. It can be used as an active ingredient of the therapeutic composition.
도 1은 HCT116 대장암 세포주에 CAPE 또는 DMSO, 및 recom ET 또는 recom NT를 동시에 1시간 동안 처리한 후 E-cadherin의 분절 양상을 확인한 도이다:
1: CAPE (80 μM) + recom ET (1:10);
2: DMSO + recom ET (1:10);
3: CAPE (80 μM) + recom NT (1:10);
4: DMSO + recom NT (1:10);
5: DMSO + BHIB (1:10); 및
6: DMSO + FBS가 포함되지 않은 DMEM 배지(serum free media).
도 2는 HCT116 대장암 세포주에 CAPE, DMSO 또는 감마-세크레타제 저해제(gamma-secretase inhibitor), 및 recom ET를 동시에 30분 또는 1시간 동안 처리한 후 E-cadherin의 분절 양상을 확인한 도이다:
7: CAPE (80 μM) + recom ET (1:10), 30분 처리;
8: DMSO + recom ET (1:10), 30분 처리;
9: 감마-세크레타제 저해제 (1.5 μM) + recom ET (1:10), 30분 처리;
10: CAPE (80 μM) + recom ET (1:10), 1시간 처리;
11: DMSO + recom ET (1:10), 1시간 처리;
12: 감마-세크레타제 저해제 (1.5 μM) + recom ET (1:10), 1시간 처리;
13: CAPE (80 μM) + recom ET (1:10), 1시간 처리;
14: 감마-세크레타제 저해제 (1.5 μM) + FBS가 포함되지 않은 DMEM 배지, 1시간 처리; 및
15: DMSO + FBS가 포함되지 않은 DMEM 배지, 1시간 처리.
도 3은 HT29/C1 대장암 세포주에 CAPE, DMSO 또는 감마-세크레타제 저해제, 및 recom ET를 동시에 30분 또는 1시간 동안 처리한 후 E-cadherin의 분절 양상을 확인한 도이다:
12: CAPE (80 μM) + recom ET (1:10), 30분 처리;
13: DMSO + recom ET (1:10), 30분 처리;
14: 감마-세크레타제 저해제 (1.5 μM) + recom ET (1:10), 30분 처리;
15: CAPE (80 μM) + recom ET (1:10), 1시간 처리;
16: DMSO + recom ET (1:10), 1시간 처리;
17: 감마-세크레타제 저해제 (1.5 μM) + recom ET (1:10), 1시간 처리;
18: DMSO + FBS가 포함되지 않은 DMEM 배지, 1시간 처리
19: CAPE (80 μM) + FBS가 포함되지 않은 DMEM 배지, 1시간 처리; 및
20: 감마-세크레타제 저해제 (1.5 μM) + FBS가 포함되지 않은 DMEM 배지, 1시간 처리.
도 4는 HT29/C1 대장암 세포주에 5 μM, 10 μM, 20 μM, 40 μM 또는 5 ㎕의 CAPE, 80 μM의 DMSO 또는 1.5 μM의 감마-세크레타제 저해제, 및 recom ET를 동시에 2시간 동안 처리한 후 E-cadherin의 분절 양상을 확인한 도이다:
13: CAPE (80 μM) + recom ET (1:10);
14: CAPE (40 μM) + recom ET (1:10);
15: CAPE (20 μM) + recom ET (1:10);
16: CAPE (10 μM) + recom ET (1:10);
17: CAPE (5 μM) + recom ET (1:10);
18: DMSO + recom ET (1:10);
19: DMSO + FBS가 포함되지 않은 DMEM 배지;
20: 감마-세크레타제 저해제 (1.5 μM) + recom ET (1:10); 및
21: 감마-세크레타제 저해제 (1.5 μM) + FBS가 포함되지 않은 DMEM 배지.
도 5a 및 도 5b는 HCT116 대장암 세포주에 CAPE 0.4 μM, 0.8 μM, 2.5 μM, 5 μM, 10 μM, 20 μM, 40 μM 또는 80 μM, 및 recom ET을 동시에 처리하거나(도 5a), recom NT, WT-NT, BHIB 또는 FBS가 포함되지 않은 DMEM 배지를 처리하고(도 5b) 1시간 후 NF-κB 프로모터 활성을 확인한 도이다.
도 6은 HCT116 대장암 세포주에 CAPE 10 μM, 20 μM, 40 μM 또는 80 μM, 및 recom ET을 동시에 처리, 또는 5 ㎕의 DMSO 또는 1.5 μM의 감마-세크레타제 저해제, 및 recom ET를 동시에 처리, 또는 recom NT, WT-NT, BHIB 또는 FBS가 포함되지 않은 DMEM 배지를 처리하고 3시간 후 CXCL8의 발현을 확인한 도이다.
도 7은 ETBF에 의해 유발된 대장 용종 마우스 그룹(ETBF/CAC), ETBF에 의해 유발된 대장 용종 마우스에 CAPE를 투여한 그룹(CAPE+ETBF/CAC) 및 ETBF에 의해 유발된 대장 용종 마우스에 프로폴리스 추출액을 투여한 그룹(Propolis+ETBF/CAC)의 대장 내 용종의 수 및 크기를 확인한 도이다.
도 8은 정상 마우스 그룹(Sham), ETBF에 의해 유발된 대장 용종 마우스 그룹(ETBF-CAC), ETBF에 의해 유발된 대장 용종 마우스에 CAPE를 투여한 그룹(ETBF-CAC+CAPE) 및 ETBF에 의해 유발된 대장 용종 마우스에 프로폴리스 추출액을 투여한 그룹(ETBF-CAC+PRP)의 막창자(cecu) 조직의 병변 부위를 관찰하고, 염증 정도 및 세포의 과형성(Hyperplasia) 정도를 그래프화한 도이다.
도 9a 및 도 9b는 정상 마우스 그룹(Sham), ETBF에 의해 유발된 대장 용종 마우스 그룹(ETBF-CAC), ETBF에 의해 유발된 대장 용종 마우스에 CAPE를 투여한 그룹(ETBF-CAC+CAPE) 및 ETBF에 의해 유발된 대장 용종 마우스에 프로폴리스 추출액을 투여한 그룹(ETBF-CAC+PRP)의 원위부 대장(distal colon) 조직의 병변 부위를 관찰하고(도 9a), 염증 정도, 세포의 과형성 정도 및 대장 용종과 관련된 지표(Aberrant crypt foci, Microadenoma, Macroadenoma)를 그래프화(도 9b)한 도이다.1 is a diagram showing the fragmentation pattern of E-cadherin after treatment for 1 hour simultaneously with CAPE or DMSO, and recom ET or recom NT in HCT116 colorectal cancer cell line:
1: CAPE (80 μΜ) + recom ET (1:10);
2: DMSO + recom ET (1:10);
3: CAPE (80 μΜ) + recom NT (1:10);
4: DMSO + recom NT (1:10);
5: DMSO + BHIB (1:10); And
6: DMEM medium without DMSO + FBS (serum free media).
Figure 2 is a diagram showing the segmentation of E-cadherin after treatment with CAPE, DMSO or gamma-secretase inhibitor, and recom ET simultaneously for 30 minutes or 1 hour in HCT116 colorectal cancer cell line:
7: CAPE (80 μΜ) + recom ET (1:10), 30 min treatment;
8: DMSO + recom ET (1:10), 30 min treatment;
9: gamma-secretase inhibitor (1.5 μM) + recom ET (1:10), 30 min treatment;
10: CAPE (80 μΜ) + recom ET (1:10), 1 hour treatment;
11: DMSO + recom ET (1:10), 1 hour treatment;
12: gamma-secretase inhibitor (1.5 μM) + recom ET (1:10), 1 hour treatment;
13: CAPE (80 μΜ) + recom ET (1:10), 1 hour treatment;
14: DMEM medium without gamma-secretase inhibitor (1.5 μM) + FBS, 1 hour treatment; And
15: DMEM medium without DMSO + FBS, 1 hour treatment.
Figure 3 is a diagram confirming the segmentation of E-cadherin after treatment with CAPE, DMSO or gamma-secretase inhibitor, and recom ET simultaneously for 30 minutes or 1 hour in HT29 / C1 colorectal cancer cell line:
12: CAPE (80 μΜ) + recom ET (1:10), 30 min treatment;
13: DMSO + recom ET (1:10), 30 min treatment;
14: gamma-secretase inhibitor (1.5 μM) + recom ET (1:10), 30 min treatment;
15: CAPE (80 μΜ) + recom ET (1:10), 1 hour treatment;
16: DMSO + recom ET (1:10), 1 hour treatment;
17: gamma-secretase inhibitor (1.5 μM) + recom ET (1:10), 1 hour treatment;
18: DMEM medium without DMSO + FBS, 1 hour treatment
19: DMEM medium without CAPE (80 μΜ) + FBS, 1 hour treatment; And
20: DMEM medium without gamma-secretase inhibitor (1.5 μM) + FBS, 1 hour treatment.
FIG. 4 simultaneously shows 5 μM, 10 μM, 20 μM, 40 μM or 5 μL CAPE, 80 μM DMSO or 1.5 μM gamma-secretase inhibitor, and recom ET in HT29 / C1 colorectal cancer cell lines simultaneously. Figure shows the segmentation of E-cadherin after treatment:
13: CAPE (80 μΜ) + recom ET (1:10);
14: CAPE (40 μΜ) + recom ET (1:10);
15: CAPE (20 μΜ) + recom ET (1:10);
16: CAPE (10 μM) + recom ET (1:10);
17: CAPE (5 μΜ) + recom ET (1:10);
18: DMSO + recom ET (1:10);
19: DMEM medium without DMSO + FBS;
20: gamma-secretase inhibitor (1.5 μM) + recom ET (1:10); And
21: DMEM medium without gamma-secretase inhibitor (1.5 μM) + FBS.
5A and 5B simultaneously treat CAPE 0.4 μM, 0.8 μM, 2.5 μM, 5 μM, 10 μM, 20 μM, 40 μM or 80 μM, and recom ET in HCT116 colorectal cancer cell lines (FIG. 5A), or recom NT After treatment with DMEM medium containing no WT-NT, BHIB or FBS (FIG. 5B), NF-κB promoter activity was confirmed after 1 hour.
FIG. 6 simultaneously treated
7 shows a group of colon polyp mice induced by ETBF (ETBF / CAC), a group administered CAPE to colonic polyp mice induced by ETBF (CAPE + ETBF / CAC), and a colon polyp mouse induced by ETBF. Figure showing the number and size of polyps in the colon of the group (Propolis + ETBF / CAC) administered the polis extract.
