TWI791190B - 具有預防或治療癌症的效果的新穎菌株 - Google Patents
具有預防或治療癌症的效果的新穎菌株 Download PDFInfo
- Publication number
- TWI791190B TWI791190B TW110103672A TW110103672A TWI791190B TW I791190 B TWI791190 B TW I791190B TW 110103672 A TW110103672 A TW 110103672A TW 110103672 A TW110103672 A TW 110103672A TW I791190 B TWI791190 B TW I791190B
- Authority
- TW
- Taiwan
- Prior art keywords
- cancer
- strain
- cells
- bifidobacterium bifidum
- gen3033
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 198
- 230000000694 effects Effects 0.000 title claims abstract description 67
- 201000011510 cancer Diseases 0.000 claims abstract description 157
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 115
- 241000186016 Bifidobacterium bifidum Species 0.000 claims abstract description 68
- 229940002008 bifidobacterium bifidum Drugs 0.000 claims abstract description 67
- 230000001093 anti-cancer Effects 0.000 claims abstract description 42
- 239000000126 substance Substances 0.000 claims abstract description 34
- 239000000203 mixture Substances 0.000 claims abstract description 20
- 238000011282 treatment Methods 0.000 claims description 34
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 29
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 29
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 23
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 23
- 230000002265 prevention Effects 0.000 claims description 21
- 238000011160 research Methods 0.000 claims description 20
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 claims description 19
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 17
- 235000013305 food Nutrition 0.000 claims description 17
- 201000005202 lung cancer Diseases 0.000 claims description 17
- 208000020816 lung neoplasm Diseases 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 16
- 229960001756 oxaliplatin Drugs 0.000 claims description 16
- 206010009944 Colon cancer Diseases 0.000 claims description 15
- 208000026310 Breast neoplasm Diseases 0.000 claims description 11
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 11
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 11
- 208000014018 liver neoplasm Diseases 0.000 claims description 11
- 241001465754 Metazoa Species 0.000 claims description 10
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 10
- 229960004316 cisplatin Drugs 0.000 claims description 10
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 9
- 230000001580 bacterial effect Effects 0.000 claims description 9
- 238000011161 development Methods 0.000 claims description 9
- 206010017758 gastric cancer Diseases 0.000 claims description 9
- 201000007270 liver cancer Diseases 0.000 claims description 9
- 201000011549 stomach cancer Diseases 0.000 claims description 9
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 8
- 229960002949 fluorouracil Drugs 0.000 claims description 8
- 229960005079 pemetrexed Drugs 0.000 claims description 8
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 claims description 8
- 108010048154 Angiopoietin-1 Proteins 0.000 claims description 7
- 108010048036 Angiopoietin-2 Proteins 0.000 claims description 7
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 6
- 229930012538 Paclitaxel Natural products 0.000 claims description 6
- 229960004397 cyclophosphamide Drugs 0.000 claims description 6
- 229960001592 paclitaxel Drugs 0.000 claims description 6
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 6
- 230000003078 antioxidant effect Effects 0.000 claims description 5
- 229960004562 carboplatin Drugs 0.000 claims description 5
- 190000008236 carboplatin Chemical compound 0.000 claims description 5
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 5
- 229960005277 gemcitabine Drugs 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 230000003053 immunization Effects 0.000 claims description 4
- 229960004679 doxorubicin Drugs 0.000 claims description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 3
- 229960005420 etoposide Drugs 0.000 claims description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 3
- 229960004528 vincristine Drugs 0.000 claims description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 3
- 239000002870 angiogenesis inducing agent Substances 0.000 claims description 2
- 210000000481 breast Anatomy 0.000 claims 3
- 210000002784 stomach Anatomy 0.000 claims 3
- 210000001072 colon Anatomy 0.000 claims 2
- 238000009472 formulation Methods 0.000 claims 2
- 210000004185 liver Anatomy 0.000 claims 2
- 201000000498 stomach carcinoma Diseases 0.000 claims 2
- 102000009088 Angiopoietin-1 Human genes 0.000 claims 1
- 102000009075 Angiopoietin-2 Human genes 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 42
- 230000035755 proliferation Effects 0.000 abstract description 25
- 210000004204 blood vessel Anatomy 0.000 abstract description 8
- 208000027866 inflammatory disease Diseases 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 230000028993 immune response Effects 0.000 abstract description 6
- 230000002708 enhancing effect Effects 0.000 abstract description 3
- 230000002757 inflammatory effect Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 133
- 241000194035 Lactococcus lactis Species 0.000 description 61
- 235000014897 Streptococcus lactis Nutrition 0.000 description 61
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 38
- 241000894006 Bacteria Species 0.000 description 23
- 210000001744 T-lymphocyte Anatomy 0.000 description 23
- 230000004611 cancer cell death Effects 0.000 description 23
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 21
- 108010074328 Interferon-gamma Proteins 0.000 description 20
- 239000004310 lactic acid Substances 0.000 description 19
- 235000014655 lactic acid Nutrition 0.000 description 19
- PFJKOHUKELZMLE-VEUXDRLPSA-N ganglioside GM3 Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@@H]([C@H](O)/C=C/CCCCCCCCCCCCC)NC(=O)CCCCCCCCCCCCC\C=C/CCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 PFJKOHUKELZMLE-VEUXDRLPSA-N 0.000 description 18
- 230000001965 increasing effect Effects 0.000 description 18
- 210000002865 immune cell Anatomy 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 230000004614 tumor growth Effects 0.000 description 17
- 102000003812 Interleukin-15 Human genes 0.000 description 15
- 108090000172 Interleukin-15 Proteins 0.000 description 15
- 241000699666 Mus <mouse, genus> Species 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 15
- 230000006870 function Effects 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 241000282414 Homo sapiens Species 0.000 description 14
- 102000000704 Interleukin-7 Human genes 0.000 description 13
- 108010002586 Interleukin-7 Proteins 0.000 description 13
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 12
- 102100034594 Angiopoietin-1 Human genes 0.000 description 12
- 102100034608 Angiopoietin-2 Human genes 0.000 description 12
- 229940100994 interleukin-7 Drugs 0.000 description 12
- 210000002540 macrophage Anatomy 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- 102100037850 Interferon gamma Human genes 0.000 description 10
- 102000008070 Interferon-gamma Human genes 0.000 description 10
- 229940044627 gamma-interferon Drugs 0.000 description 10
- 239000002207 metabolite Substances 0.000 description 10
- 230000004083 survival effect Effects 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 206010029113 Neovascularisation Diseases 0.000 description 9
- 230000000968 intestinal effect Effects 0.000 description 9
- 239000003642 reactive oxygen metabolite Substances 0.000 description 9
- -1 2-naphthyl butyrate (2-naphthyl butyrate) Chemical compound 0.000 description 8
- 150000001720 carbohydrates Chemical class 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 210000003743 erythrocyte Anatomy 0.000 description 8
- 230000001747 exhibiting effect Effects 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 210000003071 memory t lymphocyte Anatomy 0.000 description 8
- 150000003905 phosphatidylinositols Chemical class 0.000 description 8
- 238000004321 preservation Methods 0.000 description 8
- PGROHZHFGAHXNO-PMERELPUSA-N 2-[[(2s)-2-(hexadecanoylamino)-6-[(4-nitro-2,1,3-benzoxadiazol-7-yl)amino]hexanoyl]amino]ethyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)N[C@H](C(=O)NCCOP([O-])(=O)OCC[N+](C)(C)C)CCCCNC1=CC=C([N+]([O-])=O)C2=NON=C12 PGROHZHFGAHXNO-PMERELPUSA-N 0.000 description 7
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 230000004663 cell proliferation Effects 0.000 description 7
- 239000012091 fetal bovine serum Substances 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- 239000006041 probiotic Substances 0.000 description 7
- 235000018291 probiotics Nutrition 0.000 description 7
- 230000001105 regulatory effect Effects 0.000 description 7
- 101000924552 Homo sapiens Angiopoietin-1 Proteins 0.000 description 6
- 101000924533 Homo sapiens Angiopoietin-2 Proteins 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 6
- 239000002158 endotoxin Substances 0.000 description 6
- 229920006008 lipopolysaccharide Polymers 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 210000001616 monocyte Anatomy 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 210000003289 regulatory T cell Anatomy 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- YXHLJMWYDTXDHS-IRFLANFNSA-N 7-aminoactinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=C(N)C=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 YXHLJMWYDTXDHS-IRFLANFNSA-N 0.000 description 5
- 108700012813 7-aminoactinomycin D Proteins 0.000 description 5
- 206010027476 Metastases Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000002159 abnormal effect Effects 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 230000003833 cell viability Effects 0.000 description 5
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 235000013373 food additive Nutrition 0.000 description 5
- 239000002778 food additive Substances 0.000 description 5
- 230000005965 immune activity Effects 0.000 description 5
- 230000036039 immunity Effects 0.000 description 5
- 229940027941 immunoglobulin g Drugs 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 210000002429 large intestine Anatomy 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- VDABVNMGKGUPEY-UHFFFAOYSA-N 6-carboxyfluorescein succinimidyl ester Chemical compound C=1C(O)=CC=C2C=1OC1=CC(O)=CC=C1C2(C1=C2)OC(=O)C1=CC=C2C(=O)ON1C(=O)CCC1=O VDABVNMGKGUPEY-UHFFFAOYSA-N 0.000 description 4
- 241000186000 Bifidobacterium Species 0.000 description 4
- 229940045513 CTLA4 antagonist Drugs 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 102100027286 Fanconi anemia group C protein Human genes 0.000 description 4
- DJNTZVRUYMHBTD-UHFFFAOYSA-N Octyl octanoate Chemical compound CCCCCCCCOC(=O)CCCCCCC DJNTZVRUYMHBTD-UHFFFAOYSA-N 0.000 description 4
- 239000012980 RPMI-1640 medium Substances 0.000 description 4
- 208000000453 Skin Neoplasms Diseases 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000000090 biomarker Substances 0.000 description 4
- 230000009702 cancer cell proliferation Effects 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 235000013365 dairy product Nutrition 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 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 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- 235000013376 functional food Nutrition 0.000 description 4
- 208000026278 immune system disease Diseases 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 201000008968 osteosarcoma Diseases 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 201000000849 skin cancer Diseases 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 108020004465 16S ribosomal RNA Proteins 0.000 description 3
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- 102000008096 B7-H1 Antigen Human genes 0.000 description 3
- 108010074708 B7-H1 Antigen Proteins 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- VACSGJNKDJZOKY-SNPVRQPZSA-O C(CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC)(=O)P(=S)=C(O)C[N+](C)(C)C Chemical compound C(CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC)(=O)P(=S)=C(O)C[N+](C)(C)C VACSGJNKDJZOKY-SNPVRQPZSA-O 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 229920001917 Ficoll Polymers 0.000 description 3
- 206010029260 Neuroblastoma Diseases 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 239000012979 RPMI medium Substances 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
- 235000021342 arachidonic acid Nutrition 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- AFYNADDZULBEJA-UHFFFAOYSA-N bicinchoninic acid Chemical compound C1=CC=CC2=NC(C=3C=C(C4=CC=CC=C4N=3)C(=O)O)=CC(C(O)=O)=C21 AFYNADDZULBEJA-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 238000011284 combination treatment Methods 0.000 description 3
- 238000012790 confirmation Methods 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 229930182478 glucoside Natural products 0.000 description 3
- 150000008131 glucosides Chemical class 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000012139 lysis buffer Substances 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 3
- 210000000822 natural killer cell Anatomy 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000003753 real-time PCR Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 230000002100 tumorsuppressive effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 2
- QJRYPNZYBXWKEV-DUQPFJRNSA-N 1-naphthyl N-acetyl-beta-D-glucosaminide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=CC2=CC=CC=C12 QJRYPNZYBXWKEV-DUQPFJRNSA-N 0.000 description 2
- VBUYCZFBVCCYFD-JJYYJPOSSA-N 2-dehydro-D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)C(O)=O VBUYCZFBVCCYFD-JJYYJPOSSA-N 0.000 description 2
- MWHKPYATGMFFPI-LJIZCISZSA-N 2-naphthyl alpha-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC1=CC=C(C=CC=C2)C2=C1 MWHKPYATGMFFPI-LJIZCISZSA-N 0.000 description 2
- HFJUQSUBZOKELZ-FITDYDNJSA-N 2-naphthyl alpha-L-fucoside Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1OC1=CC=C(C=CC=C2)C2=C1 HFJUQSUBZOKELZ-FITDYDNJSA-N 0.000 description 2
- MWHKPYATGMFFPI-LYYZXLFJSA-N 2-naphthyl beta-D-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(C=CC=C2)C2=C1 MWHKPYATGMFFPI-LYYZXLFJSA-N 0.000 description 2
- CQTZJAKSNDFPOB-UHFFFAOYSA-N 2-naphthyl dihydrogen phosphate Chemical compound C1=CC=CC2=CC(OP(O)(=O)O)=CC=C21 CQTZJAKSNDFPOB-UHFFFAOYSA-N 0.000 description 2
- 201000003076 Angiosarcoma Diseases 0.000 description 2
- 101710180684 Beta-hexosaminidase Proteins 0.000 description 2
- 101710124976 Beta-hexosaminidase A Proteins 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 241001302654 Escherichia coli Nissle 1917 Species 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 102000053187 Glucuronidase Human genes 0.000 description 2
- 108010060309 Glucuronidase Proteins 0.000 description 2
- 208000001258 Hemangiosarcoma Diseases 0.000 description 2
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 2
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 241000917009 Lactobacillus rhamnosus GG Species 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 231100000002 MTT assay Toxicity 0.000 description 2
- 238000000134 MTT assay Methods 0.000 description 2
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- WBKDRBRGYHZWCT-UPHRSURJSA-N Piceatannol 4'-galloylglucoside Chemical compound O1C(OC=2C(=CC(\C=C/C=3C=C(O)C=C(O)C=3)=CC=2)O)C(O)C(O)C(O)C1COC(=O)C1=CC(O)=C(O)C(O)=C1 WBKDRBRGYHZWCT-UPHRSURJSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102100030122 Protein O-GlcNAcase Human genes 0.000 description 2
- 101710081801 Protein O-GlcNAcase Proteins 0.000 description 2
- 101710199095 Putative beta-hexosaminidase Proteins 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 206010057644 Testis cancer Diseases 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 102000005840 alpha-Galactosidase Human genes 0.000 description 2
- 108010030291 alpha-Galactosidase Proteins 0.000 description 2
- 108010028144 alpha-Glucosidases Proteins 0.000 description 2