FIG. 8 shows the normal mouse group (Sham), colon polyp mouse group (ETBF-CAC) induced by ETBF, colonic polyp mice induced by ETBF and CAPE administration group (ETBF-CAC + CAPE) and ETBF. The lesion area of the cecu tissue of the group (ETBF-CAC + PRP) administered propolis extract to the induced colon polyp mice was observed, and the degree of inflammation and the degree of hyperplasia of the cells were graphed.
9A and 9B show normal mouse group (Sham), colon polyp mouse group (ETBF-CAC) induced by ETBF, group CAPE administered to colon polyp mice induced by ETBF (ETBF-CAC + CAPE) and Observing the lesion site of the distal colon tissue of the group (ETBF-CAC + PRP) to which ETBF-induced colon polyp mice were administered propolis extract (ETBF-CAC + PRP) (FIG. 9A), the degree of inflammation, the degree of hyperplasia of the cells and It is a graph graphing the indicators related to colon polyps (Aberrant crypt foci, Microadenoma, Macroadenoma) (Fig. 9b).
이하, 본 발명을 보다 상세히 설명한다.
Hereinafter, the present invention will be described in more detail.
본 발명은 카페인산 페네틸 에스테르(caffeic acid phenethyl ester) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, 대장성 질환 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating colorectal diseases, containing caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에서 카페인산 페네틸 에스테르는 당업계에 공지된 추출 및 분리 방법을 사용하여 벌집, 벌꿀 또는 프로폴리스(Propolis)로부터 추출 및 분리하여 수득하거나, 화학적 합성으로 합성한 것 모두 무방하게 사용될 수 있다.Caffeic acid phenethyl ester in the present invention can be obtained by extraction and separation from honeycomb, honey or Propolis using extraction and separation methods known in the art, or can be used in any way synthesized by chemical synthesis. .
또한, 상기 카페인산 페네틸 에스테르는 하기 [화학식 1]로 기재되는 화합물인 것이 바람직하나, 이에 한정되지 않으며, 카페인산 페네틸 에스테르 유도체도 본 발명에 포함된다.In addition, the caffeic acid phenethyl ester is preferably a compound described by the following [Formula 1], but is not limited thereto, and caffeic acid phenethyl ester derivative is also included in the present invention.
[화학식 1][Formula 1]
본 발명에서, 상기 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용 가능한 염은 20 ~ 80 μM로 함유하는 것이 바람직하고, 40 ~ 80 μM로 함유하는 것이 보다 바람직하며, 감마-세크레타제 저해제(gamma-secretase inhibitor)로서, 감마-세크레타제(gamma-secretase) 활성을 억제하는 것이 바람직하다. 또한, 상기 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용 가능한 염을 20 μM 미만 또는 80 μM 초과하여 함유할 경우 카페인산 페네틸 에스테르가 감마-세크레타제 저해제로서 작용하지 못하여 치료 효과가 미비할 수 있다.In the present invention, the caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof is preferably contained at 20 to 80 μM, more preferably at 40 to 80 μM, and a gamma-secretase inhibitor (gamma As a secretase inhibitor, it is desirable to inhibit gamma-secretase activity. In addition, when the caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof is contained in less than 20 μM or more than 80 μM, the caffeic acid phenethyl ester may not function as a gamma-secretase inhibitor and thus may have insufficient therapeutic effect. have.
본 발명에서, 상기 대장성 질환은 예를 들어 장내 상재균 감염증, 선종성 용종, 유암종, 악성용종, 과형성 용종, 용종증, 용종양 점막, 과오종, 염증성 용종, 지방종, 대장암, 대장염, 결핵성 장염 또는 장폐색일 수 있고, 상기 장내 상재균 감염증은 엔테로톡시제닉 박테로이데스 프라길리스(Enterotoxigenic Bacteroides fragilis, ETBF) 세균 감염증일 수 있으나, 이에 한정되지 않는다.In the present invention, the colon disease is, for example, enterobacterial infection, adenomatous polyp, carcinoid tumor, malignant polyp, hyperplastic polyp, polyposis, polyp mucosa, hyperplasia, inflammatory polyp, lipoma, colon cancer, colitis, tuberculosis enteritis or It may be intestinal obstruction, the enterobacterial bacterial infection may be, but is not limited to, Enterotoxigenic Bacteroides fragilis (ETBF) bacterial infection.
또한, 상기 대장성 질환은 장내 상재균에 의해 유발되는 것일 수 있고, 보다 구체적으로 ETBF 세균에 의해 유발되는 것일 수 있으나, 이에 한정되지 않는다.
In addition, the colon disease may be caused by intestinal flora, and more specifically, may be caused by ETBF bacteria, but is not limited thereto.
본 발명의 구체적인 실시예에서, 본 발명자들은 대장암 세포주에 ETBF가 분비하는 활성 BFT(Bacteroides fragilis toxin)와 카페인산 페네틸 에스테르를 동시에 처리한 결과, 카페인산 페네틸 에스테르가 감마-세크레타제 저해제로 작용하여 33 kDa의 E-cadherin 절편을 생성함으로써, ETBF에 의하여 세포 내에 분포하는 E-cadherin이 분절되어 분해되는 것을 억제하는 것을 확인하였고, 특히 40 ~ 80 μM 농도에서 카페인산 페네틸 에스테르이 감마-세크레타제 저해제로 작용함을 확인하였다(도 1 내지 도 4 참조).In a specific embodiment of the present invention, the inventors have found that the active BFT ( Bacteroides) secreted by ETBF in colorectal cancer cell lines. Fragilis toxin) and caffeic acid phenethyl esters simultaneously treated caffeic acid phenethyl esters as gamma-secretase inhibitors to produce 33 kDa of E-cadherin fragments, resulting in E- It was confirmed that the cadherin is inhibited from fragmentation and degradation, and in particular, the caffeic acid phenethyl ester acts as a gamma-secretase inhibitor at a concentration of 40 to 80 μM (see FIGS. 1 to 4).
또한, 본 발명자들은 대장암 세포주에 BFT와 카페인산 페네틸 에스테르를 동시에 처리한 결과, 카페인산 페네틸 에스테르가 ETBF에 의하여 E-cadherin의 분해되고 NF-κB 경로가 활성화 되는 것을 억제하는 것을 확인하였고, 특히 40 ~ 80 μM 농도에서 NF-κB 경로의 활성 억제 효과가 우수함을 확인하였다(도 5a 및 도 5b 참조).In addition, the present inventors have simultaneously treated BFT and caffeic acid phenethyl ester in colorectal cancer cell lines, and confirmed that caffeic acid phenethyl ester inhibits the degradation of E-cadherin and activation of the NF-κB pathway by ETBF. In particular, it was confirmed that the effect of inhibiting the activity of the NF-κB pathway is excellent at a concentration of 40 ~ 80 μM (see Fig. 5a and 5b).
또한, 본 발명자들은 대장암 세포주에 BFT와 카페인산 페네틸 에스테르를 동시에 처리한 결과, 카페인산 페네틸 에스테르가 BFT에 의하여 E-cadherin이 분해되고 염증 반응과 관련된 CXCL8의 발현이 증가되는 것을 억제하는 것을 확인하였고, 특히 40 ~ 80 μM 농도에서 CXCL8의 발현 억제 효과가 우수함을 확인하였다(도 6 참조).In addition, the present inventors treated the colon cancer cell line with BFT and caffeic acid phenethyl ester at the same time, and the caffeic acid phenethyl ester inhibited the degradation of E-cadherin by BFT and increased expression of CXCL8 associated with the inflammatory response. It was confirmed that the effect of suppressing the expression of CXCL8 was particularly excellent at a concentration of 40-80 μM (see FIG. 6).
아울러, 본 발명자들은 ETBF 감염증에 의해 유발된 대장성 질환에 있어서 카페인산 페네틸 에스테르가 미치는 영향을 알아보기 위하여, ETBF에 의해 유발된 대장 용종 마우스에 카페인산 페네틸 에스테르를 투여한 결과, ETBF 감염으로 증가된 대장 내 염증, 세포 과형성(hyperplasia) 및 대장 용종이 카페인산 페네틸 에스테르에 의해 감소하는 것을 확인하였다(도 7, 도 8, 및 도 9a 및 도 9b 참조).In addition, the present inventors, in order to determine the effect of caffeic acid phenethyl ester in the colorectal disease caused by ETBF infection, ETBF infection as a result of administering caffeic acid phenethyl ester to the colon polyp mice induced by ETBF Increased intestinal inflammation, cell hyperplasia and colon polyps were reduced by caffeic acid phenethyl ester (see FIGS. 7, 8, and 9A and 9B).
따라서, 본 발명의 카페인산 페네틸 에스테르 농도가 40 ~ 80 μM일 경우에 감마-세크레타제 활성을 저해하는 감마-세크레타제 저해제로 작용하여, ETBF 세균 감염에 의한 염증을 완화하고, ETBF 세균 감염에 의해 유발되는 대장염 및 대장 용종 형성을 억제하는 것을 확인하였으므로, 상기 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용가능한 염을 ETBF 감염증에 의해 유발된 대장성 질환 예방 또는 치료용 조성물의 유효성분으로 이용할 수 있다.
Therefore, when the caffeic acid phenethyl ester concentration of the present invention is 40 ~ 80 μM acts as a gamma-secretase inhibitor that inhibits gamma-secretase activity, thereby relieving inflammation caused by ETBF bacterial infection, ETBF bacteria Since it has been confirmed to inhibit colitis and colon polyp formation caused by infection, the caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof may be used as an active ingredient of a composition for preventing or treating colorectal diseases caused by ETBF infection. It is available.
본 발명은 [화학식 1]로 표시되는 카페인산 페네틸 에스테르뿐만 아니라, 이의 약학적으로 허용되는 염, 이로부터 제조될 수 있는 가능한 용매화물, 수화물, 라세미체, 또는 입체이성질체를 모두 포함한다.The present invention includes not only the caffeic acid phenethyl ester represented by [Formula 1], but also pharmaceutically acceptable salts thereof, and possible solvates, hydrates, racemates, or stereoisomers which can be prepared therefrom.
본 발명의 [화학식 1]로 표시되는 카페인산 페네틸 에스테르는 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, 하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.