- 102000012086 alpha-L-Fucosidase Human genes 0.000 description 2
- 108010061314 alpha-L-Fucosidase Proteins 0.000 description 2
- 102000019199 alpha-Mannosidase Human genes 0.000 description 2
- 108010012864 alpha-Mannosidase Proteins 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000003064 anti-oxidating effect Effects 0.000 description 2
- 230000005975 antitumor immune response Effects 0.000 description 2
- 229960003852 atezolizumab Drugs 0.000 description 2
- 102000005936 beta-Galactosidase Human genes 0.000 description 2
- 108010005774 beta-Galactosidase Proteins 0.000 description 2
- 102000006995 beta-Glucosidase Human genes 0.000 description 2
- 108010047754 beta-Glucosidase Proteins 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000001461 cytolytic effect Effects 0.000 description 2
- HEBKCHPVOIAQTA-NGQZWQHPSA-N d-xylitol Chemical compound OC[C@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-NGQZWQHPSA-N 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 210000003608 fece Anatomy 0.000 description 2
- 230000009422 growth inhibiting effect Effects 0.000 description 2
- BJRNKVDFDLYUGJ-RMPHRYRLSA-N hydroquinone O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-RMPHRYRLSA-N 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000036737 immune function Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 229940088592 immunologic factor Drugs 0.000 description 2
- 230000008944 intestinal immunity Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 229960005386 ipilimumab Drugs 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- ZBDGHWFPLXXWRD-JGWLITMVSA-N methyl beta-D-xylopyranoside Chemical compound CO[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O ZBDGHWFPLXXWRD-JGWLITMVSA-N 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 238000002552 multiple reaction monitoring Methods 0.000 description 2
- MQAYFGXOFCEZRW-UHFFFAOYSA-N oxane-2-carboxylic acid Chemical compound OC(=O)C1CCCCO1 MQAYFGXOFCEZRW-UHFFFAOYSA-N 0.000 description 2
- 229960002621 pembrolizumab Drugs 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- CDRPUGZCRXZLFL-OWOJBTEDSA-N piceatannol Chemical compound OC1=CC(O)=CC(\C=C\C=2C=C(O)C(O)=CC=2)=C1 CDRPUGZCRXZLFL-OWOJBTEDSA-N 0.000 description 2
- MZPWKJZDOCIALD-UHFFFAOYSA-N pyrocatechol sulfate Chemical compound OC1=CC=CC=C1OS(O)(=O)=O MZPWKJZDOCIALD-UHFFFAOYSA-N 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 2
- RULSWEULPANCDV-PIXUTMIVSA-N turanose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](C(=O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O RULSWEULPANCDV-PIXUTMIVSA-N 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- CDVZCUKHEYPEQS-DOLHLQLQSA-N (2S,3R,4S)-2,3,4,5-tetrahydroxypentanal Chemical compound O=C[C@@H](O)[C@H](O)[C@@H](O)CO.O=C[C@@H](O)[C@H](O)[C@@H](O)CO CDVZCUKHEYPEQS-DOLHLQLQSA-N 0.000 description 1
- CDVZCUKHEYPEQS-IBVPOFDWSA-N (2r,3s,4r)-2,3,4,5-tetrahydroxypentanal Chemical compound OC[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@H](O)[C@@H](O)C=O CDVZCUKHEYPEQS-IBVPOFDWSA-N 0.000 description 1
- CDVZCUKHEYPEQS-AZIZVCISSA-N (2r,3s,4s)-2,3,4,5-tetrahydroxypentanal Chemical compound OC[C@H](O)[C@H](O)[C@@H](O)C=O.OC[C@H](O)[C@H](O)[C@@H](O)C=O CDVZCUKHEYPEQS-AZIZVCISSA-N 0.000 description 1
- OJDZKIIKLJJBRX-PIIYHDNRSA-N (2r,3s,4s,5r)-2,3,4,5-tetrahydroxyhexanal Chemical compound C[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O.C[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O OJDZKIIKLJJBRX-PIIYHDNRSA-N 0.000 description 1
- HOVAGTYPODGVJG-BWSJPXOBSA-N (2r,3s,4s,5s)-2-(hydroxymethyl)-6-methoxyoxane-3,4,5-triol Chemical compound COC1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O HOVAGTYPODGVJG-BWSJPXOBSA-N 0.000 description 1
- OJDZKIIKLJJBRX-KHYZTKRTSA-N (2s,3r,4r,5s)-2,3,4,5-tetrahydroxyhexanal Chemical compound C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O.C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O OJDZKIIKLJJBRX-KHYZTKRTSA-N 0.000 description 1
- VQVUBYASAICPFU-UHFFFAOYSA-N (6'-acetyloxy-2',7'-dichloro-3-oxospiro[2-benzofuran-1,9'-xanthene]-3'-yl) acetate Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(Cl)=C(OC(C)=O)C=C1OC1=C2C=C(Cl)C(OC(=O)C)=C1 VQVUBYASAICPFU-UHFFFAOYSA-N 0.000 description 1
- XUCIJNAGGSZNQT-JHSLDZJXSA-N (R)-amygdalin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O[C@@H](C#N)C=2C=CC=CC=2)O1 XUCIJNAGGSZNQT-JHSLDZJXSA-N 0.000 description 1
- GZCWLCBFPRFLKL-UHFFFAOYSA-N 1-prop-2-ynoxypropan-2-ol Chemical compound CC(O)COCC#C GZCWLCBFPRFLKL-UHFFFAOYSA-N 0.000 description 1
- 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
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 description 1
- ACOOAEDFQKSZTC-NABGWTBKSA-N 2-naphthol AS BI-beta-D-glucuronide Chemical compound COC1=CC=CC=C1NC(=O)C1=CC2=CC(Br)=CC=C2C=C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 ACOOAEDFQKSZTC-NABGWTBKSA-N 0.000 description 1
- CXVZBUOSDMLXNK-UHFFFAOYSA-N 2-naphthyl octanoate Chemical compound C1=CC=CC2=CC(OC(=O)CCCCCCC)=CC=C21 CXVZBUOSDMLXNK-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- IZSRJDGCGRAUAR-MROZADKFSA-M 5-dehydro-D-gluconate Chemical compound OCC(=O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O IZSRJDGCGRAUAR-MROZADKFSA-M 0.000 description 1
- NLRXQZJJCPRATR-CWVYHPPDSA-N 6-bromo-2-naphthyl alpha-D-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC1=CC=C(C=C(Br)C=C2)C2=C1 NLRXQZJJCPRATR-CWVYHPPDSA-N 0.000 description 1
- 108010051457 Acid Phosphatase Proteins 0.000 description 1
- 102000013563 Acid Phosphatase Human genes 0.000 description 1
- PLXMOAALOJOTIY-FPTXNFDTSA-N Aesculin Natural products OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@H]1Oc2cc3C=CC(=O)Oc3cc2O PLXMOAALOJOTIY-FPTXNFDTSA-N 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 210000005236 CD8+ effector T cell Anatomy 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- WNBCMONIPIJTSB-BGNCJLHMSA-N Cichoriin Natural products O([C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1)c1c(O)cc2c(OC(=O)C=C2)c1 WNBCMONIPIJTSB-BGNCJLHMSA-N 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 108091000069 Cystinyl Aminopeptidase Proteins 0.000 description 1
- 102000030900 Cystinyl aminopeptidase Human genes 0.000 description 1
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose 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)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 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-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- HEBKCHPVOIAQTA-QWWZWVQMSA-N D-arabinitol Chemical compound OC[C@@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-QWWZWVQMSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- QWIZNVHXZXRPDR-UHFFFAOYSA-N D-melezitose Natural products O1C(CO)C(O)C(O)C(O)C1OC1C(O)C(CO)OC1(CO)OC1OC(CO)C(O)C(O)C1O QWIZNVHXZXRPDR-UHFFFAOYSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- LKDRXBCSQODPBY-OEXCPVAWSA-N D-tagatose Chemical compound OCC1(O)OC[C@@H](O)[C@H](O)[C@@H]1O LKDRXBCSQODPBY-OEXCPVAWSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 241000283086 Equidae 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
- 108090000371 Esterases Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 206010016228 Fasciitis Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 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 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 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 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 1
- 101000894590 Homo sapiens Uncharacterized protein C20orf85 Proteins 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 229920001202 Inulin Polymers 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 1
- HEBKCHPVOIAQTA-IMJSIDKUSA-N L-arabinitol Chemical compound OC[C@H](O)C(O)[C@@H](O)CO HEBKCHPVOIAQTA-IMJSIDKUSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- JWHURRLUBVMKOT-HNNXBMFYSA-N L-leucine 2-naphthylamide Chemical compound C1=CC=CC2=CC(NC(=O)[C@@H](N)CC(C)C)=CC=C21 JWHURRLUBVMKOT-HNNXBMFYSA-N 0.000 description 1
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 description 1
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-OWMBCFKOSA-N L-ribopyranose Chemical compound O[C@H]1COC(O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-OWMBCFKOSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 241000186660 Lactobacillus Species 0.000 description 1
- 241000194036 Lactococcus Species 0.000 description 1
- 241000194041 Lactococcus lactis subsp. lactis Species 0.000 description 1
- 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 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102100020862 Lymphocyte activation gene 3 protein Human genes 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
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- JMILOTKBOBTKBB-FCQUAONHSA-N N-[(10Z)-7-Benzyl-5,8-dihydroxy-3-phenyl-2-oxa-6,9-diazabicyclo[10.2.2]hexadeca-1(14),5,8,10,12,15-hexaen-4-yl]-1-[2-(dimethylamino)-3-methylpentanoyl]pyrrolidine-2-carboximidic acid Chemical compound CCC(C)C(N(C)C)C(=O)N1CCCC1C(=O)NC1C(=O)NC(CC=2C=CC=CC=2)C(=O)N\C=C/C(C=C2)=CC=C2OC1C1=CC=CC=C1 JMILOTKBOBTKBB-FCQUAONHSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- UNBPEIBIPPJZIR-NRFANRHFSA-N N-glutaryl-L-phenylalanine 2-naphthylamide Chemical compound C([C@H](NC(=O)CCCC(=O)O)C(=O)NC=1C=C2C=CC=CC2=CC=1)C1=CC=CC=C1 UNBPEIBIPPJZIR-NRFANRHFSA-N 0.000 description 1
- DEFAKPKFXYITPZ-UHFFFAOYSA-N N-{5-carbamimidamido-1-[(naphthalen-2-yl)amino]-1-oxopentan-2-yl}benzamide Chemical compound C=1C=C2C=CC=CC2=CC=1NC(=O)C(CCCN=C(N)N)NC(=O)C1=CC=CC=C1 DEFAKPKFXYITPZ-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- CDVZCUKHEYPEQS-LKWPHFQBSA-N OC[C@@H](O)[C@H](O)[C@H](O)C=O.OC[C@@H](O)[C@H](O)[C@H](O)C=O Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)C=O.OC[C@@H](O)[C@H](O)[C@H](O)C=O CDVZCUKHEYPEQS-LKWPHFQBSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- ODRFODNLKCBNIK-UHFFFAOYSA-N Perulactone Chemical compound C1OC(=O)C(C)C1CC(O)C(C)(O)C1C2(C)CCC3C4(C)C(OC(C)=O)CC(O)CC4=CCC3C2CC1 ODRFODNLKCBNIK-UHFFFAOYSA-N 0.000 description 1
- OQGUJEDWFILVGV-UHFFFAOYSA-N Perulactone Natural products CC1C(CC(O)C(C)(O)C2CCC3C4C=CC5CC(O)CC(OC(=O)C)C5(C)C4CCC23C)OCC1=O OQGUJEDWFILVGV-UHFFFAOYSA-N 0.000 description 1
- 108091007744 Programmed cell death receptors Proteins 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- NGFMICBWJRZIBI-JZRPKSSGSA-N Salicin Natural products O([C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](CO)O1)c1c(CO)cccc1 NGFMICBWJRZIBI-JZRPKSSGSA-N 0.000 description 1
- 241000207929 Scutellaria Species 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 241000607715 Serratia marcescens Species 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000014969 Streptococcus diacetilactis Nutrition 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 102100021442 Uncharacterized protein C20orf85 Human genes 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- HUXIAXQSTATULQ-UHFFFAOYSA-N [6-bromo-3-[(2-methoxyphenyl)carbamoyl]naphthalen-2-yl] dihydrogen phosphate Chemical compound COC1=CC=CC=C1NC(=O)C1=CC2=CC(Br)=CC=C2C=C1OP(O)(O)=O HUXIAXQSTATULQ-UHFFFAOYSA-N 0.000 description 1
- 230000007488 abnormal function Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- XBJFCYDKBDVADW-UHFFFAOYSA-N acetonitrile;formic acid Chemical compound CC#N.OC=O XBJFCYDKBDVADW-UHFFFAOYSA-N 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 108010027597 alpha-chymotrypsin Proteins 0.000 description 1
- NGFMICBWJRZIBI-UHFFFAOYSA-N alpha-salicin Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=CC=C1CO NGFMICBWJRZIBI-UHFFFAOYSA-N 0.000 description 1
- 229940089837 amygdalin Drugs 0.000 description 1
- YZLOSXFCSIDECK-UHFFFAOYSA-N amygdalin Natural products OCC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC(C#N)c3ccccc3 YZLOSXFCSIDECK-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 229960000271 arbutin Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- DLRVVLDZNNYCBX-LIZSDCNHSA-N beta-D-Glcp-(1->6)-beta-D-Glcp Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)O1 DLRVVLDZNNYCBX-LIZSDCNHSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- DLRVVLDZNNYCBX-ZZFZYMBESA-N beta-melibiose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)O1 DLRVVLDZNNYCBX-ZZFZYMBESA-N 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000001217 buttock Anatomy 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 239000008004 cell lysis buffer Substances 0.000 description 1
- 239000002771 cell marker Substances 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229940009714 erythritol Drugs 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
- 229940093496 esculin Drugs 0.000 description 1
- XHCADAYNFIFUHF-TVKJYDDYSA-N esculin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC(C(=C1)O)=CC2=C1OC(=O)C=C2 XHCADAYNFIFUHF-TVKJYDDYSA-N 0.000 description 1
- AWRMZKLXZLNBBK-UHFFFAOYSA-N esculin Natural products OC1OC(COc2cc3C=CC(=O)Oc3cc2O)C(O)C(O)C1O AWRMZKLXZLNBBK-UHFFFAOYSA-N 0.000 description 1
- YGHHWSRCTPQFFC-UHFFFAOYSA-N eucalyptosin A Natural products OC1C(O)C(O)C(CO)OC1OC1C(OC(C#N)C=2C=CC=CC=2)OC(CO)C(O)C1O YGHHWSRCTPQFFC-UHFFFAOYSA-N 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 150000002339 glycosphingolipids Chemical class 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 230000003871 intestinal function Effects 0.000 description 1
- 230000007413 intestinal health Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 229940029339 inulin Drugs 0.000 description 1
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 1
- 230000006799 invasive growth in response to glucose limitation Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 108010045002 jubanine C Proteins 0.000 description 1
- JMILOTKBOBTKBB-UHFFFAOYSA-N jubanine-C Natural products CCC(C)C(N(C)C)C(=O)N1CCCC1C(=O)NC2C(Oc3ccc(C=C/NC(=O)C(Cc4ccccc4)NC2=O)cc3)c5ccccc5 JMILOTKBOBTKBB-UHFFFAOYSA-N 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229940039696 lactobacillus Drugs 0.000 description 1
- 229940059406 lactobacillus rhamnosus gg Drugs 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XFIKMPRBSORKQP-JATHGWPISA-M lithium;9-[(e)-4-[(2s,3r,4r,5s)-3,4-dihydroxy-5-[[(2s,3s)-3-[(2s,3s)-3-hydroxybutan-2-yl]oxiran-2-yl]methyl]oxan-2-yl]-3-methylbut-2-enoyl]oxynonanoate Chemical compound [Li+].C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1 XFIKMPRBSORKQP-JATHGWPISA-M 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 201000006512 mast cell neoplasm Diseases 0.000 description 1
- QWIZNVHXZXRPDR-WSCXOGSTSA-N melezitose Chemical compound O([C@@]1(O[C@@H]([C@H]([C@@H]1O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O)CO)CO)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QWIZNVHXZXRPDR-WSCXOGSTSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- HOVAGTYPODGVJG-WLDMJGECSA-N methyl D-glucoside Chemical compound COC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HOVAGTYPODGVJG-WLDMJGECSA-N 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000006872 mrs medium Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 230000037125 natural defense Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 description 1
- 229940067626 phosphatidylinositols Drugs 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 230000006697 redox regulation Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 102200082402 rs751610198 Human genes 0.000 description 1
- NGFMICBWJRZIBI-UJPOAAIJSA-N salicin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=CC=C1CO NGFMICBWJRZIBI-UJPOAAIJSA-N 0.000 description 1
- 229940120668 salicin Drugs 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000031068 symbiosis, encompassing mutualism through parasitism Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/745—Bifidobacteria
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
- A23C9/123—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt
- A23C9/1234—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt characterised by using a Lactobacillus sp. other than Lactobacillus Bulgaricus, including Bificlobacterium sp.
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K10/00—Animal feeding-stuffs
- A23K10/10—Animal feeding-stuffs obtained by microbiological or biochemical processes
- A23K10/16—Addition of microorganisms or extracts thereof, e.g. single-cell proteins, to feeding-stuff compositions
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K10/00—Animal feeding-stuffs
- A23K10/10—Animal feeding-stuffs obtained by microbiological or biochemical processes
- A23K10/16—Addition of microorganisms or extracts thereof, e.g. single-cell proteins, to feeding-stuff compositions
- A23K10/18—Addition of microorganisms or extracts thereof, e.g. single-cell proteins, to feeding-stuff compositions of live microorganisms
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/10—Feeding-stuffs specially adapted for particular animals for ruminants
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/20—Feeding-stuffs specially adapted for particular animals for horses
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/40—Feeding-stuffs specially adapted for particular animals for carnivorous animals, e.g. cats or dogs
-
- 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
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
- C12N1/205—Bacterial isolates
-
- 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
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
-
- 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
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
- A23V2400/157—Lactis
-
- 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
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/21—Streptococcus, lactococcus
- A23V2400/231—Lactis
-
- 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
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/51—Bifidobacterium
- A23V2400/517—Bifidum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/46—Streptococcus ; Enterococcus; Lactococcus
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Polymers & Plastics (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Food Science & Technology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Wood Science & Technology (AREA)
- Biomedical Technology (AREA)
- Animal Husbandry (AREA)
- Tropical Medicine & Parasitology (AREA)
- General Engineering & Computer Science (AREA)
- Virology (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Birds (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Endocrinology (AREA)
- Oncology (AREA)
Abstract
本發明係關於新穎雙歧雙歧桿菌MG731(Bifidobacterium bifidum MG731)菌株及包含其的癌症預防或治療用組合物。具體而言,本發明之雙歧雙歧桿菌MG731菌株具有抑制癌細胞增殖、降低癌細胞移動性、抑制新血管生成、增強抗癌免疫反應的效果,同時降低炎性因子的表現,從而具有預防或治療癌症或炎性疾病的效果。並且,當與化學抗癌劑或免疫抗癌劑並用時,本發明之雙歧雙歧桿菌MG731菌株展現出更優秀的抗癌效果。
Description
本發明係關於具有預防或治療癌症的優秀效果的新穎雙歧雙歧桿菌MG731(Bifidobacterium bifidum
MG731)菌株及乳酸乳球菌GEN3033(Lactococcus lactis
GEN3033)菌株。
具體而言,本發明之新穎雙歧雙歧桿菌MG731菌株不僅具有抑制癌細胞的增殖的效果,而且具有降低癌細胞的移動性並調節參與新血管生成的基因的表現的效果,從而具有比現有的雙歧雙歧桿菌菌株顯著優秀的效果。不僅如此,本發明之雙歧雙歧桿菌MG731菌株具有抗炎、抗氧化及增強免疫效果。
並且,本發明之新穎乳酸乳球菌GEN3033菌株不僅具有癌細胞自身的增殖抑制效果,而且增強免疫活性,由此具有比現有的乳酸乳球菌菌株顯著優秀的效果。具體地,本發明之乳酸乳球菌GEN3033菌株在腸道定植過程中分泌具有抗癌功效的代謝產物,從而具有優異的抗癌效果。
人體的腸道具有藉由多種細菌的共生來吸收因食物消化所帶來的營養素的吸收及將體內不必要的物質排泄至體外的重要功能。並且,因腸道內細菌的環境變化也與腸道免疫直接聯繫,這最終還影響到體內免疫力。經由這幾年持續對此種有益於腸內健康的微生物的研究,世界各地正在積極公佈有關乳酸菌的腸道功能、免疫力及參與體內代謝活動的研究結果。益生菌(probiotics)係指存活的微生物,其起到如下功能,即,藉由改善消化道內的不平衡,抑制有害細菌並增強自然防禦效果來提高體內免疫反應。過去,用於提高腸道免疫功能的益生菌的功能研究利用乳酸菌屬(Lactobacillus
)、乳球菌屬(Lactococcus
)、雙歧桿菌屬(Bifidobacterium
)等,根據種(species)及屬(genus)之分類學形式進行研究。
乳酸菌的研究始於1900年代由梅奇尼科夫發表乳酸菌延長壽命的效果,1946年將釀膿鏈球菌(Streptococcus pyogenes
)及黏質沙雷氏菌(Serratia marcescen
)以骨肉瘤(Osteosarcoma)患者為對象直接注入腫瘤內時,一部分患者出現了腫瘤治療反應,以此為基礎,關於乳酸菌的抗癌治療的研究正在全面展開,目前為止,多項臨床前研究一直在活躍進行。
2016年El-Nezami研究組表明,當給小鼠同種腫瘤模型口服給藥按既定比例混合的鼠李糖乳桿菌GG(L. rhamnosus GG)、大腸桿菌尼斯勒1917(E. coli Nissle 1917)以及熱處理的VSL#3時,與作為抗癌劑之順鉑(Cisplatin)相比,具有藉由抑制新血管生成過程而帶來的抗癌效果。並且,給藥了抗癌劑的組出現因抗癌劑之毒性而導致的小鼠體重減輕,相反,給藥了益生菌的組卻未出現此種情況,從而證明益生菌可具有作為抗癌治療劑的功能。然而,上述多項研究中所使用的益生菌含有多種複合微生物,並且缺乏對於每種微生物的功能性研究。
與普通細胞不同,癌症為可怕的疾病之一,癌症細胞增殖能力無限,其增殖速度也快,並且利用圍繞癌細胞的血管、淋巴管及成纖維細胞等來形成腫瘤微環境,誘發向其他組織之轉移及普通細胞的功能喪失等而導致死亡。
為了治療這些癌症,世界各地的研究人員正在開展關於癌細胞的細胞內信號轉導及轉移、藥物的副作用等的多種主題的多項研究,每年開發出新藥,並進行著使許多癌症患者期待治療效果的臨床試驗。
除了藉由手術切除腫瘤組織和放射線治療之外,用於抗癌治療的當前多種抗癌劑根據各個癌症種類而不同地應用。通常,給癌症患者所開處方中的化學抗癌劑並非以癌細胞作為靶,因此雖然具有殺死癌細胞的效果,但也影響正常細胞,因此患者發生脫髮、腹瀉、發燒、免疫力低下等副作用。此後,基於癌症的遺傳研究等開發出由各種癌症中產生的基因突變作為對象的靶向抗癌劑,雖然大大改善了因現有的化學抗癌劑產生的副作用,但快速適應環境的癌細胞為了脫離靶向抗癌劑的攻擊而誘發對抗癌劑的抗藥性,因此存在無法100%期待靶向抗癌劑之持續性癌症治療效果的問題。
近年來,積極開展著對抗癌劑及腫瘤微環境的研究,並開發出保持抗癌效果的同時調節患者之免疫力的諸多免疫檢查點抑制劑的免疫抗癌劑,並作為治療劑來使用於患者。據悉,其中,對PD-1/PD-L1之治療對皮膚癌、肺癌等的患者呈現出較高的治療反應。此種免疫抗癌劑在腫瘤微環境內調節免疫細胞的功能,從而具有癌細胞的增殖抑制及提高免疫細胞的活性的功能。然而,還存在如下問題:免疫抗癌劑亦無法對所有患者呈現出相同的抗癌效果,並且還未明確披露對於免疫抗癌劑的生物標誌物(biomarker),JAK-STAT(兩面神激酶-信號轉導子和轉錄活化子)會因基因突變對抗癌劑產生抗藥性,或者會導致因抗體合成物的特性引起的自身免疫疾病,產生昂貴的治療費用。
基於該些研究結果,本發明人進行過實質性地對癌症患者可呈現出治療改善效果的微生物的研究,發現雙歧雙歧桿菌MG731(Bifidobacterium bifidum
MG731)菌株和乳酸乳球菌GEN3033(Lactococcus lactis
GEN3033)菌株分別對癌細胞的增殖抑制等呈現出優秀的效果的事實,從而完成了本發明。
待解決之問題
本發明用於將呈現出抗癌及抗炎效果的益生菌或其提取物適用於新穎抗癌劑、炎性疾病治療劑或免疫疾病治療劑等的開發。
因此,本發明之目的之一在於,提供具有優秀的癌症預防或治療效果的雙歧雙歧桿菌MG731(Bifidobacterium bifidum
MG731)菌株。
本發明之另一目的在於,提供包含雙歧雙歧桿菌MG731(Bifidobacterium bifidum
MG731)菌株的癌症預防或治療用醫藥組合物。
並且,本發明之目的在於,提供包含雙歧雙歧桿菌MG731(Bifidobacterium bifidum
MG731)菌株的癌症預防或改善用食品組合物或動物用飼料組合物。
並且,本發明用於提供具有優秀的癌症預防或治療效果的新穎乳酸乳球菌GEN3033(Lactococcus lactis
GEN3033)菌株。
本發明之另一目的在於,提供包含乳酸乳球菌GEN3033(Lactococcus lactis
GEN3033)菌株的癌症預防或治療用醫藥組合物。
並且,本發明之目的在於,提供包含乳酸乳球菌GEN3033(Lactococcus lactis
GEN3033)菌株的癌症預防或改善用食品組合物或動物用飼料組合物。
解決問題之方案
為了實現上述目的,本發明提供新穎雙歧雙歧桿菌MG731(Bifidobacterium bifidum
MG731)菌株。上述菌株於2018年01月04日以保藏號KCTC13452BP保藏在韓國生命工程研究院生物資源中心。
並且,本發明提供包含雙歧雙歧桿菌MG731菌株的癌症預防或治療用醫藥組合物。具體而言,上述雙歧雙歧桿菌MG731菌株可意指包含菌株本身、菌株的培養液或破碎菌株而獲得的細胞質組分(Cytoplasmic fraction)。
本發明提供在受試者中預防或治療癌症的方法,包含將有效量的雙歧雙歧桿菌MG731(Bifidobacterium bifidum
MG731)菌株向需要預防或治療癌症的受試者(subject)給藥。在本申請中使用的用語「受試者」包括人類及非人類動物。非人類動物包括所有脊椎動物,例如,哺乳類及非哺乳類,例如,非人類靈長類、羊、狗、牛、馬等。並且,本發明提供用於預防或治療癌症的雙歧雙歧桿菌MG731(Bifidobacterium bifidum
MG731)菌株的用途。
尤其,本發明之雙歧雙歧桿菌MG731菌株的特徵在於,均呈現出抗癌、抗炎、抗氧化及免疫增強效果。
在本發明中,癌症可以為黑色素瘤、鱗狀細胞癌、乳腺癌、頭頸部癌、甲狀腺癌、軟組織肉瘤、骨肉瘤、睾丸癌、前列腺癌、卵巢癌、膀胱癌、皮膚癌、腦癌、血管肉瘤、肥大細胞瘤、白血病、淋巴瘤、肝癌、肺癌、胰腺癌、胃癌、腎癌、結腸直腸癌、造血系統腫瘤、神經母細胞瘤、表皮癌或其的轉移癌,但不限定於此。優選地,在本發明中,癌症可以為肺癌、結腸直腸癌、胃癌、乳腺癌或肝癌。
在本發明中,炎性疾病可以為骨關節炎、類風濕性關節炎、痛風、強直性脊柱炎、肌腱炎、腱膜炎、風濕熱、狼瘡、纖維肌痛、牛皮癬性關節炎、哮喘、特應症、克羅恩病或潰瘍性結腸炎,但不限定於此。
本發明之雙歧雙歧桿菌MG731菌株阻礙癌細胞的增殖,並降低癌細胞的移動性,從而可呈現出抗癌效果。並且,本發明之雙歧雙歧桿菌MG731菌株抑制作為血管生成因子的血管內皮生長因子(VEGF;Vascular endothelial growth factor)、血管生成素1(Ang1;Angiopoetin1)、血管生成素2(Ang2;Angiopoetin2)的表現,從而可呈現出抗癌效果。