The caffeic acid phenethyl ester represented by [Formula 1] of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Do. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, Xylene Sulfonate, Phenyl Acetate, Phenylpropionate, Phenyl Butyrate, Citrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate , Naphthalene-2-sulfonate or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, [화학식 1]로 표시되는 카페인산 페네틸 에스테르를 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한, 이 혼합물에서 용매나 과량의 산을 증발시켜서 건조하거나 또는 석출 된 염을 흡입 여과시켜 제조할 수도 있다.
The acid addition salt according to the present invention is dissolved in a conventional method, for example, the caffeic acid phenethyl ester represented by [Formula 1] in an excess of an aqueous acid solution, and the salt is a water miscible organic solvent such as methanol, It can be prepared by precipitation with ethanol, acetone or acetonitrile. The mixture may also be prepared by evaporation of a solvent or excess acid to evaporate or by precipitation filtration of the precipitated salt.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻는다.
Bases can also be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
상기 조성물을 제제화할 경우, 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다.When formulating the composition, it is prepared using commonly used diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants.
경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 화학식 1로 표시되는 카페인산 페네틸 에스테르에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose) 또는 락토오스(lactose) 또는 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, and such solid preparations include at least one excipient example in the at least one caffeic acid phenethyl ester represented by
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.
As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
본 발명에 따른 조성물은 약제학적으로 유효한 양으로 투여한다. 본 발명에 있어서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The composition according to the invention is administered in a pharmaceutically effective amount. In the present invention, “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level means the type, severity, and activity of the patient's disease. , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of the drug, and other factors well known in the medical arts. The compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with a minimum amount without side effects, which can be readily determined by one skilled in the art.
구체적으로, 본 발명에 따른 화합물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 1 kg 당 0.001 mg 내지 100 mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.
Specifically, the effective amount of the compound according to the present invention may vary depending on the age, sex, and weight of the patient, and generally, 0.001 mg to 100 mg per kg of body weight is administered daily or every other day or divided into 1 to 3 times a day. can do. However, since the dose may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.
또한, 본 발명은 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, 대장성 질환 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention provides a functional food for preventing or improving colorectal disease, containing caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에서, 상기 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용 가능한 염은 0.1 ~ 80 μM로 함유하는 것이 바람직하고, 20 ~ 80 μM로 함유하는 것이 보다 바람직하며, 40 ~ 80 μM로 함유하는 것이 보다 더 바람직하고, 감마-세크레타제 저해제로서, 감마-세크레타제 활성을 억제하는 것이 바람직하다.In the present invention, the caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof is preferably contained in 0.1 to 80 μM, more preferably in 20 to 80 μM, more preferably 40 to 80 μM Even more preferred, and as a gamma-secretase inhibitor, it is desirable to inhibit gamma-secretase activity.
본 발명에서, 상기 대장성 질환은 예를 들어 장내 상재균 감염증, 선종성 용종, 유암종, 악성용종, 과형성 용종, 용종증, 용종양 점막, 과오종, 염증성 용종, 지방종, 대장암, 대장염, 결핵성 장염 또는 장폐색일 수 있고, 상기 장내 상재균 감염증은 ETBF 세균 감염증일 수 있으나, 이에 한정되지 않는다.In the present invention, the colon disease is, for example, enterobacterial infection, adenomatous polyp, carcinoid tumor, malignant polyp, hyperplastic polyp, polyposis, polyp mucosa, hyperplasia, inflammatory polyp, lipoma, colon cancer, colitis, tuberculosis enteritis or It may be intestinal obstruction, and the intestinal flora infection may be ETBF bacterial infection, but is not limited thereto.
또한, 상기 대장성 질환은 장내 상재균에 의해 유발되는 것일 수 있고, 보다 구체적으로 ETBF 세균에 의해 유발되는 것일 수 있으나, 이에 한정되지 않는다.In addition, the colon disease may be caused by intestinal flora, and more specifically, may be caused by ETBF bacteria, but is not limited thereto.
본 발명의 카페인산 페네틸 에스테르 농도가 40 ~ 80 μM일 경우에 감마-세크레타제 활성을 저해하는 감마-세크레타제 저해제로 작용하여, ETBF 세균 감염에 의한 염증을 완화하고, ETBF 세균 감염에 의해 유발되는 대장염 및 대장 용종 형성을 억제하는 것을 확인하였으므로, 상기 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용가능한 염을 ETBF 감염증에 의해 유발된 대장성 질환 예방 또는 치료용 조성물의 유효성분으로 이용할 수 있다.
When the caffeic acid phenethyl ester concentration of the present invention is 40 ~ 80 μM acts as a gamma-secretase inhibitor that inhibits gamma-secretase activity, thereby alleviating inflammation caused by ETBF bacterial infection, Since it was confirmed to inhibit colitis and colon polyp formation caused by the above, the caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof can be used as an active ingredient of a composition for preventing or treating colorectal diseases caused by ETBF infection. have.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the kind of food. Examples of foods to which the above-mentioned substances may be added include dairy products, various soups, drinks, meat, sausages, breads, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, and the like, and include all health foods in the conventional sense.
본 발명의 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용가능한 염은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합량은 그의 사용 목적에 따라 적합하게 결정될 수 있다. 일반적으로, 건강식품 중의 상기 화합물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.Caffeic acid phenethyl ester of the present invention or a pharmaceutically acceptable salt thereof may be added to a food product as is or used with other food or food ingredients, and may be appropriately used according to a conventional method. The amount of the active ingredient to be mixed may be appropriately determined depending on the purpose of use thereof. Generally, the amount of the compound in the health food can be added at 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for health and hygiene or health control purposes, the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 본 발명의 화합물을 함유하는 것 외에는 다른 성분에 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 15 g이다.The health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound of the present invention as an essential ingredient in the indicated ratios, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. Can be. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of said natural carbohydrate is generally about 1-20 g, preferably about 5-15 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용가능한 염은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용가능한 염은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 카페인산 페네틸 에스테르 또는 이의 약학적으로 허용가능한 염 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.
In addition to the above, the caffeic acid phenethyl ester of the present invention or a pharmaceutically acceptable salt thereof may be flavored with various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and neutralizing agents (cheese, chocolate). Etc.), and the salts of pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonated drinks used in carbonated drinks and the like. In addition, the caffeic acid phenethyl ester of the present invention or a pharmaceutically acceptable salt thereof may contain pulp for preparing natural fruit juice and fruit juice beverage and vegetable beverage. These components can be used independently or in combination. The proportion of such additives is not so critical but is generally selected from the range of 0.1 to about 20 parts by weight per 100 parts by weight of the caffeic acid phenethyl ester of the present invention or pharmaceutically acceptable salts thereof.
이하 본 발명을 실시예 및 제조예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by Examples and Preparation Examples.
단, 하기 실시예 및 제조예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예, 실험예 및 제조예에 한정되는 것은 아니다.
However, the following Examples and Preparation Examples are merely illustrative of the present invention, the contents of the present invention is not limited to the following Examples, Experimental Examples and Preparation Examples.
<< 실시예Example 1> 1> ETBFETBF (( EnterotoxigenicEnterotoxigenic BacteroidesBacteridees fragilisfragilis ) 균주 용액의 제조) Preparation of Strain Solution
장내 상재균인 ETBF(Enterotoxigenic Bacteroides fragilis) 균주를 마우스로 감염시키기 위해 ETBF 균주 용액을 제조하였다.Enterotoxigenic Bacteroides (ETBF) fragilis ) strains were prepared to infect ETBF strains with mice.
구체적으로 WT(Wild type)-ETBF 균주를 Ca2 +, Mg2 +이 없는 PBS 용매로 용해시켜 200 ㎕ 용량의 배양용액으로 만들었다. 그 다음, WT-ETBF 배양용액을 동결 튜브(cryotube) 안에 담아 초저온 냉장고(deep freezer)에서 얼렸다. 이후, 목면봉(Wood applicator)으로 표면을 긁은 다음, 면봉(applicator) 끝에 묻은 균액 고체 덩어리를 미리 만들어둔 BHIA(Brain heart infusion agar)에 배지에 발라 주었다. BHIA는 BHIA 1 L를 기준으로 아가(Agar) 15 g/L, BHI 배지(media) 37 g, 효모 추출물(Yeast extract) 5 g, 시스테인(Cysteine) 0.5 g, 헤민(Hemin) 1 ml (final 농도: 5 μg/ml)와 항생제(Gentamicin sulfate, 50 mg/ml; Clindamycin, 6 mg/ml)로 구성되었다.Specifically, WT (Wild type) -ETBF strain was dissolved in a PBS solvent without Ca 2 + , Mg 2 + to prepare a 200 μl culture solution. Then, the WT-ETBF culture solution was placed in a cryotube and frozen in a deep freezer. Afterwards, the surface was scraped with a wood applicator, and then applied to the medium in a brain heart infusion agar (BHIA), which previously prepared a solid mass of fungus stained on the end of the applicator. BHIA contains 15 g / L of Agar, 37 g of BHI media, 5 g of yeast extract, 5 g of cysteine, and 1 ml of hemin (final concentration) based on 1 L of BHIA. : 5 μg / ml) and antibiotic (Gentamicin sulfate, 50 mg / ml; Clindamycin, 6 mg / ml).
항생제가 포함된 BHIA에 얼려진 WT-ETBF 균액을 스트리킹(streaking) 해준 다음에 혐기성 챔버(Anaerobic chamber)에 넣고 37℃에서 2일 동아 배양하였다. 2일의 배양기간이 끝난 뒤, 배양기에 균을 접종한 BHIA를 꺼내서 단일 콜로니(mono-colony)를 형성한 것을 확인한 후, 플라스틱 루프(plastic loop)를 이용하여 단일 콜로니를 취한 후에, BHIB에 접종하고 2일 동안 배양하였다. BHIB는 BHIB 1 L를 기준으로 BHI 배지(media) 37 g, 효모 추출물(Yeast extract) 5 g, 시스테인(Cysteine) 0.5 g, 헤민(Hemin) 1 ml (final 농도: 5 μg/ml)와 항생제(Gentamicin sulfate, 50 mg/ml; Clindamycin, 6 mg/ml)로 구성되었다.Streaking the frozen WT-ETBF bacteria in BHIA containing antibiotics and put in an anaerobic chamber and cultured for 2 days at 37 ℃. After the two-day incubation period, BHIA inoculated into the incubator was taken out to confirm that a single colony was formed. After taking a single colony using a plastic loop, inoculated into BHIB. And incubated for 2 days. BHIB is based on 1 L of BHIB, 37 g of BHI media, 5 g of yeast extract, 5 g of cysteine, 1 ml of hemin (final concentration: 5 μg / ml) and antibiotics ( Gentamicin sulfate, 50 mg / ml; Clindamycin, 6 mg / ml).