並且,本發明之雙歧雙歧桿菌MG731菌株抑制TNF-α的表現,從而可呈現出抗炎或抗癌效果。腫瘤壞死因子-α(TNF-α)為人體內感染、外傷、敗血症、類風濕性關節炎等的慢性或急性炎症反應時從免疫細胞分泌的細胞因子,當腫瘤壞死因子-α(TNF-α)的濃度增加時,細胞內脂質及糖代謝過程中會誘發損傷。據悉,腫瘤壞死因子-α(TNF-α)為誘導細胞壞死的細胞因子,但據研究結果發表,持續TNF-α的刺激傳遞至細胞時,反而因影響到細胞內代謝而產生腫瘤形成基因,產生細胞的異常增殖,從而促進癌症的誘發。
本發明係關於一種癌症預防或治療用醫藥組合物,其特徵在於,包含雙歧雙歧桿菌MG731菌株及化學抗癌劑或免疫抗癌劑。此外,本發明提供在受試者中預防或治療癌症的方法,包含將有效量的雙歧雙歧桿菌MG731菌株與化學抗癌劑或免疫抗癌劑並用,從而向需要預防或治療癌症的受試者給藥。
上述化學抗癌劑可以為奧沙利鉑(Oxaliplatin)、培美曲塞(Pemetrexed)、順鉑(Cisplatin)、吉西他濱(Gemcitabine)、卡鉑(Carboplatin)、5-氟尿嘧啶(5-FU)、環磷醯胺(Cyclophosphamide)、紫杉醇(Paclitaxel)、長春新鹼(Vincristine)、依託泊苷(Etoposide)、多柔比星(Doxorubicin),但不限定於此。
並且,上述免疫抗癌劑可以為具有免疫檢查點抑制功能的抗-PD1(anti-PD1,程序性死亡受體1抗體)、抗-PDL1(anti-PDL1,細胞程序性死亡配體1抗體)、抗-CTLA(anti-CTLA,細胞毒性T淋巴細胞相關抗原)、抗-Tim3(anti-Tim3,T淋巴細胞膜蛋白3抗體)、抗-LAG3(anti-LAG3,淋巴細胞活化基因-3抗體),但不限定於此。
本發明之雙歧雙歧桿菌MG731菌株及化學抗癌劑或免疫抗癌劑可依次或同時給藥於需要其之患者。
並且,本發明係關於包含雙歧雙歧桿菌MG731(Bifidobacterium bifidum
MG731)菌株的用於預防或改善癌症的食品組合物或動物用飼料組合物。
上述食品組合物可以為保健功能食品、乳製品、發酵產品或食品添加劑,但不限定於此。
本發明提供新穎乳酸乳球菌GEN3033(Lactococcus lactis
GEN3033)菌株。上述乳酸乳球菌GEN3033菌株於2018年10月25日以保藏號KCTC13684BP保藏於韓國生命工程研究院生物資源中心。
並且,本發明提供包含乳酸乳球菌GEN3033(Lactococcus lactis
GEN3033)菌株的癌症預防或治療用醫藥組合物。具體而言,上述乳酸乳球菌GEN3033(Lactococcus lactis GEN3033)菌株可包含菌株本身、菌株的培養液或破碎菌株而獲得的細胞質組分(Cytoplasmic fraction)。
本發明提供在受試者中預防或治療癌症的方法,包含將有效量的乳酸乳球菌GEN3033(Lactococcus lactis
GEN3033)菌株向需要預防或治療癌症的受試者(subject)給藥。並且,本發明提供用於預防或治療癌症的乳酸乳球菌GEN3033(Lactococcus lactis
GEN3033)菌株的用途。
尤其,本發明之乳酸乳球菌GEN3033菌株的特徵在於,均呈現出抗癌效果及免疫增強效果。
上述癌症可以為黑色素瘤、鱗狀細胞癌、乳腺癌、頭頸部癌、甲狀腺癌、軟組織肉瘤、骨肉瘤、睾丸癌、前列腺癌、卵巢癌、膀胱癌、皮膚癌、腦癌、血管肉瘤、肥大細胞瘤、白血病、淋巴瘤、肝癌、肺癌、胰腺癌、胃癌、腎癌、結腸直腸癌、造血系統腫瘤、神經母細胞瘤、表皮癌或其的轉移癌,但不限定於此。
本發明之乳酸乳球菌GEN3033菌株直接阻礙癌細胞的增殖,並活化免疫細胞,從而可呈現出抗癌效果。並且,本發明之乳酸乳球菌GEN3033菌株可根據腸道定植來調節代謝產物,從而可呈現出抗癌效果。
具體而言,本發明之乳酸乳球菌GEN3033菌株可增加神經節苷脂GM3(Ganglioside GM3;monosialodihexosylganglioside,單唾液酸二己糖神經節苷脂)。神經節苷脂GM3(Ganglioside GM3)為具有以下化學式I結構的化合物,其為[(2S,4S,5R)-2-{[(2S,3R,4S,5S,6R)-2-{[(2R,3S,4R,5R,6R)-6-{[(2S,3R)-2-二十二烷醯胺基-3-羥基十八烷基]氧基}-4,5-二羥基-2-(羥甲基)氧雜環己-3-基]氧基}-3,5-二羥基-6-(羥甲基)氧雜環己-4-基]氧基-5-乙醯胺基-4-羥基-6-[(1R,2R)-1,2,3-三羥基丙基]氧雜環己烷-2-甲酸]([(2S,4S,5R)-2-{[(2S,3R,4S,5S,6R)-2-{[(2R,3S,4R,5R,6R)-6-{[(2S,3R)-2-docosanamido-3-hydroxyoctadecyl]oxy}-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy}-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy}-5-acetamido-4-hydroxy-6-[(1R,2R)-1,2,3-trihydroxypropyl]oxane-2-carboxylic acid])。
據悉,醣神經鞘脂質(Glycosphingolipids)之一的神經節苷脂GM3(Ganglioside GM3)為細胞膜的組成成分,抑制血管內皮生長因子(VEGF;Vascular endothelial growth factor),從而阻止新血管生成並調節淋巴細胞的花生四烯酸級聯反應(Arachidonic acid cascade),經由調節免疫作用而呈現出抗癌功效。進而,據悉,用順鉑(Cisplatin)處理時,神經節苷脂GM3(Ganglioside GM3)進一步增加癌細胞的凋亡(apoptosis)。
因此,本發明係關於一種癌症預防或治療用醫藥組合物,其特徵在於,上述乳酸乳球菌GEN3033菌株增加神經節苷脂GM3(GangliosideGM3)。
並且,本發明之乳酸乳球菌GEN3033菌株增加基於記憶性T細胞(Memory T cells)活性的γ-干擾素(IFN-γ)的生成,並且增加誘發T細胞(T cells)的活化的白細胞介素-15(IL-15)和白細胞介素-7(IL-7)的表現,從而可呈現出抗癌及增強免疫效果。
因此,本發明係關於一種癌症預防或治療用醫藥組合物,其特徵在於,上述乳酸乳球菌GEN3033菌株增加γ-干擾素(IFN-γ)的生成。
並且,本發明係關於一種癌症預防或治療用醫藥組合物,其特徵在於,上述乳酸乳球菌GEN3033菌株增加白細胞介素-15(IL-15)或白細胞介素-7(IL-7)的表現。
本發明係關於一種癌症預防或治療用醫藥組合物,其特徵在於,包含乳酸乳球菌GEN3033菌株及化學抗癌劑或免疫抗癌劑。並且,本發明提供在受試者中預防或治療癌症的方法,包含將有效量的乳酸乳球菌GEN3033菌株與化學抗癌劑或免疫抗癌劑並用,從而向需要預防或治療癌症的受試者給藥。
上述化學抗癌劑可以為奧沙利鉑(Oxaliplatin)、培美曲塞(Pemetrexed)、順鉑(Cisplatin)、吉西他濱(Gemcitabine),卡鉑(Carboplatin)、5-氟尿嘧啶(5-FU)、環磷醯胺(Cyclophosphamide)、紫杉醇(Paclitaxel)、長春新鹼(Vincristine)、依託泊苷(Etoposide)、多柔比星(Doxorubicin)等,但不限定於此。
並且,上述免疫抗癌劑可以為具有免疫檢查點抑制功能的抗-PD1、抗-PDL1、抗-CTLA、抗-Tim3、抗-LAG3等免疫抗癌劑,但不限定於此。
本發明之乳酸乳球菌GEN3033菌株及化學抗癌劑或免疫抗癌劑可依次或同時給藥於需要其之患者。
並且,本發明係關於包含乳酸乳球菌GEN3033(Lactococcus lactis GEN3033)菌株的用於預防或改善癌症的食品組合物或動物用飼料組合物。
上述食品組合物可以為保健功能食品、乳製品、發酵產品或食品添加劑,但不限定於此。
發明效果
本發明之新穎雙歧雙歧桿菌MG731菌株對多種癌細胞株具有增殖抑制效果。並且,本發明之雙歧雙歧桿菌MG731菌株減少癌細胞的移動性,同時還具有抑制新血管的生成的效果,相比於以往已知的雙歧雙歧桿菌,具有顯著優秀的效果。
並且,本發明之雙歧雙歧桿菌MG731菌株具有抗炎、抗氧化或增強免疫效果,從而亦可使用於炎症疾病或免疫疾病。
尤其,本發明之雙歧雙歧桿菌MG731菌株不僅單獨給藥時呈現出優秀的抗癌效果,而且與化學抗癌劑或免疫抗癌劑組合給藥時,與單獨給藥相比,具有更優秀的抗癌效果。
本發明之新穎乳酸乳球菌GEN3033菌株不僅對多種癌細胞株具有抑制增殖的效果,而且呈現出免疫活性,相比於現有的乳酸乳球菌菌株具有顯著優秀的效果。
尤其,就本發明之乳酸乳球菌GEN3033菌株而言,不僅單獨給藥時呈現出優秀的抗癌效果,而且與化學抗癌劑或免疫抗癌劑組合給藥時,與單獨給藥相比,具有更優秀的抗癌效果。
本發明人為了發掘具有優秀的抗癌治療或預防效果的益生菌而進行研究的結果,確認新穎雙歧雙歧桿菌MG731菌株及乳酸乳球菌GEN3033菌株具有優秀的抗癌效果,由此完成了本發明。
令人驚訝的是,MG731菌株對肺癌、結腸直腸癌、胃癌、乳腺癌及肝癌等的多種癌細胞株具有優秀的癌細胞增殖抑制效果。
並且,用MG731菌株處理癌細胞株的情況下,癌細胞的移動性明顯降低。癌細胞不同於正常細胞,具有即使細胞受損亦能增殖並移動的特徵,所謂癌細胞之移動性減少係指癌症轉移可能性降低,因此MG731菌株具有癌症轉移抑制效果。
並且,MG731菌株可全部抑制作為血管生成相關主要因子的血管內皮生長因子(VEGF;Vascular endothelial growth factor)、血管生成素1(Ang1;angiopoetin1)及血管生成素2(Ang2;angiopoetin2)的表現。新血管的生成為癌細胞的特徵之一,藉由抑制它來阻礙經由血管向癌細胞供給營養成分,從而可抑制癌細胞的增殖。
炎性疾病之一個明顯的狀態之一為活性含氧物(Reactive oxygen species;ROS)的增加。中等程度的活性含氧物濃度係藉由調節細胞信號傳遞系統來發揮效果,但實際上若長期暴露於高濃度的活性含氧物,則對蛋白質、脂質及核酸導致非特異性損傷。活性含氧物在如蛋白質磷酸化、離子通道及轉錄因子的氧化還原調節之類的正常生理過程中起到重要作用,並且在包括甲狀腺激素生成及細胞外基質的交聯的生物合成過程中也具有主要功能。並且,眾所周知,在大部分的癌細胞中,此種活性含氧物也具有高活性,從而誘發異常的細胞增殖。因此,本發明之MG731菌株具有藉由減少活性含氧物來抑制癌細胞的增殖,並預防發生各種疾病的效果。
並且,本發明之MG731菌株誘導具有抑制腫瘤細胞的增殖的功能的細胞毒性T細胞(Cytotoxic T cells)(CD8 + 效應T細胞)及自然殺傷細胞(NK cells;Natural killer cells)更多地滲透到腫瘤組織內,減少用於阻礙細胞毒性T細胞(Cytotoxic T cells)功能的調節性T細胞(T regulatory cells)的數量,從而調節免疫細胞的功能,並呈現出優秀的抗癌效果。
分別用MG731菌株及公知的化學抗癌劑或免疫抗癌劑分別處理組合處理多種癌細胞株時,經MG731處理的癌細胞株相比於經抗癌劑處理的癌細胞株具有更優秀的細胞增殖抑制效果,用MG731及抗癌劑組合處理的癌細胞株相比於僅用MG731或抗癌劑處理的癌細胞株具有突出的細胞增殖抑制效果,因此MG731與現有的抗癌劑組合給藥時具有得以提高的抗癌效果。
因此,本發明之雙歧雙歧桿菌MG731菌株同時呈現出抑制癌細胞增殖、降低癌細胞移動性及抑制新血管生成效果,可用作優秀的抗癌劑,並可與現有的化學抗癌劑或免疫抗癌劑組合給藥。
本發明之雙歧雙歧桿菌MG731菌株可以與上述化學抗癌劑或免疫抗癌劑用一個製劑同時給藥,或者可以用單獨的製劑同時或依次給藥。
並且,藉由顯著減少由作為炎症誘導因子的脂多醣(LPS,lipopolysaccharide)而誘導的腫瘤壞死因子-α(TNF-α)的表現,MG731菌株可同時預防或治療炎性疾病及癌症。
本發明提供藉由向體內給藥雙歧雙歧桿菌MG731菌株來預防或治療癌症、炎性疾病、免疫疾病等的方法。
本發明之包含雙歧雙歧桿菌MG731菌株的組合物可使用於藥品、保健功能食品、乳製品、發酵產品、食品添加劑或動物用飼料等。
並且,本發明之乳酸乳球菌GEN3033菌株對多種癌細胞株具有優秀的增殖抑制效果。
當處理本發明之乳酸乳球菌GEN3033菌株時,癌細胞的增殖直接降低,根據記憶性T細胞(Memory T cells)的活性的γ-干擾素(IFN-γ)的生成增加,並且誘發T細胞(T cell)的活化的白細胞介素-15(IL-15)和白細胞介素-7(IL-7)的表現被增加,從而呈現出抗癌及增強免疫效果。
並且,本發明之乳酸乳球菌GEN3033菌株根據腸道定植來調節代謝產物,從而呈現出抗癌效果。尤其,乳酸乳球菌GEN3033菌株抑制血管內皮生長因子(VEGF;Vascular endothelial growth factor),由此阻礙新血管生成並調節淋巴細胞的花生四烯酸級聯反應(Arachidonic acid cascade),由此增加公知為藉由調節免疫作用來呈現出抗癌功效的神經節苷脂GM3(Ganglioside GM3),可呈現出優秀的抗癌效果。並且,乳酸乳球菌GEN3033菌株增加藉由使巨噬細胞(Macrophage)活化而調節免疫反應的磷脂醯肌醇(Phosphatidylinositol)(PI)18 : 1及20 : 4。並且,藉由單獨給藥GEN3033或單獨給藥免疫抗癌劑,雖然對公知為表示細胞膜的損傷和炎症反應的標誌物的花生四烯酸硫代磷酸膽鹼(Arachidonoylthiophosphorylcholine)及PC16 : 0/22 : 6沒有影響,但是當組合給藥GEN3033和免疫抗癌劑時,增加花生四烯酸硫代磷酸膽鹼(Arachidonoylthiophosphorylcholine)及PC16 : 0/22 : 6,從而呈現出抗癌效果。
當在多種癌細胞株中分別處理或組合處理GEN3033菌株及公知的化學抗癌劑或免疫抗癌劑時,經GEN3033與抗癌劑組合處理的癌細胞株相比於僅經GEN3033或抗癌劑處理的癌細胞株具有更優秀的細胞增殖抑制效果,故而GEN3033在與現有的抗癌劑組合給藥時呈現出得以提高的抗癌效果。
因此,本發明之乳酸乳球菌GEN3033菌株同時呈現出癌細胞增殖抑制效果和免疫增強效果,可用作優秀的抗癌劑,並且可與現有的化學抗癌劑或免疫抗癌劑組合給藥。
本發明之乳酸乳球菌GEN3033菌株可以與上述化學抗癌劑或免疫抗癌劑用一個製劑同時給藥,或者可以用單獨的製劑同時或依次給藥。
本發明提供藉由向體內給藥乳酸乳球菌GEN3033菌株來預防或治療癌症、炎性疾病、免疫疾病等的方法。
本發明之包含乳酸乳球菌GEN3033菌株的組合物可使用於藥品、保健功能食品、乳製品、發酵產品、食品添加劑或動物用飼料等。
以下,透過實例來更詳細說明本發明。這些實例僅用於更具體說明本發明,本發明之範圍不限定於這些實例。
實例1雙歧雙歧桿菌 MG731 的分離及培養
MG731利用對於雙岐桿菌屬(Bifidobacterium
spp.)的選擇性培養基,從健康幼兒的糞便中分離出菌株。
將收集的糞便試樣在0.85%NaCl中分階段稀釋10倍之後,塗抹於添加有50mg/L莫匹羅星鋰(Lithium mupirocin)的TOS丙酸鹽瓊脂(TOS-propionate agar)(默克集團(Merck KGaA),達姆施塔特(Darmstadt),德國(Germany))中,並在37℃的溫度下厭氧培養48小時後,篩選出菌落(colony)的形態不同的菌株。被篩選的菌株在膽鹽乳糖培養液(BL broth)中進行繼代培養之後,在-80℃下,在含有20%甘油的膽鹽乳糖培養液(BL broth)中冷凍保管。
分析所得的菌株的rRNA的鹼基序列,並以序列號1表示,其鑑定結果確認MG731為雙歧雙歧桿菌(Bifidobacterium bifidum
)。上述MG731菌株於2018年1月04日以保藏號KCTC13452BP保藏於韓國生命工程研究院生物資源中心。
將本實驗中要使用的雙歧雙歧桿菌MG731接種於MRS培養液(Difco,USA)培養基,在37℃及厭氧條件下培養並在乳酸菌的增殖為OD=1時結束培養。培養結束的培養物藉由離心分離來回收菌體,所回收的菌體用磷酸鹽緩衝液(PBS)清洗之後,在磷酸鹽緩衝液中懸浮並以超聲波粉碎法粉碎了菌體。所粉碎的菌體藉由離心分離而獲得上清液,並藉由0.42 μm濾網進行過濾,從而製備了雙歧雙歧桿菌MG731的提取物。
實例2雙歧雙歧桿菌 MG731菌 株的腫瘤增殖抑制效果
為了確認雙歧雙歧桿菌MG731是否在多種癌細胞株中呈現出抗癌功效,利用人源癌細胞株來進行四甲基偶氮唑藍測定(MTT測定)。
四甲基偶氮唑藍測定(MTT測定)中所使用的癌細胞株為肺癌(A549,H1975,HCC827,H1299,SW900)、結腸直腸癌(HCT116,LoVo,SNU-C2A,SNU-C1,Colo205)、胃癌(SNU216,AGS,MKN-28,MKN-1,SNU-601,SNU-1)、乳腺癌(Hs578T,BT20,MDA-MB-231,MCF7)、肝癌(HepG2,Hep3B),利用總計5種癌症種類來進行實驗。
以1-5×103
細胞/孔的方式,將癌細胞株分注於96-孔板(96-well plate)中,經過24小時後添加乳酸菌試樣1%(1% = 12.147 μg,藉由BCA分析測定提取物的濃度),培養72小時之後,用MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化噻唑藍(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide thiazolyl blue)試劑處理各個孔(well),反應2小時。
此後,與存活的細胞的線粒體反應,經過從黃色的MTT變成紫色的過程。此後,加入MTT的培養液均被去除,向各個孔(well)中添加100 µl的二甲基亞碸(DMSO),利用酶標儀(Microplate reader)設備在540 nm吸光度下測定紫色的濃度,並且將對人源癌細胞株的實驗結果在第1圖中示出。
實例3雙歧雙歧桿菌 MG731菌 株的癌細胞移動性降低效果
由於癌細胞不同於正常細胞,具有即使細胞受損也增殖並移動的特徵,因此為了確認是否因MG731菌株而導致癌細胞的移動性降低,進行傷口癒合試驗(Wound healing assay)。將A549(5 × 105
個細胞)及 HCT116(6 × 105
個細胞)菌株附著於6孔板(well plate),若細胞處於90%-95%增殖的狀態,則利用tip以既定間隔使細胞受損。處理磷酸鹽緩衝液或MG731菌株24小時,用顯微鏡觀察了細胞是否移動,其結果在第2圖中示出。
如第2a及2b圖所示,當以使細胞受損的A549(第2a圖)和HCT116(第2b圖)細胞株的0時間段的細胞狀態為基準來看時,24小時後,A549為65.31 ± 1.69%,HCT116為33.82 ± 5.86%,表示癌細胞的移動性活躍,反之,用MG731處理的A549和HCT116分別為42.59 ± 4.01%及22.63 ± 3.11%,可確認細胞的移動性被降低。
最終,可知MG731菌株抑制癌症轉移,具有優秀的抗癌效果。
實例4雙歧雙歧桿菌 MG731菌 株的新血管生成抑制效果
為了確認MG731菌株是否抑制癌細胞的特徵之一的新血管生成過程,對新血管生成相關因子如下進行表現試驗。
在HCT116細胞株中用MG731處理24小時之後,獲得RNA來合成cDNA,利用其,藉由普通聚合酶鏈式反應(PCR,Polymerase Chain Reaction)確認了作為血管生成因子的血管內皮生長因子(VEGF;vascular endothelial growth factor)的表現,藉由即時聚合酶鏈式反應(real-time PCR)確認了血管生成素1(Ang1;angiopoetin1)及血管生成素2(Ang2;angiopoetin2)的表現,其結果分別在第3圖及第4圖中示出。
如第3圖所示,確認到MG731的處理組相比於對照組,血管內皮生長因子(VEGF;vascular endothelial growth factor)的121同功型(isoform)及165同功型的表現明顯減少。
並且,如第4a及4b圖所示,除了血管內皮生長因子(VEGF;vascular endothelial growth factor)之外,當比較參與新血管生成的因子血管生成素1(Ang1;angiopoetin1)(第4a圖)及血管生成素2(Ang2;angiopoetin2)(第4b圖)的表現時,確認到血管生成素1(Ang1;angiopoetin1)和血管生成素2(Ang2;angiopoetin2)的表現在MG731的處理組中,相比於對照組,表現率明顯降低70%以上。
最終,MG731抑制新血管生成來阻礙藉由血管向癌細胞供給營養成分,由此可知對異常癌細胞的增殖具有優秀的抑制效果。
實例5雙歧雙歧桿菌 MG731菌 株的抗炎效果
為了確認MG731菌株的抗炎效果,用MG731菌株處理作為小鼠巨噬細胞的RAW264.7細胞18小時之後,將作為炎症誘導因子的LPS 100 ng/ml處理6小時,獲得RNA。
用1µg的上述RNA合成了cDNA,由此藉由即時PCR確認了公知為炎性因子的腫瘤壞死因子-α(TNF-α)是否表現,在第5圖中示出了其結果。
如第5圖所示,當以腫瘤壞死因子-α(TNF-α)的表現因LPS而增加的程度為相對指數1時,確認到MG731處理組的腫瘤壞死因子-α(TNF-α)的表現增加的程度為0.5以下。腫瘤壞死因子-α(TNF-α)還被公知為誘發癌症的因子,因此因MG731而使腫瘤壞死因子-α(TNF-α)的表現明顯減少,由此可知,MG731同時具有抗炎及抗癌功能。
實例6雙歧雙歧桿菌 MG731菌 株的抗氧化活性效果
為了確認MG731的抗氧化活性,在A549癌細胞株中用MG731處理24小時之後,用0.5 μM的H2
O2
處理4小時,藉由DCFDA螢光染料,利用FACs設備測定了細胞內活性含氧物量,並將其結果在第6圖中示出。
如第6圖所示,可知僅用磷酸鹽緩衝液處理的組呈現出4.66%的活性含氧物量,僅用H2
O2
處理的組的活性含氧物增加為64.8%。反之,分別用0.1%、0.5%、1%的MG731處理的組的活性含氧物的量減少為57.8%、39.3%及32.5%。因此,確認到MG731呈現出減少活性含氧物的量的效果,若MG731的濃度增加,則阻礙活性含氧物的效果也增加。
最終,藉由上述實驗結果可知,MG731具有抗氧化效果。即,在正常細胞中可起到保護因活性含氧物而致使細胞損傷的作用,在癌細胞中可起到藉由減少異常的活性含氧物的濃度來控制線粒體的異常功能的作用。
實例7基於雙歧雙歧桿菌 MG731菌 株和抗癌劑的組合處理的癌細胞增殖抑制效果(體外( in vitro ) 實驗)
在A549、HCT116中,進行基於MG731和抗癌劑組合處理的癌細胞增殖抑制實驗。利用奧沙利鉑(Oxaliplatin)或培美曲塞(Pemetrexed)來作為抗癌劑,藉由以下方法進行實驗。
以1-2 × 103
的方式,將上述兩種癌細胞株向6孔板(well plate)的各個孔(well)中稀釋後分注,附著24小時之後,在每個孔處理乳酸菌和抗癌劑,間隔2-3天,更換培養基,誘導7天細胞增殖。
用4%福爾馬林,將孔板處理30分鐘,使細胞定植並停止細胞增殖之後,經過2次的磷酸鹽緩衝液清洗過程,用結晶紫(crystal violet)溶液染色5分鐘之後,用蒸餾水清洗,並觀察了是否發生細胞的增殖。其結果在第7圖中示出。
如第7圖所示,可知將MG731菌株和抗癌劑組合處理的癌細胞株,相比於僅用MG731或抗癌劑處理的癌細胞株,呈現更優秀的細胞增殖抑制效果。
並且,關於染色的細胞的菌落(colony)的數值藉由用醋酸(Acetic acid)溶解結晶紫(Crystal violet)並利用酶標儀(Microplate reader)設備測定了濃度,其結果在第8圖中示出。並確認到在第8圖中也呈現出與第7圖相同的效果。
實例8基於雙歧雙歧桿菌 MG731菌 株和免疫抗癌劑的組合給藥的抗腫瘤增進效果(體外( in vitro ) 實驗)
從人的血液利用Ficoll採集末梢血液單核細胞(PBMC,Peripheral blood mononuclear cells)之後,藉由紅細胞裂解液(RBC lysis buffer)去除紅細胞,並計數存活的細胞數,在包含乳酸菌(6 x 105
/50ul/孔)的底部圓形的96孔板的各個孔中按3x104
細胞/50μl添加末梢血液單核細胞(PBMC),培養24小時。
結腸癌細胞株HCT116在不包含胎牛血清(FBS)的RPMI培養基中與5μM的羧基螢光素琥珀醯亞胺酯(CFSE,Carboxyfluorescein succinimidyl ester)混合,在37℃下反應5分鐘之後,添加包含胎牛血清的RPMI1640培養基,在冰塊(ice)中保管10分鐘。藉由離心分離去除上層液之後,在獲得的細胞中與含有10%的胎牛血清的RPMI1640混合之後,計數細胞數,在上述準備的96孔板的每個孔中按3x104
個/100μl添加。
之後,在添加有癌細胞的每個孔中將各個抗體PD1(派姆單抗(Pembrolizumab), A2005, Selleckem)、PD-L1(達雷木單抗(Atezolizumab), A2004, Selleckem)、CTLA-4(伊匹單抗(
Ipilimumab), A2001, Selleckem)在20~30 μg/mL濃度範圍內進行處理,培養24小時之後,為了確認在末梢血液單核細胞及癌細胞株的混合物中所溶菌的細胞,用7-胺基放線菌素D(7-AAD; BD Pharmingen,美國加州聖地亞哥市)對細胞染色。利用FACSDiVa軟件(碧迪醫療器械有限公司))測定針對CFSE及7-AAD的染色,從而確認針對癌細胞株的末梢血液單核細胞的細胞溶解能力,其結果示出在第9圖中。
將基於末梢血液單核細胞的癌細胞死亡(細胞毒性)看做100%標準時,顯示出基於MG731單獨的癌細胞死亡(細胞毒性)增加到204.4%,作為臨床上正在使用的免疫抗癌劑的抗-PD1誘發122.4%的癌細胞死亡,抗-PD-L1誘發133.6%的癌細胞死亡,抗CTLA-4誘發108%的癌細胞死亡。相反,當組合處理免疫抗癌劑和MG731時,確認為抗-PD1誘發243.2%的癌細胞死亡,抗-PD-L1誘發221.6%的癌細胞死亡,抗CTLA-4誘發214.4%的癌細胞死亡。
最終,與單獨給藥時的癌細胞死亡效果比較,組合給藥時的癌細胞死亡效果顯著優異。
實例9基於雙歧雙歧桿菌 MG731菌 株和抗癌劑的組合給藥的腫瘤增殖抑制效果(體內( in vivo ) 實驗)
在建立腫瘤模型之前,向小鼠給藥乳酸菌試樣2週,以實現腸道定植及提高免疫力之後,每組C57BL/6小鼠(mouse)8只的右屁股附近皮下注射2 × 105
MC38癌細胞(cancer cells),從而建立了腫瘤誘發模型。注入腫瘤細胞的同時,將乳酸菌試樣給上述動物模型口服給藥3週(週一-週六)。經給藥的乳酸菌的試樣在200μl的磷酸鹽緩衝液中稀釋後口服給藥,使得每只給藥CFU 1 × 109
。癌症誘發後,將奧沙利鉑(3 mg/kg,藍木化工有限公司(Sellekchem))或抗-PD1(2 mg/kg,欣博盛生物科技有限公司(BioXCell))作為抗癌劑,每週星期一和星期四進行腹腔注射。
對於僅處理了乳酸菌的組、僅處理了奧沙利鉑或抗-PD1的組及兩者都處理的組觀察了腫瘤抑制效果之後,在第9圖及第10圖中示出。
如第10圖及11圖所示,確認到單獨給藥MG731的情況相比於單獨給藥奧沙利鉑或抗-PD1的情況,腫瘤抑制效果突出,當將MG731與奧沙利鉑或抗-PD1組合給藥的情況下,腫瘤抑制效果更為優秀。
實例10基於雙歧雙歧桿菌 MG731菌 株和抗癌劑的組合給藥的抗腫瘤免疫反應增強效果(體內( in vivo ) 實驗)
基於上述實例9的結果,為了確認滲透至腫瘤內的免疫細胞的分佈,要進行FACs實驗,如下進行了動物實驗。
藉由與實例9相同的方法,建立腫瘤誘發模型並給藥乳酸菌試樣及抗癌劑後,分離腫瘤和脾,並確認小鼠的免疫細胞分佈圖,粉碎組織並分離了免疫細胞。所分離的免疫細胞利用與各個功能免疫細胞標誌物相應的螢光抗體來進行反應之後,利用FACs設備進行確認。上述實驗結果在第12圖和第13圖中示出。
如第12及13圖所示,確認到給藥了MG731的組與作為對照組的IgG或磷酸鹽緩衝液相比,在抗癌免疫反應中呈現重要功能的CD4T細胞、CD8 T細胞、CD8 效應T細胞的分佈增加了1.5-2倍以上,可知用於調節T細胞(T cells)的功能的調節性T細胞(regulatory T cells)的數量明顯減少。