24개의 미량 원심분리기 튜브에 상기 2일 동안 배양하여 균이 자란 broth를 1.5 ml씩 피펫(pipet)으로 분주한 후, 12000 x g, 30 분, 20℃에서 원심분리하였다. 원심 분리가 끝난 뒤 상층액을 제거하고, 고착화된 펠렛은 500 ㎕ 의 Ca2 +, Mg2 +이 없는 PBS로 피펫팅(pipetting)한 후 1개의 튜브로 농축하여, 평균적으로 1 x 108~9 CFU(colony forming unit)/ml 농도의 균 농도를 갖는 WT-ETBF 균액 6 ml를 획득하였다.
The microorganisms were cultured in 24 microcentrifuge tubes for 2 days, and the broths grown with bacteria were dispensed by pipette 1.5 ml, and then centrifuged at 12000 xg, 30 minutes, and 20 ° C. Centrifuged to remove the rear supernatant end and solidify the pellets is concentrated to a pipetting (pipetting) 1 of the tube and then in a 500 ㎕ Ca 2 +, PBS without Mg 2 +, on average, 1 x 10 8 ~ 6 ml of WT-ETBF bacteria solution having a bacterial concentration of 9 CFU (colony forming unit) / ml concentration were obtained.
<< 실시예Example 2> 2> ETBFETBF 에 의해 유발된 대장 Colon induced by 용종Polyp 동물 모델 제작 Animal model making
ETBF 감염증에 의해 유발된 대장성 질환에 있어서 카페인산 페네틸 에스테르(caffeic acid phenethyl ester, CAPE)가 미치는 영향을 알아보기 위하여, ETBF에 의해 유발된 대장 용종 마우스를 제작하였다.To investigate the effect of caffeic acid phenethyl ester (CAPE) on colorectal diseases caused by ETBF infection, colon polyp mice induced by ETBF were constructed.
구체적으로, 8~10주령 암컷 Balb/c 마우스를 주문하여, 동물 시설에서 1주 동안 유지시켰다. 정제된 아족시메탄(Azoxymethane, AOM)(Sigma-aldrich)을 Ca2 +, Mg2+ 없는 PBS(Phosphate buffered saline)에 용해하여 10 mg/kg 농도의 용액으로 제조한 후 AOM 용액(solution) 200 ㎕을 1 ml 시린지(syringe)를 이용하여 상기 마우스의 복강에 주사한다. 주사 전에 마우스 복강은 70% 알코올로 소독해 주었다.Specifically, 8-10 week old female Balb / c mice were ordered and maintained for 1 week in an animal facility. When the purified methane subgroup (Azoxymethane, AOM) (Sigma- aldrich) the Ca 2 +, Mg 2+ free PBS (Phosphate buffered saline) AOM solution (solution) was dissolved to prepare a solution of 10 mg / kg concentration and 200 [Mu] l is injected into the abdominal cavity of the mice using a 1 ml syringe. The mouse abdominal cavity was sterilized with 70% alcohol before injection.
AOM 용액을 마우스에 복강주사 시킨 날로부터 2일 후, 기존의 음수였던 멸균된 1차 증류수(autoclaved 1'W)를 항생제(Gentamicin sulfate, 300 mg/liter; Clindamycin, 100 mg/liter)가 포함된 멸균된 1차 증류수로 교체해 주고 12일간 음용하게 하였다. 그리고 그 이후에는 아무것도 포함되지 않은 순수한 멸균된 1차 증류수는 7일간 음용시켰다.Two days after the AOM solution was intraperitoneally injected into mice, sterile primary distilled water (autoclaved 1'W), which was previously negative, contained antibiotics (Gentamicin sulfate, 300 mg / liter; Clindamycin, 100 mg / liter). Replaced with sterile primary distilled water and allowed to drink for 12 days. After that, pure sterilized primary distilled water containing nothing was drunk for 7 days.
AOM 복강주사를 시켜준 7일 뒤에는 상기 <실시예 1>에서 제조한 WT-ETBF 균주 용액 200 ㎕를 존대(Inoculation needle)를 이용하여 구강접종 하였다. 또한, 상기 순수한 멸균된 1차 증류수를 7일간 음용시킨 후, 즉 실험 시작일로부터 21일이 지난 후에, 덱스트란 설페이트 소듐(Dextran sulfate sodium, DSS)(MP biochemical)을 멸균된 1차 증류수를 용매로 하여 1% (w/v) 농도의 DSS 용액으로 만든 다음 이를 5일간 투여하였다. 그 이후에는 아무것도 용해되지 않은 멸균된 1차 증류수를 16일 동안 투여하였다. 상기 DSS 용액 및 증류수 투여를 한 번 더 반복한 후 마우스를 이산화탄소를 이용하여 안락사시켰다. 마우스에게 사료는 Harlan 2018s 사료로 처음부터 끝까지 부족하지 않도록 충분히 공급해주었다.
Seven days after the AOM intraperitoneal injection, 200 μl of the WT-ETBF strain solution prepared in Example 1 was orally inoculated using an inoculation needle. In addition, after 7 days of drinking the pure sterilized primary distilled water, that is, 21 days after the start of the experiment, dextran sulfate sodium (DSS) (MP biochemical) in sterilized primary distilled water as a solvent To a DSS solution of 1% (w / v) concentration and then administered for 5 days. Thereafter, sterile primary distilled water, in which nothing was dissolved, was administered for 16 days. After repeated administration of the DSS solution and distilled water, the mice were euthanized using carbon dioxide. The mice were fed enough Harlan 2018's feed from start to finish.
<< 실시예Example 3> 3> BFTBFT (( BacteroidesBacteridees fragilisfragilis toxin)를 처리한 대장암 세포주에서 CAPE에 의한 감마- Gamma Induced by CAPE in Colorectal Cancer Cell Lines Treated with Toxin 세크레타제Secretase 활성 저해 효과 확인 Confirmation of activity inhibitory effect
ETBF가 분비한 BFT(Bacteroides fragilis toxin)에 의하여 세포에 분포하는 E-cadherin이 분절되어 분해되며, 이 때 감마-세크레타제(gamma-secretase)가 33 kDa 크기의 E-cadherin 절편을 28 kDa 크기의 E-cadherin 절편으로 분절하여 세포 내에서 빠르게 분해되고, 결과적으로 인접한 장 상피세포 사이의 틈이 벌어져 그 사이로 장내 내용물이 조직으로 침입하면 염증 경로가 활성화되어 대장염 및 대장 용종의 생성이 촉진된다고 알려져 있다. 따라서, BFT를 처리한 대장암 세포주에서 CAPE가 E-cadherin 분절 과정에 미치는 영향을 알아보기 위하여 다음의 실험을 수행하였다.
Bacteroides secreted by ETBF fragilis toxin) fragments and breaks down the E-cadherin distributed in the cell, while gamma-secretase breaks up the 33 kDa E-cadherin fragment into 28 kDa E-cadherin fragment. As a result, the cells are rapidly degraded in cells, and as a result, gaps between adjacent intestinal epithelial cells are opened, and when the intestinal contents invade tissue, the inflammatory pathway is activated to promote the formation of colitis and colon polyps. Therefore, the following experiments were performed to investigate the effect of CAPE on E-cadherin fragmentation in BFT-treated colon cancer cell lines.
<3-1> <3-1> BFTBFT 를 처리한 대장암 세포주에서 CAPE에 의한 감마-In CAPE-treated Colorectal Cancer Cell Lines 세크레타제Secretase 활성 저해 효과 확인 Confirmation of activity inhibitory effect
BFT(Bacteroides fragilis toxin)를 처리한 대장암 세포주에서 CAPE가 E-cadherin 분절 과정에 미치는 영향을 알아보기 위하여 다음과 같이 웨스턴 블럿팅 분석을 수행하였다. Western blotting analysis was performed to investigate the effect of CAPE on E-cadherin fragmentation in colorectal cancer cell lines treated with BFT (Bacteroides fragilis toxin).
구체적으로, HCT116 대장암 세포주를 10 % FBS 및 1 % 페니실린-스트렙토 마이신이 포함된 DMEM 배지로, 37℃, 5% CO2 조건 하에서 배양하였다. 그 다음, 상기 세포에 CAPE (tokyo chemical industry, JP) 또는 DMSO 80 μM, 및 재조합을 통해 활성화된 BFT인 recom ET (HCT116 대장암 세포주 : recom ET = 1:10) 또는 재조합을 통해 비활성화된 돌연변이 BFT인 recom NT(HCT116 대장암 세포주 : recom NT = 1:10)를 동시에 1시간 동안 처리한 후 세포를 회수하였다. Specifically, HCT116 colon cancer cell line was cultured in 37%, 5% CO 2 conditions in DMEM medium containing 10% FBS and 1% penicillin-streptomycin. Then, to the cells, CAPE (tokyo chemical industry, JP) or
상기 recom ET는 상기 <실시예 1>에 기재된 방법에서 WT-ETBF 균주 대신 활성화된 BFT 유전자를 포함하는 플라스미드로 재조합된 B. fragilis NCTC 9343 균주를 이용하는 것을 제외하고 나머지 과정은 동일하게 진행하고 원심분리한 후 회수한 상층액을 말한다. 상기 recom NT는 상기 <실시예 1>에 기재된 WT-ETBF 균주 대신 B. fragilis H352Y 균주를 이용하는 것을 제외하고 나머지 과정은 동일하게 진행하고 원심분리한 후 회수한 상층액을 말한다. The recom ET proceeds in the same manner except for using the B. fragilis NCTC 9343 strain recombined with the plasmid containing the activated BFT gene instead of the WT-ETBF strain in the method described in Example 1 and centrifugation Refers to the collected supernatant. The recom NT refers to the supernatant recovered after centrifugation, except that the B. fragilis H352Y strain is used instead of the WT-ETBF strain described in <Example 1>.
또한, 대조군으로 이용하기 위하여 상기 세포에 DMSO 5 ㎕, 및 BHIB (HCT116 대장암 세포주 : BHIB = 1:10) 또는 FBS가 포함되지 않은 DMEM 배지(serum free media)를 동시에 1시간 동안 처리한 후 세포를 회수하였다. In addition, 5 μl of DMSO, and BMEM (HCT116 colorectal cancer cell line: BHIB = 1: 10) or DMEM medium (serum free media) containing no FBS were simultaneously treated for 1 hour for use as a control cell. Was recovered.