並且,在MG731和抗癌劑組合給藥的組中,藉由CD4 T細胞、CD8 T細胞、CD8效應T細胞的分佈比將抗癌劑單獨給藥的組顯著增加,調節T細胞(T cells)的功能的調節性T細胞的數量明顯減少,藉由這一結果可知組合給藥MG731和抗癌劑比單獨處理抗癌劑的抗腫瘤免疫反應明顯增加。
從上述結果可知,基於MG731的免疫細胞功能的調節還對腫瘤增殖的抑制帶來影響。
實例11乳酸乳球菌 GEN3033菌 株的分離及鑑定
為了分離GEN3033菌株,接收到滿41歲的正常女性提供的糞便。將約4g的所收集的新鮮糞便試樣添加至磷酸鹽緩衝液(PBS;Phosphate buffered saline)80ml中,進行渦流(vortexing)之後再懸浮(re-suspension)。經均質化的試樣在相同溶液中連續稀釋10倍,其中,將稀釋為10-5
、10-6
、10-7
、10-8
倍的試樣200µl塗抹於作為乳酸菌選擇培養基的De Man Rogosa,Sharpe瓊脂(MRS培養基;迪福庫(Difco),美國)培養基中,並在37℃溫度、好氧條件下培養了48小時。利用菌落PCR方法從固體培養基中所生成的各個菌落獲得了所擴增的16S rRNA基因(1.5kb)。純化PCR試樣之後,藉由測序(sequencing)獲得的各個16S rRNA基因鹼基序列代入NCBI blast程序並搜索相關物種。
其中,將與乳酸乳球菌亞種乳酸菌(Lactococcus lactis subsp. lactis strain)41MoQuesillo的相似度高的菌株(1448/1448 bp,100%)命名為GEN3033,為了純種分離,在固體培養基中進行6次菌落再劃線(restreaking)工作之後,重新確認了16S rRNA基因鹼基序列。所篩選的GEN3033菌株進行液體培養之後,添加20%甘油,在-80℃溫度下冷凍保管。
對所獲得的菌株的rRNA的鹼基序列進行分析,以序列號2(SEQ ID NO: 2)表示,對其進行鑑定的結果,確認到GEN3033為乳酸乳球菌(Lactococcus lactis)。上述GEN3033菌株於2018年10月25日以保藏號KCTC13684BP保藏於韓國生命工程研究院生物資源中心。1. 糖發酵特性的確認
對於GEN3033菌株,使用API CHL套組(法國生物梅裡埃公司(BioMetrieux Co. France)來調查了糖發酵特性,其結果在下列表1中示出。表 1
+:呈現糖發酵效果;-:未呈現糖發酵效果2. 酶活性的確認
編號 | 碳水化合物( Carbohydrates ) | GEN3033 | 編號 | 碳水化合物( Carbohydrates ) | GEN3033 |
0 | 對照組(Control) | - | 25 | 七葉靈(Esculin) | + |
1 | 甘油(Glycerol) | - | 26 | 水楊甙(Salicin) | + |
2 | 赤蘚糖醇(Erythritol) | - | 27 | 纖維二糖(Cellobiose) | + |
3 | D-阿拉伯糖(D-arabinose) | - | 28 | 麥芽糖(Maltose) | + |
4 | L-阿拉伯糖(L-arabinose) | - | 29 | 乳糖(Lactose) | - |
5 | 核糖(Ribose) | + | 30 | 蜜二糖(Melibiose) | - |
6 | D-木糖(D-xylose) | - | 31 | 蔗糖(Sucrose) | + |
7 | L-木糖(L-xylose) | - | 32 | 海藻糖(Trehalose) | + |
8 | 核糖醇(Adonitol) | - | 33 | 菊粉(Inulin) | - |
9 | ß-甲基木糖甙(ß-Methyl-xyloside) | - | 34 | 松三糖(Melezitose) | - |
10 | 半乳糖(Galactose) | + | 35 | 棉子糖(Raffinose) | - |
11 | 葡萄糖(Glucose) | + | 36 | 澱粉(Starch) | + |
12 | 果糖(Fructose) | + | 37 | 糖原(Glycogen) | - |
13 | 甘露糖(Mannose) | + | 38 | 木糖醇(Xylitol) | - |
14 | 山梨糖(Sorbose) | - | 39 | ß龍膽二糖(ßGentiobiose) | + |
15 | 鼠李糖(Rhamnose) | - | 40 | D-松二糖(D-turanose) | - |
16 | 甜醇(Dulcitol) | - | 41 | D-來蘇糖(D-lyxose) | - |
17 | 肌醇(Inositol) | - | 42 | D-塔格糖(D-tagatose) | - |
18 | 甘露醇(Mannitol) | - | 43 | D-岩藻糖(D-fucose) | - |
19 | 山梨糖醇(Sorbitol) | - | 44 | L-岩藻糖(L-fucose) | - |
20 | 甲基-D-甘露糖苷(Methyl-D-mannoside) | - | 45 | D-阿拉伯醇(D-arabitol) | - |
21 | 甲基-D-葡萄糖苷(Methyl-D-glucoside) | - | 46 | L-阿拉伯醇(L-arabitol) | - |
22 | N-乙醯-葡萄糖胺(N-Acelyl-Glucosamine) | + | 47 | 葡萄糖酸鹽(Gluconate) | - |
23 | 苦杏仁甙(Amygdalin) | + | 48 | 2-酮-葡萄糖酸鹽 (2-Keto-Gluconate) | - |
24 | 熊果苷(Arbutin) | - | 49 | 5-酮-葡萄糖酸鹽(5-Keto-Gluconate) | - |
為了調查GEN3033菌株的生化特性,利用API ZYM套組(法國生物梅裡埃公司)來調查酶活性特性,並將其結果在表2中示出。表 2
編號 | 酶( Enzyme ) | 基質 ( Substrate ) | GEN3033* |
1 | 對照組 | - | 0 |
2 | 鹼性磷酸酶(Alkaline phosphatase) | 2-萘基磷酸酯(2-naphthyl phosphate) | 1 |
3 | 酯酶(Esterase)(C4) | 2-萘基丁酸酯(2-naphthyl butyrate) | 0 |
4 | 酯酶脂解酶(Esterase Lipase)(C8) | 2-萘基辛酸酯(2-naphthyl caprylate) | 0 |
5 | 脂解酶(Lipase)(C14) | 2-萘基肉豆蔻酸酯(2-naphthyl myristate) | 0 |
6 | 白胺酸芳基醯胺酶(Leucine arylamidase) | L-白胺醯-2-萘胺(L-leucyl-2-naphthylamide) | 3 |
7 | 纈胺酸芳基醯胺酶(Valine Arylamidase) | L-纈胺醯-2-萘胺(L-valyl-2-naphthylamide) | 0 |
8 | 胱胺酸芳基醯胺酶(Cystine arylamidase) | L-胱胺醯二-2-萘胺(L-cystyl-2-naphthylamide) | 0 |
9 | 胰蛋白酶(Trypsin) | N-苯甲醯基-DL-精胺酸-2-萘胺(N-benzoyl-DL-arginine-2-naphthylamide) | 0 |
10 | α-糜蛋白酶(α-chymotrypsin) | N-戊二醯-苯丙胺酸-2-萘胺(N-glutaryl-phenylalanine-2-naphthylamide5) | 0 |
11 | 酸性磷酸酶(Acid phosphatase) | 2-萘基磷酸酯(2-naphthyl phosphate)(pH 5.4) | 5 |
12 | 萘酚-AS-BI-磷酸水解酶(Naphthol-AS-BI-phosphogydrolase) | 萘酚-AS-BI-磷酸酯(Naphthol-AS-BI-phosphate) | 2 |
13 | α-半乳糖苷酶(α-galactosidase) | 6-溴-2-萘基αD-吡喃半乳糖苷(6-Br-2-naphthyl-αD-galactopyranoside) | 0 |
14 | β-半乳糖苷酶(β-galactosidase) | 2-萘基-βD-吡喃半乳糖苷(2-naphthyl-βD-galactopyranoside) | 0 |
15 | β-葡萄糖醛酸酶(β-glucuronidase) | 萘酚-AS-BI-βD葡萄糖醛酸苷(Naphthol-AS-BI-βDglucuronide) | 0 |
16 | α-葡萄糖苷酶(α-glucosidase) | 2-萘基αD-D-吡喃葡萄糖苷(2-naphthyl-αD-glucopyranoside) | 0 |
17 | β-葡萄糖苷酶(β-glucosidase) | 6-溴-2-萘基βD-D-吡喃葡萄糖苷(6-Br-2-naphthyl-βD-glucopyranoside) | 0 |
18 | N-乙醯基-β-胺基葡萄糖苷酶(N-acetyl-β-glucosaminidase) | 1-萘基N-乙醯基βD胺基葡糖苷(1-naphthyl-N-acetyl-βD-glucosaminide) | 0 |
19 | α-甘露糖苷酶(α-mannosidase) | 6-溴-2-萘基αD-D-吡喃甘露糖苷(6-Br-2-naphthyl-αD-mannopyranoside) | 0 |
20 | α-岩藻糖苷酶(α-fucosidase) | 2-萘基-αL-岩藻吡喃糖苷(2-naphthyl-αL- fucopyranoside) | 0 |
* 0 : 0奈莫爾(nanomol);1 : 5奈莫爾;2 : 10奈莫爾;3 : 20奈莫爾;4 : 30奈莫爾;5 : > 40奈莫爾
實例12乳酸乳球菌 GEN3033菌 株的免疫細胞活性效果
為了確認GEN3033的免疫活性,藉由以下方法對基於記憶性T細胞的活性的γ-干擾素(IFN-γ)的分泌變化進行實驗。
藉由聚蔗糖(Ficoll),從人體血液(human blood)中分離末梢血液單核細胞(PBMC)之後,用紅細胞裂解液(RBC lysis buffer)去除紅細胞,並利用LS柱(column)和MACS緩衝液(buffer)來分離單核細胞(monocytes)。在被分注GEN3033的96孔板(well plate)中放入單核細胞使得每孔達到5 × 103
,以GEN3033將單核細胞(monocytes)分化為巨噬細胞(macrophages)的方式反應2小時。
在單核細胞和GEN3033進行反應期間,利用MACS緩衝液和LS 柱從剩餘的PBMC細胞中分離了CD4及CD8被表現的T細胞(T cell),上述分離的T細胞用100µl的RPMI培養基稀釋,使得成為5 × 104
個細胞,並分注於具有單核細胞和GEN3033的上述孔之後,以培養成48小時期間產生免疫活性。在經過既定時間之後,將各孔的細胞培養液均收集於1.5ml的試管(tube)中,僅分離上清液,利用ELISA套組(ELISA kit)來測定γ-干擾素(IFN-γ)的生成度,將其結果在第14圖中示出。
如第14圖所示,確認到僅具有單核細胞和T細胞(T cell)的孔板不生成γ-干擾素(IFN-γ),反之,使大腸桿菌(E.coli)反應的孔板生成50 pg/mL的γ-干擾素(IFN-γ),使GEN3033反應的孔板生成約210 pg/mL的γ-干擾素(IFN-γ)。
即,確認到GEN3033使巨噬細胞(Macrophages)活化,從而刺激記憶性T細胞(Memory T cells)來誘導γ-干擾素(IFN-γ)的生成。最終可知,GEN3033顯著增加記憶性T細胞(Memory T cells)的活性,並誘發優秀的免疫活性。
實例13乳酸乳球菌 GEN3033 的抗腫瘤效果(體外
,(in vitro))
為了確認GEN3033在多種癌細胞株中是否呈現抗癌功效,利用11種人源癌症細胞株,進行CCK-8測定。
將癌細胞株分注於96-孔板中,以使達到1-5 × 103
細胞/孔,穩定化24小時之後,將破碎的乳酸菌試樣添加為1%(1% = 4.965μg,藉由二喹啉甲酸(BCA)分析來測定提取物的濃度),培養72小時,利用CCK-8(美國東仁化學科技有限公司(DOJINDO,USA))確認癌細胞存活率並在下列表3中示出。表 3
癌症種類 | 細胞株名 | 細胞存活率(對照組 % )( Cell viability ( % of control )) |
結腸直腸癌 | HCT116 | 20.688 ± 0.711 |
乳腺癌 | MDA-MB-231 | 28.919 ± 1.393 |
神經母細胞瘤 | SH-SY5Y | 54.599 ± 5.182 |
腦瘤 | T98G | 84.040 ± 2.904 |
胃癌 | MKN28 | 25.262 ± 1.675 |
慢性粒細胞白血病 | K562 | 37.569 ± 5.139 |
胰腺癌 | PANC-1 | 30.436 ± 3.045 |
肺癌 | A549 | 85.461 ± 3.033 |
骨肉瘤 | U2-OS | 81.037 ± 4.412 |
肝癌 | HepG2 | 62.015 ± 5.618 |
表皮癌 | A431 | 59.303 ± 2.929 |
如上述表3所示,根據癌細胞所具有的特性,雖然呈現出GEN3033中的細胞存活率差異,但進行GEN3033處理的所有細胞株與未處理的對照組(100%的細胞存活率)相比,確認到細胞存活率減小的共同點。
實例14乳酸乳球菌 GEN3033菌 株的腫瘤增殖抑制效果(體內
,(in vivo))
同種的小鼠腫瘤模型在短時間內腫瘤極速產生,因腫瘤的壞死而無法確認精確的功效,因而在建立腫瘤模型之前,給小鼠給藥乳酸菌試樣2週,並誘導了基於GEN3033的腸道定植的免疫活性。
之後,將2 × 105
的MC38癌細胞株皮下注射至小鼠的右腿並進行腫瘤移植,之後,將乳酸菌試樣口服給藥到上述動物模型3週(週一-週六),給藥的乳酸菌的試樣稀釋於200µl的磷酸鹽緩衝液,使得每只給藥CFU 1 × 109
。此後,在小鼠中測定腫瘤的大小,並在第15圖中示出。
如第15圖所示,給藥作為陰性對照組的磷酸鹽緩衝液的組隨著時間經過,腫瘤快速增加,反之,GEN3033的給藥組相比於上述對照組,可確認到腫瘤的增殖速度顯著減少。最終,可知GEN3033呈現出抗腫瘤治療效果。
實例15乳酸乳球菌 GEN3033菌 株的免疫因子表現效果
巨噬細胞(Macrophages)及樹狀細胞(Dendritic cells)受到刺激分泌用於誘發T細胞(T cells)的活化的白細胞介素-15(IL-15)和白細胞介素-7(IL-7)。因此,藉由qPCR從上述實例13的小鼠的大腸和腫瘤組織中確認了誘發T細胞的活性的白細胞介素-15(IL-15)和白細胞介素-7(IL-7)的表現。其結果在第16圖及第17圖中示出。
如第16圖及第17圖所示,在GEN3033的給藥組的小鼠中確認到與陰性對照組相比,腫瘤和大腸組織均增加了白細胞介素-15(IL-15)和白細胞介素-7(IL-7)的表現。
並且,確認大腸組織呈現出比腫瘤更高的免疫因子的表現,這表明在腸道中定植的GEN3033活化大腸組織的免疫細胞,並參與腫瘤微環境內的免疫細胞的滲透。
實例16乳酸乳球菌 GEN3033菌 株和免疫抗癌劑的組合給藥
將GEN3033和作為免疫抗癌劑的抗-PD1組合給藥時,為了確認腫瘤的增殖抑制效果,進行如下的實驗。
以實例13的腫瘤模型為對象,作為對於抗-PD1及GEN3033的陰性對照組,分為免疫球蛋白G(IgG)(腹腔給藥)和磷酸鹽緩衝液(口服給藥)的給藥組、GEN3033的給藥組、抗-PD1的給藥組、抗-PD1和GEN3033的組合給藥組來確認其功效,將抗-PD1(2 mg/kg,BioXCell)誘發癌症後,在第3天、第7天、第10天、第14天、第17天、第21天進行腹腔注射。在第18圖中示出各實驗組的腫瘤增殖速度。
如第18圖所示,GEN3033的給藥組和抗-PD1的給藥組相比於陰性對照組,確認到腫瘤的增殖速度減小。並且,確認到抗-PD1及GEN3033的組合給藥組相比於各個單獨給藥組,腫瘤增殖速度更減小。
最終,可知GEN3033不僅單獨抑制腫瘤增殖,而且在與抗-PD1組合給藥的情況下,相比於單獨給藥抗-PD1的情況,呈現出提高的腫瘤增殖抑制效果。
實例17乳酸乳球菌 GEN3033 的代謝產物調節
藉由腸道定植,乳酸菌幫助在消化道中所分解的食物的分解及吸收並供給到體內各個器官。因此,為了確認因GEN3033引起的代謝產物的變化,將實例15的腫瘤模型中確保的小鼠的血清以如下方法進行分析。
為了分析給藥GEN3033的小鼠的血清內所存在的代謝產物,利用了由Cortex C18 +(2.1 mm × 100 mm,2.7 um)柱形成的HPLC-MS/MS系統(戴安(DIONEX)UltiMate 3000,戴安公司(Dionex Corporation),森尼韋爾(Sunnyvale),加利福尼亞(CA),美國(USA)),為了檢測從柱分離的物質,使用了Triple TOF 5600 +(美國應用生物系統公司(AB Sciex,USA))。作為移動相,使用了0.1%的甲酸水溶液和0.1%的甲酸乙腈,所有試樣以對兩種離子轉導進行分析的多反應監測(MRM)模式(Multiple reaction monitoring(MRM)mode)進行分析,其結果在第19圖至第21圖中示出。
如第19圖所示,與對照組相比,確認到GEN3033的給藥組顯著增加白皮杉醇4’-沒食子醯基葡萄糖苷(Piceatannol 4’-galloylglucoside)、神經節苷脂GM3(Ganglioside GM3),燈籠草內酯(Perulactone)、辛酸辛酯(Octyl octanoate)。
如第20圖所示,就抗-PD1給藥組而言,相比於對照組,呈現出燈籠草內酯、白皮杉醇4’-沒食子醯葡萄糖苷、辛酸辛酯、鄰苯二酚硫酸鹽(Pyrocatechol sulfate)、神經節苷脂GM3增加的態勢。
並且,如第21圖所示,就將GEN3033和抗-PD1一同給藥的組而言,相比於對照組,呈現燈籠草內酯、神經節苷脂GM3、白皮杉醇4’-沒食子醯基葡萄糖苷、辛酸辛酯相同地增加的態勢。並且,與將GEN3033單獨給藥的組相比,確認到花生四烯酸硫代磷酸膽鹼(Arachidonoylthiophosphorylcholine)、PC16 : 0/22 : 6增加。並且,與將抗-PD1單獨給藥的組相比,確認到十二烷基硫酸鹽(Dodecyl sulfate)、花生四烯酸硫代磷酸膽鹼、PC16 : 0/22 : 6增加。
並且,就作為類固醇的一種的燈籠草內酯,主要用作食品添加劑的Jubanine C、白皮杉醇4’-沒食子醯基葡萄糖苷、辛酸辛酯而言,與對照組相比,在GEN3033的單獨給藥的組、抗-PD1的單獨給藥的組、GEN3033和抗-PD1組合給藥的組中同樣較高地測定。
尤其,與抗-PD1單獨給藥的組相比,在GEN3033單獨給藥的組及GEN3033和抗-PD1組合給藥的組中神經節苷脂GM3更增加。
就磷脂醯肌醇(PI:Phosphatidylinositol)18 : 1及20 : 4而言,在GEN3033單獨給藥的組(相對於對照組1.32倍)和GEN3033和抗-PD1組合給藥的組中增加,但已知,上述PI 20 : 4為活化巨噬細胞(macrophage)來幫助調節免疫反應。並且,據悉,與正常人相比,癌症患者中呈現出較低的上述PI18 : 1、PI20 : 4、PI20 : 2的3種磷脂醯肌醇的血液中含量。因此,上述磷脂醯肌醇可成為用於區分正常人和癌症患者的重要生物標誌物。花生四烯酸硫代磷酸膽鹼和PC 16 : 0/22: 6為屬於磷脂(phospholipid)的代謝產物,當引起如炎症反應等的刺激時,膽鹼代謝出現異常而誘發細胞膜的損傷,從而磷脂數值減少,因此這種花生四烯酸硫代磷酸膽鹼及PC 16: 0/22 : 6的減少被認知為表示細胞膜的損傷及炎症反應的標誌物。
如第21圖所示,當對GEN3033和抗-PD1進行組合給藥時,與對照組相比,花生四烯酸硫代磷酸膽鹼及PC 16 : 0/22 : 6數值顯著增加,這意味著GEN3033和抗-PD1的組合給藥使細胞內的炎症反應緩解。
藉由分析這種代謝產物,可知根據GEN3033的腸道定植的代謝產物的變化對免疫反應及抗癌功效起到重要作用。
實例18免疫抗癌劑抗藥性肺癌模型中的 GEN3033菌 株的腫瘤增殖抑制效果(體內,( in vivo ))
基於實例16中的結果,確認了當在免疫抗癌劑有效的大腸癌模型中組合給藥GEN3033和作為免疫抗癌劑的抗-PD1時,腫瘤的增殖抑制效果提高。基於此,為了確認當在對免疫抗癌劑具有抗藥性的肺癌模型中也組合給藥GEN3033和抗-PD1時抗癌效果是否提高,執行了以下實驗。
將移植LLC1肺癌的腫瘤模型作為對象,用與實例16中實行的方法相同的方法執行試驗。作為對於抗-PD1及GEN3033的陰性對照組,分為免疫球蛋白G(IgG)(腹腔給藥)和磷酸鹽緩衝液(口服給藥)的給藥組、GEN3033的給藥組、抗-PD1的給藥組、抗-PD1和GEN3033的組合給藥組來確認其功效。將抗-PD1(2 mg/kg,BioXCell)誘發癌症後,在第10天、第14天、第17天、第21天、第23天進行腹腔注射。在第22圖中示出各實驗組的腫瘤增殖速度。
如第22圖所示,GEN3033的給藥組和抗-PD1的給藥組相比於陰性對照組,確認到腫瘤的增殖速度減小。並且,確認到抗-PD1及GEN3033的組合給藥組的腫瘤增殖速度相比於各個的單獨給藥組,腫瘤增殖速度更減小。
最終,可知在對免疫抗癌劑具有抗藥性的肺癌模型中GEN3033不僅單獨抑制腫瘤增殖,而且在與抗-PD1組合給藥的情況下,相比於單獨給藥抗-PD1的情況,呈現出提高的腫瘤增殖抑制效果。
實例19乳酸乳球菌 GEN3033 和化學抗癌劑或免疫抗癌劑的組合給藥功效確認
為了追加確認GEN3033和除了抗-PD1之外的化學抗癌劑或免疫抗癌劑的組合處理中抗腫瘤效果是否也顯著增加,進行以下實驗。
作為化學抗癌劑,使用了順鉑、奧沙利鉑、5-氟尿嘧啶、環磷醯胺、紫杉醇,在作為結腸直腸癌細胞株的HCT116中,當各個濃度的抗癌劑和0.5%濃度的GEN3033進行組合給藥時,確認到的細胞存活率的結果示於第23圖至第27圖中。
如第23圖所示,可知與單獨處理7 μM順鉑的情況相比,當對GEN3033進行組合處理時,細胞存活率顯著減小。並且如第24圖至第27圖所示,與單獨處理在HCT116中呈現90%以上的細胞存活率的各個濃度的奧沙利鉑、5-氟尿嘧啶、環磷醯胺及紫杉醇的情況相比,對GEN3033進行組合處理時,癌細胞的死亡明顯高。
即,可知GEN3033與化學抗癌劑的組合給藥中顯著降低癌細胞存活率,因此具有提高的抗癌效果。
並且,為了確認藉由與作為其他免疫抗癌劑的抗-PDL1的組合處理,免疫細胞的活性及根據其的腫瘤細胞的生存率降低,進行以下實驗。從小鼠的脾和骨髓分離PBMC及T細胞,PBMC藉由與GEN3033之間的反應來誘導巨噬細胞的分化之後,刺激了T細胞的活性。分離活化的免疫細胞的上清液並與抗-PDL1一同放入MC38腫瘤細胞中,反應24小時之後,用FACs設備確認了MC38的生存率。其結果在第28圖中示出。
如第28圖所示,確認了即使和處理免疫抗癌劑,隨著與GEN3033之間的反應癌細胞株的生存率減少12.82%、22.02%。並且,確認了藉由單獨處理抗-PDL1(1mg/mL)而使癌細胞株的生存率減少18.33%,反之,對抗-PDL1(1mg/mL)和GEN3033進行組合處理時,癌細胞株的生存率減少25.44%、41.23%。由此,確認了除了抗-PD1之外,在與如抗-PDL1等的其他免疫抗癌劑的組合給藥中GEN3033也具有優秀的抗癌功效。
實例20基於乳 酸乳球菌 GEN3033菌 株和免疫抗癌劑的組合給藥的抗腫瘤增進效果(體外( in vitro ) 實驗)
從人的血液利用Ficoll採集末梢血液單核細胞(PBMC,Peripheral blood mononuclear cells)之後,藉由紅細胞裂解液(RBC lysis buffer)去除紅細胞,並計數存活的細胞數,在包含乳酸菌(3 x 105
/50ul/孔)的底部為圓形的96孔板的各個孔中添加末梢血液單核細胞(PBMC)3x104
細胞/50μl,培養24小時。
結腸癌細胞株HCT116在不包含胎牛血清的RPMI培養基中與5μM的羧基螢光素琥珀醯亞胺酯(CFSE,Carboxyfluorescein succinimidyl ester)混合,在37℃下反應5分鐘之後,添加包含胎牛血清的RPMI1640培養基,在冰塊(ice)中保管10分鐘。藉由離心分離去除上層液之後,在獲得的細胞中與含有10%的胎牛血清的RPMI1640混合之後,計數細胞數,在上述準備的96孔板的每個孔中添加3x104
個/100μl。
之後,在添加有癌細胞的每個孔中將各個抗體PD1(派姆單抗(Pembrolizumab),A2005,Selleckem)、PD-L1(達雷木單抗(Atezolizumab), A2004, Selleckem)、CTLA-4(伊匹單抗(Ipilimumab), A2001, Selleckem)在20~30μg/mL濃度範圍內進行處理,培養24小時之後,為了確認在PBMC及癌細胞株的混合物中所溶菌的細胞,用7-胺基放線菌素D(7-AAD; BD Pharmingen, 美國加州聖地亞哥市)對細胞染色。利用FACSDiVa軟件(碧迪醫療器械有限公司)測定針對CFSE及7-AAD的染色,從而確認針對癌細胞株的末梢血液單核細胞的細胞溶解能力,其結果示出在第29圖中。
如第29圖所示,將基於末梢血液單核細胞的癌細胞死亡(cytotoxicity)看做100%標準時,顯示出基於GEN3033單獨的癌細胞死亡(cytotoxicity)增加107.0%,作為臨床上正在使用的免疫抗癌劑的抗-PD1誘發113.9%的癌細胞死亡,抗-PD-L1誘發123.5%的癌細胞死亡,抗CTLA-4誘發116.0%的癌細胞死亡。相反,當組合處理免疫抗癌劑和GEN3033時,確認為抗-PD1誘發156.7%的癌細胞死亡,抗-PD-L1誘發154.0%的癌細胞死亡,抗CTLA-4誘發128.3%的癌細胞死亡。
最終,與單獨處理時的癌細胞死亡效果比較,組合處理時的癌細胞死亡效果顯著增加。
保藏號雙歧雙歧桿菌 MG731 ( Bifidobacterium bifidum MG731 )
保藏機構名稱:韓國生命工程研究院生物資源中心
保藏號:KCTC13452BP
保藏日:2018年01月04日乳酸乳球菌 GEN3033 ( Lactococcus lactis GEN3033 )
保藏機構名稱:韓國生命工程研究院生物資源中心
保藏號:KCTC13684BP
保藏日:2018年10月25日
無
第1圖用圖表示出在人源癌細胞株中根據MG731處理的細胞增殖抑制情況。
第2a圖及第2b圖為示出藉由MG731的癌細胞株的移動性降低的結果。
第3圖示出MG731阻礙作為新血管生成相關因子的血管內皮生長因子(VEGF;vascular endothelial growth factor)的表現。
第4a圖及第4b圖為確認阻礙血管內皮生長因子(VEGF;vascular endothelial growth factor)之外的作為新血管生成相關因子的血管生成素1(Ang1;angiopoetin1)、血管生成素2(Ang2;angiopoetin2)之表現的MG731的功效的結果。
第5圖示出MG731抑制藉由LPS的炎症反應誘導因子中腫瘤壞死因子-α(TNF-α)的表現。
第6圖示出根據MG731的不同濃度處理的活性含氧物的減少。
第7圖為示出根據化學抗癌劑(奧沙利鉑(Oxaliplatin)、培美曲塞(Pemetrexed))和MG731的組合處理的癌細胞的增殖抑制效果的結果。
第8圖對第7圖中染色的細胞進行脫色之後將癌細胞的增殖抑制效果進行數值化並示出。
第9圖利用人的血液和癌細胞株來示出基於MG731和免疫抗癌劑(抗-PD1、抗-PDL1、抗-CTLA4)的組合處理的癌細胞死亡的功效。
第10圖利用小鼠同種移植模型來示出根據化學抗癌劑(奧沙利鉑)和MG731的組合給藥的腫瘤增殖抑制效果。
第11圖利用小鼠同種移植模型來示出根據免疫抗癌劑(抗-PD1)和MG731的組合給藥的腫瘤增殖抑制效果。
第12圖分析滲透至根據化學抗癌劑(奧沙利鉑)和MG731的組合給藥的小鼠同種移植模型的腫瘤組織內的免疫細胞的分佈。
第13圖分析滲透至根據免疫抗癌劑(抗-PD1)和MG731的組合給藥的小鼠同種移植模型的腫瘤組織內的免疫細胞的分佈。
第14圖用基於GEN3033菌株的免疫活性的生物標誌物來確認γ-干擾素(IFN-γ)生成增加效果。