그 다음, 프로테아제 및 포스파타아제 억제제 (Roche, Basel, Switzerland)가 풍부한 RIPA 완충액을 사용하여 상기 회수한 세포를 용해하여 단백질을 분리하였다. 상기 세포의 단백질 용해물(30 ㎍)을 SDS-PAGE로 전기영동한 후, 니트로셀룰로오스 막(nitrocellulose membranes)(PALL Life Sciences)으로 전달시켰다. 그 다음, 일차 항체로 항-E-cadherin 항체, 항-GAPDH를 처리하여 반응시킨 후, 상기 막에 붙은 일차 항체에 HRP-접합 이차 항체를 붙이고, 이를 ECL(BIO-RAD, USA)을 이용하여 확인하였다. 이미지는 FUSION SOLO S chemiluminescence & optional fluorescence imaging (VILBER, France)을 이용하였다(도 1).The recovered cells were then lysed using RIPA buffer enriched with protease and phosphatase inhibitors (Roche, Basel, Switzerland) to separate proteins. Protein lysates (30 μg) of the cells were electrophoresed by SDS-PAGE and then transferred to nitrocellulose membranes (PALL Life Sciences). Then, the reaction was performed by treating anti-E-cadherin antibody and anti-GAPDH with the primary antibody, and then attaching the HRP-conjugated secondary antibody to the primary antibody attached to the membrane, and using the ECL (BIO-RAD, USA). Confirmed. Images were subjected to FUSION SOLO S chemiluminescence & optional fluorescence imaging (VILBER, France) (FIG. 1).
그 결과, 도 1에 나타낸 바와 같이, CAPE와 BFT를 동시에 처리한 대장암 세포주에서는 33 kDa의 E-cadherin 절편이 생성되는 것을 확인하였다(도 1).
As a result, as shown in FIG. 1, it was confirmed that 33 kDa E-cadherin fragments were generated in the colorectal cancer cell line treated with CAPE and BFT simultaneously (FIG. 1).
이에, CAPE가 감마-세크레타제 활성을 억제하는지 알아보기 위하여, 다음과 같이 웨스턴 블럿팅 분석을 수행하였다.Thus, to determine whether CAPE inhibits gamma-secretase activity, Western blotting analysis was performed as follows.
구체적으로, 상기 HCT116 대장암 세포주에 CAPE 80 μM, DMSO 5 ㎕ 또는 감마-세크레타제 저해제(gamma-secretase inhibitor, L-685, 458; Calbiochem, SanDiego, CA) 1.5 μM, 및 recom ET (HCT116 대장암 세포주 : recom ET = 1:10)를 동시에 30분 또는 1시간 동안 처리한 후 세포를 회수하였다. 또한, 대조군으로 이용하기 위하여, 상기 HCT116 대장암 세포주에 CAPE 80 μM, DMSO 5 ㎕ 또는 감마-세크레타제 저해제 1.5 μM, 및 FBS가 포함되지 않은 DMEM 배지(serum free media)를 동시에 1시간 동안 처리한 후 세포를 회수하였다. 그 다음, 상기에 기재된 방법과 동일한 방법으로 웨스턴 블럿팅 분석을 수행하였다(도 2).Specifically,
또한, 또 다른 대장암 세포주인 HT29/C1 세포주에 10 % FBS 및 1 % 페니실린-스트렙토 마이신이 포함된 DMEM 배지로, 37℃, 5% CO2 조건 하에서 배양하였다. 그 다음, 상기에 기재된 방법과 동일한 방법으로 CAPE, DMSO 또는 감마-세크레타제 저해제, 및 recom ET 또는 FBS가 포함되지 않은 DMEM 배지를 동시에 30분 또는 1시간 동안 처리한 후 세포를 회수하여 웨스턴 블럿팅 분석을 수행하였다(도 3). In addition, another colon cancer cell line, HT29 / C1 cell line, was cultured in 37%, 5% CO 2 conditions in DMEM medium containing 10% FBS and 1% penicillin-streptomycin. Next, the cells were recovered by treatment with CAPE, DMSO or gamma-secretase inhibitor, and DMEM medium without recom ET or FBS simultaneously for 30 minutes or 1 hour in the same manner as described above. Routing analysis was performed (FIG. 3).
그 결과, 도 2 및 도 3에 나타낸 바와 같이, HCT116 대장암 세포주에서 CAPE 및 BFT를 동시에 처리한 그룹과 감마-세크레타제 저해제 및 BFT를 동시에 처리한 그룹 모두 33 kDa의 E-cadherin 절편을 형성하는 것을 확인하였다(도 2, 레인 7, 9, 10 및 12). 또한, HT29/C1 대장암 세포주에서도 CAPE 및 BFT를 동시에 처리한 그룹과 감마-세크레타제 저해제 및 BFT를 동시에 처리한 그룹 모두 33 kDa의 E-cadherin 절편을 형성하는 것을 확인하였다(도 3, 레인 12, 14, 15 및 17). 따라서, 상기 결과를 통해 CAPE가 감마-세크레타제 활성을 저해하는 감마-세크레타제 저해제로 작용하여 BFT에 의해 세포 내부에서 형성된 E-cadherin이 분해되는 것을 억제함을 확인하였다.
As a result, as shown in FIG. 2 and FIG. 3, both the group treated with CAPE and BFT and the group treated with gamma-secretase inhibitor and BFT simultaneously formed 33 kDa E-cadherin fragments in HCT116 colorectal cancer cell line. (Fig. 2,
<3-2> <3-2> BFTBFT 를 처리한 대장암 세포주에서 CAPE 처리 농도에 의한 감마-By CAPE Treatment Concentration in Colorectal Cancer Cell Lines 세크레Secre 타제 활성 억제 효과 확인Confirmation of inhibitory effect of other drugs
CAPE의 농도에 따른 감마-세크레타제 활성 억제 효과를 알아보기 위하여, 다음과 같이 웨스턴 블럿팅 분석을 수행하였다. In order to determine the effect of inhibiting gamma-secretase activity according to the concentration of CAPE, Western blotting analysis was performed as follows.
구체적으로, HT29/C1 세포주에 10 % FBS 및 1 % 페니실린-스트렙토 마이신이 포함된 DMEM 배지로, 37℃, 5% CO2 조건 하에서 배양하였다. 그 다음, 상기 세포주에 5 μM, 10 μM, 20 μM, 40 μM 또는 80 μM의 CAPE, 5 ㎕의 DMSO 또는 1.5 μM의 감마-세크레타제 저해제, 및 recom ET (HCT116 대장암 세포주 : recom ET = 1:10)를 동시에 2시간 동안 처리한 후 세포를 회수하였다. 또한, 대조군으로 이용하기 위하여, 상기 HT29/C1 대장암 세포주에 DMSO 80 μM 또는 감마-세크레타제 저해제 1.5 μM, 및 FBS가 포함되지 않은 DMEM 배지(serum free media)를 동시에 2시간 동안 처리한 후 세포를 회수하였다. 그 다음, 상기 실시예 <3-2>에 기재된 방법과 동일한 방법으로 웨스턴 블럿팅 분석을 수행하였다(도 4).Specifically, HT29 / C1 cell line in DMEM medium containing 10% FBS and 1% penicillin-streptomycin, was cultured under 37 ℃, 5% CO 2 conditions. Then, in the cell line, 5 μM, 10 μM, 20 μM, 40 μM or 80 μM CAPE, 5 μL DMSO or 1.5 μM gamma-secretase inhibitor, and recom ET (HCT116 colorectal cancer cell line: recom ET = 1:10) were treated simultaneously for 2 hours and then cells were recovered. In addition, in order to use as a control, the HT29 / C1 colorectal cancer cell line was treated with 80 μM DMSO or 1.5 μM gamma-secretase inhibitor and DMEM medium (serum free media) containing no FBS simultaneously for 2 hours. The cells were recovered. Then, Western blotting analysis was performed in the same manner as described in Example <3-2> (FIG. 4).
그 결과, 도 4에 나타낸 바와 같이, CAPE를 40 ~ 80 μM로 처리한 경우 33 kDa의 E-cadherin 절편이 생성되는 것을 확인하였다. 따라서, 상기 결과를 통해 CAPE 농도가 40 ~ 80 μM일 경우에 감마-세크레타제 활성을 저해하는 감마-세크레타제 저해제로 작용함을 확인하였다(도 4).
As a result, as shown in FIG. 4, it was confirmed that 33-kDa E-cadherin fragments were produced when CAPE was treated with 40-80 μM. Therefore, the results confirmed that when the CAPE concentration is 40 ~ 80 μM acts as a gamma-secretase inhibitor that inhibits gamma-secretase activity (Fig. 4).
<< 실시예Example 4> 4> BFTBFT 를 처리한 대장암 세포주에서 CAPE 처리에 의한 Treatment by colorectal cancer cell line NFNF -κB 활성 억제 확인Confirmation of -κB activity inhibition
BFT를 처리한 대장암 세포주에서 CAPE가 NF-κB 경로에 미치는 영향을 알아보기 위하여, BFT를 처리한 대장암 세포주에 CAPE를 처리한 후 NF-κB 프로모터 활성을 측정하였다.To determine the effect of CAPE on the NF-κB pathway in BFT-treated colon cancer cell lines, NF-κB promoter activity was measured after CAPE treatment in BFT-treated colon cancer cell lines.
구체적으로, HCT116 세포를 10 % FBS 및 1 % 페니실린-스트렙토 마이신이 포함된 DMEM 배지로, 37℃, 5% CO2 조건 하에서 배양하였다. 그 다음, NF-κB-루시퍼라아제(luciferase)를 상기 세포에 SureENTRY transduction reagent를 사용하여 형질감염하였다. 그 다음, CAPE 0.4 μM, 0.8 μM, 2.5 μM, 5 μM, 10 μM, 20 μM, 40 μM 또는 80 μM, 및 recom ET을 동시에 처리하고 24시간 후 PBS로 세척하였다(도 5a). 또한, 대조군으로 이용하기 위하여, 상기 HCT116 세포주에 recom NT, WT-NT, BHIB 또는 FBS가 포함되지 않은 DMEM 배지만 처리하고 1시간 후 PBS로 세척하였다(도 5b). 상기 WT-NT는 상기 <실시예 1>에 기재된 방법에서 WT-ETBF 균주 대신 B. fragilis NCTC 9343 균주를 이용하는 것을 제외하고 나머지 과정은 동일하게 진행하고 원심분리한 후 회수한 상층액을 말한다.Specifically, HCT116 cells were cultured in DMEM medium containing 10% FBS and 1% penicillin-streptomycin under 37 ° C., 5% CO 2 conditions. NF-κB-luciferase was then transfected into the cells using SureENTRY transduction reagent. Then, CAPE 0.4 μM, 0.8 μM, 2.5 μM, 5 μM, 10 μM, 20 μM, 40 μM or 80 μM, and recom ET were simultaneously treated and washed with PBS 24 hours later (FIG. 5A). In addition, to use as a control, the HCT116 cell line was treated only with DMEM medium containing no recom NT, WT-NT, BHIB or FBS and washed with PBS after 1 hour (FIG. 5B). The WT-NT refers to the supernatant recovered after centrifugation except that B. fragilis NCTC 9343 strain is used instead of the WT-ETBF strain in the method described in <Example 1>.
그 후, 루시퍼라아제 활성을 luciferase reporter assay (Promega, WI)를 이용하여 측정하였다.Thereafter, luciferase activity was measured using luciferase reporter assay (Promega, WI).
그 결과, 도 5a 및 도 5b에 나타낸 바와 같이, recom ET만 처리한 그룹에서는 E-cadherin의 분해로 인해 NF-κB 경로가 활성화 되어 NF-κB의 전사 활성이 증가하는 반면, recom ET와 40 ~ 80 μM의 CAPE를 동시에 처리한 그룹에서는 CAPE가 감마-세크레타제 저해제로 작용하여 E-cadherin 분해가 억제되고, 그 결과 NF-κB 경로의 활성화도 억제되어 NF-κB의 전사 활성이 현저히 감소하는 것을 확인하였다(도 5a 및 도 5b).
As a result, as shown in Figures 5a and 5b, in the recom ET-only group, the NF-κB pathway is activated due to the degradation of E-cadherin to increase the transcriptional activity of NF-κB, whereas recom ET and 40 ~ In the group treated with 80 μM CAPE at the same time, CAPE acts as a gamma-secretase inhibitor, inhibiting E-cadherin degradation, which in turn inhibits the activation of the NF-κB pathway, resulting in a significant decrease in the transcriptional activity of NF-κB. It was confirmed that (Figs. 5a and 5b).
<< 실시예Example 5> 5> BFTBFT 를 처리한 대장암 세포주에서 CAPE 처리에 의한 Treatment by colorectal cancer cell line CXCL8CXCL8 발현 억제 확인 Expression suppression confirmation
BFT를 처리한 대장암 세포주에서 CAPE가 염증 반응에 미치는 영향을 알아보기 위하여, BFT를 처리한 대장암 세포주에 CAPE를 처리한 후 CXCL8의 발현을 측정하였다.To determine the effect of CAPE on the inflammatory response in BFT-treated colon cancer cell lines, the expression of CXCL8 was measured after CAPE treatment in BFT-treated colon cancer cell lines.
구체적으로, HCT116 세포를 10 % FBS 및 1 % 페니실린-스트렙토 마이신이 포함된 DMEM 배지로, 37℃, 5% CO2 조건 하에서 배양하였다. 그 다음, CAPE 0 μM, 10 μM, 20 μM, 40 μM 또는 80 μM, 및 recom ET를 동시에 처리하고 3시간 후 PBS로 세척하고 세포를 회수하였다. 또한, 상기 HCT116 대장암 세포주에 CAPE 80 μM, DMSO 5 ㎕ 또는 감마-세크레타제 저해제(gamma-secretase inhibitor) 1.5 μM, 및 recom ET (HCT116 대장암 세포주 : recom ET = 1:10) 또는 recom NT를 동시에 처리하고 3시간 후 PBS로 세척하고 세포를 회수하였다. 또한, 대조군으로 이용하기 위하여, 상기 HCT116 대장암 세포주에 recom NT, WT-NT, BHIB 또는 FBS가 포함되지 않은 DMEM 배지(serum-free media)를 처리하고 3시간 후 PBS로 세척하고 세포를 회수하였다. 그 후, 상기 회수한 세포를 Trizol(Invitrogen, Carlsbad, CA)를 이용하여 제조사의 프로토콜에 따라 총 RNA를 분리한 후, 분리한 RNA 1을 고용량 cDNA 역전사 키트 (Invitrogen, Carlsbad, CA)를 사용하여 제조사의 절차에 따라 cDNA를 합성하였다. 상기 cDNA은 Taqman-probe(GAPDH; Cat number:4331182, CXCL8; Cat number:4331182, Themofisher)를 이용하여 실시간 q-PCR을 수행하였다. Q-PCR은 Applied Biosystems의 2x real-time PCR 마스터(Foster City, CA, USA)를 사용하여 수행하였다(도 6).Specifically, HCT116 cells were cultured in DMEM medium containing 10% FBS and 1% penicillin-streptomycin under 37 ° C., 5% CO 2 conditions. Then, CAPE 0 μM, 10 μM, 20 μM, 40 μM or 80 μM, and recom ET were simultaneously treated and washed 3 hours later with PBS and cells were recovered. In addition, the HCT116 colorectal cancer
그 결과, 도 6에 나타낸 바와 같이, recom ET만 처리한 그룹에서는 E-cadherin의 분해로 인해 CXCL8의 발현이 증가하는 반면, recom ET와 40 ~ 80 μM의 CAPE를 동시에 처리한 그룹에서는 CAPE가 감마-세크레타제 저해제로 작용하여 E-cadherin 분해가 억제되고, 그 결과 CXCL8의 발현이 억제되는 것을 확인하였다(도 6).
As a result, as shown in FIG. 6, in the group treated with recom ET only, expression of CXCL8 increased due to the decomposition of E-cadherin, whereas in the group treated with recom ET and CAPE of 40 to 80 μM simultaneously, CAPE was gamma. It was confirmed that by acting as a secretase inhibitor, E-cadherin degradation was inhibited and, as a result, expression of CXCL8 was inhibited (FIG. 6).
<< 실시예Example 6> 6> ETBFETBF 에 의해 유발된 대장 Colon induced by 용종Polyp 동물 모델에서 CAPE에 의한 대장 용종 억제 효과 확인 Confirmation of CAPE-induced Colon Polyp Inhibition in Animal Model
<6-1> 대장 <6-1> large intestine 용종의Polyp 수 및 크기 분석을 통한, CAPE에 의한 대장 Large intestine by CAPE, through number and size analysis 용종Polyp 억제 효과 확인 Confirm inhibitory effect
ETBF 감염증에 의해 유발된 대장성 질환에 있어서, CAPE가 미치는 영향을 알아보기 위하여, ETBF에 의해 유발된 대장 용종 마우스에 CAPE를 투여한 후 대장에서 형성된 대장 용종의 수와 크기를 관찰하였다.In order to examine the effect of CAPE on colon disease caused by ETBF infection, the number and size of colon polyps formed in the colon were observed after administration of CAPE to colon colon polyps induced by ETBF.
구체적으로, 상기 <실시예 2>에서 제작한 ETBF에 의해 유발된 대장 용종 마우스에 AOM 투여 후 15일 뒤부터 프로폴리스 추출액(Propolis, COMVITA PROPLIS PFL30, COMVITA, New Zealand) 또는 CAPE를 투여하기 시작하여, 일주일에 3회(1 내지 2일 간격) 실험이 종료될 때까지 투여하였다. 프로폴리스 추출액은 1 : 100의 비율로 존대를 이용하여 구강 투여하였고, CAPE는 20 mg/kg 농도로 200 ㎕ PBS에 희석하고 1 ㎖ 실린지를 이용하여 복강 투여하였다. 실험 종료 후 대장에서 형성된 대장 용종의 수와 크기를 관찰하였다(도 7).Specifically, the propolis extract (Propolis, COMVITA PROPLIS PFL30, COMVITA, New Zealand) or CAPE was started to be administered 15 days after AOM administration to the ETBF-induced colon polyp mice prepared in Example 2. 3 times a week (1 to 2 days apart) until the end of the experiment. Propolis extracts were orally administered using a zone at a ratio of 1: 100, CAPE was diluted in 200 μl PBS at a concentration of 20 mg / kg and intraperitoneally administered using 1 ml syringe. After the experiment, the number and size of colon polyps formed in the colon were observed (FIG. 7).
그 결과, 도 7에 나타낸 바와 같이, ETBF에 의해 유발된 대장 용종 마우스에서 대장 용종의 개수의 중간값이 약 35인 반면, CAPE를 투여한 경우 대장 용종의 개수의 중간값이 약 20임을 확인하였다. 또한, 프로폴리스를 투여한 경우보다도 대장 용종의 개수의 중간값이 낮음을 확인하였다. 따라서, 상기 결과를 통해 CAPE에 의해 ETBR 감염증에 의해 유발되는 대장 용종 형성이 억제됨을 확인하였다(도 7).
As a result, as shown in FIG. 7, the median number of colon polyps was about 35 in colon polyp mice induced by ETBF, whereas the median number of colon polyps was about 20 when CAPE was administered. . It was also confirmed that the median value of the number of colon polyps was lower than that in the case of administration of propolis. Therefore, the above results confirmed that the formation of colon polyps caused by ETBR infection by CAPE was suppressed (FIG. 7).
<6-2> 조직학적 분석을 통한, CAPE에 의한 대장 <6-2> Large intestine by CAPE through histological analysis 용종Polyp 억제 효과 확인 Confirm inhibitory effect
ETBF 감염증에 의해 유발된 대장성 질환에 있어서, CAPE가 미치는 영향을 알아보기 위하여, ETBF에 의해 유발된 대장 용종 마우스에 CAPE를 투여한 후 조직학적 분석을 수행하였다.To determine the effect of CAPE on colorectal diseases caused by ETBF infection, colonic polyps mice induced by ETBF were administered followed by histological analysis.
구체적으로, 상기 <실시예 2>에서 제작한 ETBF에 의해 유발된 대장 용종 마우스에 상기 실시예 <6-1>에 기재된 방법으로 프로폴리스 추출액 또는 CAPE를 투여한 후 막창자(cecum) 조직을 채취하였다. 그 다음, 상기 조직에 파라핀을 침투시키고 4 ㎛ 두께로 절편화하였다. 상기 파라핀 절편을 H&E 염색을 한 후 병변 부위를 관찰하고, 염증 정도 및 세포의 과형성(hyperplasia) 정도를 그래프화하였다(도 8). Specifically, cecum tissues were collected after administration of propolis extract or CAPE to the colonic polyp mice induced by ETBF prepared in <Example 2> by the method described in Example <6-1>. . Paraffin was then infiltrated into the tissue and sectioned to 4 μm thickness. After paraffin sections were stained with H & E, the lesion site was observed, and the degree of inflammation and the degree of hyperplasia of the cells were graphed (FIG. 8).
또한, 상기 <실시예 2>에서 제작한 ETBF에 의해 유발된 대장 용종 마우스 상기 실시예 <6-1>에 기재된 방법으로 프로폴리스 추출액 또는 CAPE를 투여한 후 용종이 발생하는 원위부 대장(distal colon) 조직을 채취하고 상기에 기재된 방법과 같이 H&E 염색을 통해 병변 부위를 관찰하고, 염증 정도, 세포의 과형성 정도, 대장 용종 관련 지표(Aberrant crypt foci, Microadenoma, Macroadenoma)를 확인하여 그래프화하였다(도 9a 및 도 9b).In addition, a colonic polyp mouse induced by ETBF prepared in <Example 2> A distal colon in which polyps develop after administration of a propolis extract or CAPE by the method described in Example <6-1>. Tissues were collected and the lesion site was observed by H & E staining as described above, and the degree of inflammation, degree of hyperplasia of the cells, colonic polyp-related indicators (Aberrant crypt foci, Microadenoma, Macroadenoma) were confirmed and graphed (FIG. 9A). And Figure 9b).
그 결과, 도 8에 나타낸 바와 같이, ETBF에 의해 유발된 대장 용종 마우스 그룹(ETBF-CAC)의 경우 ETBF에 의해 대장 내 염증이 증가하는 반면, ETBF에 의해 유발된 대장 용종 마우스에 CAPE를 투여한 경우(ETBF-CAC+CAPE) 염증 및 세포의 과형성이 감소하는 것을 확인하였다(도 8).As a result, as shown in FIG. 8, ETBF-induced colon polyp mouse group (ETBF-CAC) increased colonic inflammation by ETBF, whereas CAPE was administered to ETBF-induced colon polyp mice. Case (ETBF-CAC + CAPE) was found to reduce inflammation and hyperplasia of the cells (FIG. 8).
또한, 도 9a 및 도 9b에 나타낸 바와 같이, ETBF에 의해 유발된 대장 용종 마우스에 CAPE를 투여한 경우(ETBF-CAC+CAPE) ETBF에 의해 유발된 대장 용종 마우스 그룹(ETBF-CAC)에 비해 대장 용종과 관련된 지표가 모두 감소하는 것을 확인하였다(도 9a 및 도 9b).In addition, as shown in FIGS. 9A and 9B, when CAPE was administered to colonic polyp mice induced by ETBF (ETBF-CAC + CAPE), the colon compared to the colonic polyp mouse group induced by ETBF (ETBF-CAC). It was confirmed that all the indicators related to the polyp are reduced (FIGS. 9A and 9B).
따라서, 상기 <실시예 1> 내지 <실시예 6>의 결과를 통해 CAPE 농도가 40 ~ 80 μM일 경우에 감마-세크레타제 활성을 저해하는 감마-세크레타제 저해제로 작용하여, ETBF 감염에 의해 유발되는 대장염 및 대장 용종 형성을 억제하는 것으로 나타나므로, 상기 CAPE를 ETBF 감염증에 의해 유발된 대장성 질환 치료에 이용할 수 있음을 확인하였다.
Therefore, the results of <Example 1> to <Example 6> act as a gamma-secretase inhibitor that inhibits gamma-secretase activity when the CAPE concentration is 40-80 μM, thereby preventing It has been shown to inhibit colitis and colon polyp formation caused by the above, and thus, it was confirmed that the CAPE can be used to treat colonic diseases caused by ETBF infection.
이하, 본 발명에 따른 각 제제의 제조예를 예시한다. 하기 제조예는 본 발명의 실시에 대한 이해를 돕기 위한 것이지 본 발명에 따른 제형의 제조방법이 하기 제조예로 한정되는 것을 의미하지 않는다.
Hereinafter, the manufacture example of each formulation which concerns on this invention is illustrated. The following preparation examples are intended to aid the understanding of the practice of the present invention and do not mean that the preparation method of the formulation according to the present invention is limited to the following preparation examples.
<제조예 1> 약학적 제제의 제조Preparation Example 1 Preparation of Pharmaceutical Formulation
<1-1> 산제의 제조 <1-1> Preparation of Powder
CAPE 또는 이의 약학적으로 허용가능한 염 2 g2 g of CAPE or a pharmaceutically acceptable salt thereof
유당 1 g1 g lactose
상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.
The above ingredients were mixed and filled in airtight cloth to prepare a powder.
<1-2> 정제의 제조<1-2> Preparation of Tablet
CAPE 또는 이의 약학적으로 허용가능한 염 10 mgCAPE or its pharmaceutically
옥수수전분 100 mg
유 당 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.
After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
<1-3> 캡슐제의 제조<1-3> Preparation of Capsule
CAPE 또는 이의 약학적으로 허용가능한 염 10 mgCAPE or its pharmaceutically
옥수수전분 100 mg
유 당 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.
After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
<1-4> 환의 제조<1-4> Preparation of the ring
CAPE 또는 이의 약학적으로 허용가능한 염 1 g1 g of CAPE or a pharmaceutically acceptable salt thereof
유당 1.5 gLactose 1.5 g
글리세린 1 g1 g of glycerin
자일리톨 0.5 gXylitol 0.5 g
상기의 성분을 혼합한 후, 통상의 방법에 따라 1 환 당 4 g이 되도록 제조하였다.
After mixing the above components, it was prepared to be 4 g per ring according to a conventional method.
<1-5> 과립의 제조<1-5> Preparation of Granules
CAPE 또는 이의 약학적으로 허용가능한 염 1 g 1 g of CAPE or a pharmaceutically acceptable salt thereof
포도당 200 mgGlucose 200 mg
전분 600 mgStarch 600 mg
상기의 성분을 혼합한 후, 30% 에탄올 200 mg을 첨가하여 60℃에서 건조하여 과립을 형성한 후 포에 충진하였다.
After mixing the above ingredients, 200 mg of 30% ethanol was added and dried at 60 ° C. to form granules, and then filled into fabrics.
<제조예 2> 건강식품의 제조Preparation Example 2 Preparation of Health Food
본 발명의 CAPE 또는 이의 약학적으로 허용가능한 염을 포함하는 식품들을 다음과 같이 제조하였다.Foods containing the CAPE of the present invention or a pharmaceutically acceptable salt thereof were prepared as follows.
<2-1> 밀가루 식품의 제조<2-1> Preparation of Flour Food
본 발명의 CAPE 또는 이의 약학적으로 허용가능한 염의 0.5 내지 5.0 중량부를 밀가루에 첨가하고, 이 혼합물을 이용하여 빵, 케이크, 쿠키, 크래커 및 면류를 제조하였다.
0.5-5.0 parts by weight of CAPE of the present invention or pharmaceutically acceptable salts thereof was added to the flour and this mixture was used to make bread, cakes, cookies, crackers and noodles.
<2-2> 스프 및 육즙(gravies)의 제조<2-2> Preparation of Soups and Gravys
본 발명의 CAPE 또는 이의 약학적으로 허용가능한 염의 0.1 내지 5.0 중량부를 스프 및 육즙에 첨가하여 건강 증진용 육가공 제품, 면류의 수프 및 육즙을 제조하였다.
0.1 to 5.0 parts by weight of CAPE of the present invention or its pharmaceutically acceptable salts were added to soups and gravy to prepare health promoting meat products, soups of noodles and gravy.
<2-3> 유제품(dairy products)의 제조<2-3> Manufacture of Dairy Products
본 발명의 CAPE 또는 이의 약학적으로 허용가능한 염의 5 내지 10 중량부를 우유에 첨가하고, 상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다.
5 to 10 parts by weight of the CAPE of the present invention or a pharmaceutically acceptable salt thereof is added to milk, and the milk is used to prepare various dairy products such as butter and ice cream.
<2-4> 선식의 제조<2-4> Preparation of Wire
현미, 보리, 찹쌀, 율무를 공지의 방법으로 알파화시켜 건조시킨 것을 배전한 후 분쇄기로 입도 60 메쉬의 분말로 제조하였다.Brown rice, barley, glutinous rice, and yulmu were alphad by a known method, and then dried and roasted to prepare a powder having a particle size of 60 mesh.
검정콩, 검정깨, 들깨도 공지의 방법으로 쪄서 건조시킨 것을 배전한 후 분쇄기로 입도 60 메쉬의 분말로 제조하였다.Black beans, black sesame seeds, and perilla were also steamed and dried in a known manner, and then roasted to prepare a powder having a particle size of 60 mesh.
본 발명의 CAPE 또는 이의 약학적으로 허용가능한 염을 진공 농축기에서 감압농축하고, 분무, 열풍건조기로 건조하여 얻은 건조물을 분쇄기로 입도 60 메쉬로 분쇄하여 건조분말을 얻었다.CAPE or a pharmaceutically acceptable salt thereof of the present invention was concentrated under reduced pressure in a vacuum concentrator, dried by spraying and drying with a hot air dryer, and then pulverized with a particle size of 60 mesh to obtain a dry powder.
상기에서 제조한 곡물류, 종실류 및 CAPE 또는 이의 약학적으로 허용가능한 염을 다음의 비율로 배합하여 제조하였다.The grains, seeds and CAPE or pharmaceutically acceptable salts thereof prepared above were prepared by combining the following ratios.
곡물류(현미 30 중량부, 율무 15 중량부, 보리 20 중량부),Cereals (30 parts by weight brown rice, 15 parts by weight brittle, 20 parts by weight of barley),
종실류(들깨 7 중량부, 검정콩 8 중량부, 검정깨 7 중량부),Seeds (7 parts by weight perilla, 8 parts by weight black beans, 7 parts by weight black sesame seeds),
CAPE 또는 이의 약학적으로 허용가능한 염(3 중량부),CAPE or its pharmaceutically acceptable salt (3 parts by weight),
영지(0.5 중량부),Ganoderma lucidum (0.5 parts by weight),
지황(0.5 중량부)
Foxglove (0.5 part by weight)
<제조예 3> 건강음료의 제조Preparation Example 3 Preparation of Health Beverage
<3-1> 건강음료의 제조<3-1> Preparation of health drink
액상과당(0.5%), 올리고당(2%), 설탕(2%), 식염(0.5%), 물(75%)과 같은 부재료와 본 발명의 CAPE 또는 이의 약학적으로 허용가능한 염 5 g을 균질하게 배합하여 순간 살균을 한 후 이를 유리병, 패트병 등 소포장 용기에 포장하여 제조하였다.
Homogeneous subsidiary materials such as liquid fructose (0.5%), oligosaccharides (2%), sugars (2%), salts (0.5%), water (75%) and 5 g of the CAPE of the invention or pharmaceutically acceptable salts thereof After sterilization and instant sterilization, it was prepared by packaging in small packaging containers such as glass bottles and plastic bottles.
<3-2> 야채 주스의 제조<3-2> Preparation of Vegetable Juice
본 발명의 CAPE 또는 이의 약학적으로 허용가능한 염 5 g을 토마토 또는 당근 주스 1,000 ㎖에 가하여 야채 주스를 제조하였다.
Vegetable juice was prepared by adding 5 g of CAPE of the present invention or a pharmaceutically acceptable salt thereof to 1,000 ml of tomato or carrot juice.
<3-3> 과일 주스의 제조<3-3> Preparation of Fruit Juice
본 발명의 CAPE 또는 이의 약학적으로 허용가능한 염 1 g을 사과 또는 포도 주스 1,000 ㎖에 가하여 과일 주스를 제조하였다.
1 g of CAPE or a pharmaceutically acceptable salt thereof of the present invention was added to 1,000 ml of apple or grape juice to prepare a fruit juice.
Claims (11)
상기 장내 상재균은 엔테로톡시제닉 박테로이데스 프라길리스(Enterotoxigenic Bacteroides fragilis, ETBF) 세균이고,
상기 대장성 질환은 장내 상재균 감염증, 선종성 용종, 유암종, 악성용종, 과형성 용종, 용종증, 용종양 점막, 과오종, 염증성 용종, 지방종, 대장암, 대장염, 결핵성 장염 및 장폐색으로 이루어진 군으로부터 선택되는 조성물.
A pharmaceutical composition for preventing or treating colonic diseases caused by enterobacteriaceae, containing caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof as an active ingredient,
The intestinal flora is Enterotoxigenic Bacteroides fragilis (ETBF) bacteria,
The colorectal disease is selected from the group consisting of enterococcus infectious disease, adenomatous polyp, carcinoid, malignant polyp, hyperplastic polyp, polyposis, polyp mucosa, hyperplasia, inflammatory polyp, lipoma, colorectal cancer, colitis, tuberculous enteritis and intestinal obstruction Composition.
The method of claim 1, wherein the caffeic acid phenethyl ester or its pharmaceutically acceptable salt is contained in 20 to 80 μM, characterized in that the pharmaceutical composition for preventing or treating colon diseases caused by enterobacteriaceae .
The method of claim 1, wherein the caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof is a gamma-secretase inhibitor, characterized in that the prevention of colorectal diseases caused by enterobacteriaceae Or therapeutic pharmaceutical compositions.
According to claim 1, wherein the caffeic acid phenethyl ester or pharmaceutically acceptable salts thereof is characterized by inhibiting gamma-secretase activity, colon diseases caused by enterobacteriaceae Prophylactic or therapeutic pharmaceutical compositions.
상기 장내 상재균은 엔테로톡시제닉 박테로이데스 프라길리스(Enterotoxigenic Bacteroides fragilis, ETBF) 세균이고,
상기 대장성 질환은 장내 상재균 감염증, 선종성 용종, 유암종, 악성용종, 과형성 용종, 용종증, 용종양 점막, 과오종, 염증성 용종, 지방종, 대장암, 대장염, 결핵성 장염 및 장폐색으로 이루어진 군으로부터 선택되는 건강기능식품.
As a functional food for preventing or ameliorating colonic diseases caused by enterobacteriaceae containing caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof as an active ingredient,
The intestinal flora is Enterotoxigenic Bacteroides fragilis (ETBF) bacteria,
The colorectal disease is selected from the group consisting of enterococcus infectious disease, adenomatous polyp, carcinoid, malignant polyp, hyperplastic polyp, polyposis, polyp mucosa, hyperplasia, inflammatory polyp, lipoma, colorectal cancer, colitis, tuberculous enteritis and intestinal obstruction Health functional food.
The health functional food for preventing or improving colon diseases caused by enterobacteriaceae, characterized in that the caffeic acid phenethyl ester or its pharmaceutically acceptable salt is contained in 0.1 ~ 80 μM. .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170151787A KR102060227B1 (en) | 2017-11-14 | 2017-11-14 | Pharmaceutical composition for preventing or treating colonic disease comprising caffeic acid phenethyl ester or pharmaceutically acceptable salts thereof as an active ingredient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170151787A KR102060227B1 (en) | 2017-11-14 | 2017-11-14 | Pharmaceutical composition for preventing or treating colonic disease comprising caffeic acid phenethyl ester or pharmaceutically acceptable salts thereof as an active ingredient |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20190054801A KR20190054801A (en) | 2019-05-22 |
| KR102060227B1 true KR102060227B1 (en) | 2019-12-27 |
Family
ID=66679589
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020170151787A KR102060227B1 (en) | 2017-11-14 | 2017-11-14 | Pharmaceutical composition for preventing or treating colonic disease comprising caffeic acid phenethyl ester or pharmaceutically acceptable salts thereof as an active ingredient |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR102060227B1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20230084059A (en) * | 2021-12-01 | 2023-06-12 | 연세대학교 산학협력단 | A composition for preventing or treating biliary tract cancer |
| CN115671049B (en) * | 2022-07-29 | 2024-01-12 | 西华大学 | S/O/W triple nano emulsion for targeted delivery of caffeic acid phenethyl ester and preparation method and application thereof |
| CN116492324A (en) * | 2023-01-04 | 2023-07-28 | 河南科技大学第一附属医院 | Application of caffeic acid in prevention and treatment of colorectal cancer and medicine containing caffeic acid |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101450617B1 (en) * | 2012-11-16 | 2014-10-15 | 가톨릭대학교 산학협력단 | Composition for preventing or treating immune disease comprising Caffeic acid phenethyl ester |
-
2017
- 2017-11-14 KR KR1020170151787A patent/KR102060227B1/en active IP Right Grant
Non-Patent Citations (3)
| Title |
|---|
| Journal of Photochemistry and Photobiology B: Biology, Volume 96, Issue 1, pp. 17-23, 2009.04.02 |
| Turk J Med Sci, 40 (6), pp. 897-903, 2010.03.31 |
| 생명과학회지 제19권 제12호, pp.1787-1793, 2009.12.31 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20190054801A (en) | 2019-05-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102060227B1 (en) | Pharmaceutical composition for preventing or treating colonic disease comprising caffeic acid phenethyl ester or pharmaceutically acceptable salts thereof as an active ingredient | |
| KR102153080B1 (en) | A novel strain of Lactobacillus salivarius HEM 1047, and composition for improving gut environment comprising the strain or its culture fluid | |
| US20240058396A1 (en) | NOVEL STRAIN OF Bifidobacterium animalis subsp. lactis HEM20-01 AND COMPOSITION FOR treating depression, COMPRISING the same OR its culture fluid | |
| KR102084973B1 (en) | Composition for preventing or treating colitis comprising enterococcus faecalis | |
| KR101807328B1 (en) | Dna damage repair promoter for oral application, and elastase activity inhibitor for oral application | |
| KR102174095B1 (en) | A novel strain of Enterococcus faecium HEM 200, and composition for improving gut environment comprising the strain or its culture fluid | |
| JP7531865B2 (en) | Discovery of a novel Akkermansia muciniphila AK32 strain and its application for the prevention or treatment of intestinal damage | |
| EP4095231A1 (en) | Novel lactobacillus sakei strain hem224, and composition for treating inflammation or asthma, comprising strain or culture product thereof | |
| JP2023540711A (en) | Lactobacillus plantarum microorganisms having anticancer activity, compositions containing the same, and methods for preventing or treating cancer using the same | |
| KR100793081B1 (en) | A composition comprising the compound isolated from the extract of gracilaria verucosa for preventing and treating inflammatory disease | |
| KR101466317B1 (en) | A composition for inhibiting cancer metastasis comprising Hwangryunhaedoktang or its product fermented by lactic acid bacteria | |
| KR102201517B1 (en) | A novel strain of Lactobacillus acidophilus HEM 960, and composition for improving gut environment comprising the strain or its culture fluid | |
| KR101772335B1 (en) | A composition for treating, improving and preventing of papilloma virus infection comprising phlorotannin | |
| KR20170045462A (en) | Composition comprising Morifolium extract asan effective component for preventing and treatingarthritis | |
| US7611715B2 (en) | Agaricus extract for preventing the induction or metastasis of cancer | |
| US20130041023A1 (en) | Composition for Preventing or Treating Rotavirus Infection Comprising Licorice Extract | |
| KR20170111763A (en) | Pharmaceutical Composition for Preventing or Treating Enteric Diseases Caused by Clostridium difficile Comprising Lactobacillus acidophilus KCNU | |
| KR102215592B1 (en) | A novel strain of Lactobacillus fermentum HEM 1036, and composition for improving gut environment comprising the strain or its culture fluid | |
| KR101600884B1 (en) | Composition for improving, treating or preventing constipation comprising Cassia fermented by lactic acid bacteria as an active ingredient | |
| KR100526992B1 (en) | Fermented extract of a fruit of the trifoliate orange, and a composition for treating the disease caused by infection of helicobacter pylori | |
| KR101618503B1 (en) | Novel endolichenic fungi and composition for preventing or treatment of gastric cancer or colorectal cancer comprising extracts thereof | |
| KR102215596B1 (en) | A novel strain of Streptococcus thermophilus HEM 14, and composition for improving gut environment comprising the strain or its culture fluid | |
| KR102092729B1 (en) | Pharmaceutical composition for preventing or treating liver damage comprising Curcuma longa extract | |
| KR20200000956A (en) | Compositions for Treatment or Prevention of Intestinal Diseases Comprising Propionibacterium freudenreichii, it culture broth or heat killed Propionibacterium freudenreichii as an active ingredient | |
| KR102542476B1 (en) | Composition for preventing or treating cancer comprising odoribacter splanchnicus or its cell-free supernatant as an effective component |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right |