第15圖藉由將GEN3033菌株給藥到小鼠腫瘤模型來確認腫瘤增殖抑制效果。
第16圖為在給藥GEN3033菌株的小鼠腫瘤模型的大腸和腫瘤組織中測定白細胞介素-15(IL-15)的表現的結果。
第17圖在給藥GEN3033菌株的小鼠腫瘤模型的大腸和腫瘤組織中測定白細胞介素-7(IL-7)的表現。
第18圖在對小鼠大腸癌模型給藥GEN3033菌株時、給藥免疫抗癌劑(抗-PD1)時及將其組合給藥時示出腫瘤增殖抑制效果。
第19圖至第21圖示出在將GEN3033菌株和免疫抗癌劑(抗-PD1)單獨給藥或將其組合給藥的小鼠的血清中分析代謝產物的結果。
第22圖示出根據對小鼠肺癌模型組合給藥免疫抗癌劑(抗-PD1)和GEN3033的腫瘤增殖抑制效果。
第23圖至第27圖示出根據GEN3033菌株和化學抗癌劑(順鉑、奧沙利鉑、5-氟尿嘧啶、環磷醯胺、紫杉醇)的組合處理對癌細胞株起到的癌細胞死亡效果。
第28圖利用小鼠的血液和癌細胞株示出GEN3033菌株和免疫抗癌劑(抗-PDL1)的癌細胞死亡效果。
第29圖利用人的血液和癌細胞株示出基於GEN3033和免疫抗癌劑(抗-PD1、抗-PD-L1、抗-CTLA4)的組合處理的癌細胞死亡效果。
國內寄存資訊 (請依寄存機構、日期、號碼順序註記)
乳酸乳球菌Lactococcus lactis
GEN3033:
財團法人食品工業發展研究所、108年6月13日、BCRC 910904
雙歧雙歧桿菌Bifidobacterium bifidum
MG731:
財團法人食品工業發展研究所、108年6月13日、BCRC 910905
國外寄存資訊 (請依寄存國家、機構、日期、號碼順序註記)
乳酸乳球菌Lactococcus lactis
GEN3033:
韓國、Korean Collection for Type Cultures (KCTC)、2018年10月25日、KCTC 13684BP
雙歧雙歧桿菌Bifidobacterium bifidum
MG731:
韓國、Korean Collection for Type Cultures (KCTC)、2018年1月4日、KCTC 13452BP
Claims (12)
- 一種雙歧雙歧桿菌MG731菌株(韓國寄存編號:KCTC13452BP;財團法人食品工業發展研究所寄存編號:BCRC 910905)。
- 一種癌症預防或治療用醫藥組合物,其特徵在於,包含雙歧雙歧桿菌MG731菌株(韓國寄存編號:KCTC13452BP;財團法人食品工業發展研究所寄存編號:BCRC 910905),其中該癌症係肺癌、結腸直腸癌、胃癌、乳腺癌或肝癌。
- 一種癌症預防或治療用醫藥組合物,其特徵在於,包含雙歧雙歧桿菌MG731菌株(韓國寄存編號:KCTC13452BP;財團法人食品工業發展研究所寄存編號:BCRC 910905),該雙歧雙歧桿菌MG731菌株展現出抗癌、抗炎、抗氧化及增強免疫的效果,其中該癌症係肺癌、結腸直腸癌、胃癌、乳腺癌或肝癌。
- 如請求項2所述之癌症預防或治療用醫藥組合物,其特徵在於,該雙歧雙歧桿菌MG731菌株係藉由降低癌細胞的移動性來展現出抗癌效果。
- 如請求項2所述之癌症預防或治療用醫藥組合物,其特徵在於,該雙歧雙歧桿菌MG731菌株係藉由抑制作為血管生成因子的血管內皮生長因子、 血管生成素1及血管生成素2的表現來展現出抗癌效果。
- 如請求項3所述之癌症預防或治療用醫藥組合物,其特徵在於,該雙歧雙歧桿菌MG731菌株抑制腫瘤壞死因子-α的表現。
- 一種癌症預防或治療用醫藥組合物,其特徵在於,包含雙歧雙歧桿菌MG731菌株(韓國寄存編號:KCTC13452BP;財團法人食品工業發展研究所寄存編號:BCRC 910905),進一步包含化學抗癌劑或免疫抗癌劑,其中該癌症係肺癌、結腸直腸癌、胃癌、乳腺癌或肝癌。
- 如請求項7所述之癌症預防或治療用醫藥組合物,其特徵在於,該化學抗癌劑係選自由奧沙利鉑、培美曲塞、順鉑、吉西他濱、卡鉑、5-氟尿嘧啶、環磷醯胺、紫杉醇、長春新鹼、依託泊苷及多柔比星組成之群中的一種以上。
- 如請求項7所述之癌症預防或治療用醫藥組合物,其特徵在於,該免疫抗癌劑係選自由抗-PD1、抗-PDL1、抗-CTLA、抗-Tim3及抗-LAG3組成之群中的一種以上。
- 如請求項7所述之癌症預防或治療用組合物,其特徵在於,雙歧雙歧桿菌MG731菌株與化學 抗癌劑或免疫抗癌劑用一個製劑同時給藥,或者用單獨的製劑同時或依次給藥。
- 一種用於預防或改善癌症的食品組合物,其特徵在於,包含雙歧雙歧桿菌MG731菌株(韓國寄存編號:KCTC13452BP;財團法人食品工業發展研究所寄存編號:BCRC 910905),其中該癌症係肺癌、結腸直腸癌、胃癌、乳腺癌或肝癌。
- 一種用於預防或改善癌症的動物用飼料組合物,包含雙歧雙歧桿菌MG731菌株(韓國寄存編號:KCTC13452BP;財團法人食品工業發展研究所寄存編號:BCRC 910905),其中該癌症係肺癌、結腸直腸癌、胃癌、乳腺癌或肝癌。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2018-0054195 | 2018-05-11 | ||
KR20180054195 | 2018-05-11 | ||
KR10-2018-0133030 | 2018-11-01 | ||
KR20180133030 | 2018-11-01 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW202118864A TW202118864A (zh) | 2021-05-16 |
TWI791190B true TWI791190B (zh) | 2023-02-01 |
Family
ID=68466740
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW108116028A TWI791111B (zh) | 2018-05-11 | 2019-05-09 | 具有預防或治療癌症的效果的新穎菌株 |
TW110103672A TWI791190B (zh) | 2018-05-11 | 2019-05-09 | 具有預防或治療癌症的效果的新穎菌株 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW108116028A TWI791111B (zh) | 2018-05-11 | 2019-05-09 | 具有預防或治療癌症的效果的新穎菌株 |
Country Status (9)
Country | Link |
---|---|
US (2) | US20210322490A1 (zh) |
EP (1) | EP3792343A4 (zh) |
JP (2) | JP7119220B2 (zh) |
KR (1) | KR102148223B1 (zh) |
CN (2) | CN110468061B (zh) |
AU (2) | AU2019267042B8 (zh) |
CA (2) | CA3104023C (zh) |
TW (2) | TWI791111B (zh) |
WO (1) | WO2019216649A1 (zh) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101864347B1 (ko) * | 2017-09-06 | 2018-06-05 | 주식회사 지놈앤컴퍼니 | 락토바실러스 람노수스 lm1019 균주 및 이를 포함하는 비만 또는 당뇨병 예방 및 치료용 조성물 |
CN110468061B (zh) * | 2018-05-11 | 2024-03-08 | 韩国亿诺生物有限公司 | 具有预防或治疗癌症的效果的新型菌株 |
KR102485269B1 (ko) * | 2019-10-18 | 2023-01-06 | 주식회사 지놈앤컴퍼니 | 비피도박테리움 비피덤을 포함하는 면역력 증강 또는 개선용 조성물 |
CN112852682A (zh) * | 2020-08-11 | 2021-05-28 | 刘树林 | 与芽孢杆菌属近缘的厚壁菌门细菌菌株及其抗癌应用 |
KR102291725B1 (ko) * | 2021-04-06 | 2021-08-23 | 주식회사 지놈앤컴퍼니 | 항-cntn4 항체 및 그의 용도 |
KR102391017B1 (ko) * | 2021-07-13 | 2022-04-29 | 한국식품연구원 | 락토코커스 락티스 WiKim0133을 포함하는 암의 예방, 개선 또는 치료용 조성물 |
CN115702908A (zh) * | 2021-08-05 | 2023-02-17 | 香港中文大学 | 用于治疗和预防结肠直肠癌的益生菌组合物 |
KR20230092708A (ko) | 2021-12-16 | 2023-06-26 | 주식회사 엔테로바이옴 | 암 또는 염증성 질환 예방 또는 치료용 약학적 조성물 |
KR102672734B1 (ko) | 2022-01-19 | 2024-06-10 | 록야 주식회사 | 새싹인삼에서 분리한 락토바실러스 람노서스 b3421 및 이를 포함하는 조성물 |
KR20230123429A (ko) | 2022-02-15 | 2023-08-23 | 주식회사 엔테로바이옴 | 암 예방 또는 치료용 약학적 조성물 |
KR102457422B1 (ko) * | 2022-05-04 | 2022-10-21 | 주식회사 메디오젠 | 프로바이오틱스 혼합균주를 유효성분으로 포함하는 대장암의 예방 또는 치료용 조성물 |
CN115011518A (zh) * | 2022-06-13 | 2022-09-06 | 东北农业大学 | 一种具有缓解结肠炎相关结直肠癌作用的乳酸菌混合物及其应用 |
KR102645456B1 (ko) * | 2023-04-24 | 2024-03-13 | 주식회사 메디오젠 | 면역 증진 및 장 건강 증진 활성을 가진 락토코쿠스 락티스 mg5474 균주 및 이를 포함하는 조성물 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3841495B2 (ja) * | 1995-09-14 | 2006-11-01 | サンエイ糖化株式会社 | L−乳酸生産能及びtnf産生誘導活性を有する乳酸菌 |
ID29150A (id) * | 1999-01-15 | 2001-08-02 | Entpr Ireland Cs | Penggunaan lactobacillus salivarius |
WO2009049932A1 (en) * | 2007-10-20 | 2009-04-23 | Universite De Liege | Bifidobacterial species |
CN101575582B (zh) * | 2008-05-08 | 2011-10-12 | 景岳生物科技股份有限公司 | 具有抗炎活性的乳杆菌分离株及其用途 |
ES2668096T3 (es) * | 2010-12-28 | 2018-05-16 | Kirin Holdings Kabushiki Kaisha | Uso de bacterias de Lactococcus en el tratamiento o la prevención de infecciones virales |
KR101599769B1 (ko) * | 2012-08-10 | 2016-03-04 | 한국생명공학연구원 | 신규한 락토코쿠스 종 균주 및 이의 용도 |
EP2951285A4 (en) * | 2013-02-04 | 2016-10-26 | Seres Therapeutics Inc | COMPOSITIONS AND METHODS FOR INHIBITING THE GROWTH OF PATHOGENIC BACTERIA |
US20140341853A1 (en) * | 2013-05-14 | 2014-11-20 | Vanna Hovanky | Bacteria-Mediated Therapy for Cancer |
EP3373943A1 (en) * | 2015-11-10 | 2018-09-19 | Elizabeth Mckenna | Control of cellular redox levels |
US9999641B2 (en) * | 2016-06-14 | 2018-06-19 | Vedanta Biosciences, Inc. | Treatment of clostridium difficile infection |
KR102205829B1 (ko) * | 2017-06-14 | 2021-01-21 | 기초과학연구원 | 신규한 비피도박테리움 비피덤 균주 및 균주 유래 다당체 |
CN107629988B (zh) * | 2017-11-03 | 2020-10-27 | 江南大学(扬州)食品生物技术研究所 | 一种可缓解结直肠癌的两歧双歧杆菌及其用途 |
CN107603921B (zh) * | 2017-11-03 | 2020-08-11 | 江南大学(扬州)食品生物技术研究所 | 一种可调节结肠肿瘤信号通路的乳酸乳球菌乳酸亚种及其用途 |
CN110468061B (zh) * | 2018-05-11 | 2024-03-08 | 韩国亿诺生物有限公司 | 具有预防或治疗癌症的效果的新型菌株 |
AU2019289987A1 (en) * | 2018-06-22 | 2020-12-24 | Synformulas Gmbh | Non-viable Bifidobacterium bifidum bacteria and uses thereof |
CN117203234A (zh) * | 2021-04-29 | 2023-12-08 | 韩国亿诺生物有限公司 | 抗cntn4特异性抗体及其用途 |
CN115261426B (zh) * | 2022-09-26 | 2023-01-03 | 东北农业大学 | 一种具有抗氧化能力的两歧双歧杆菌e3胞外多糖 |
-
2019
- 2019-01-14 CN CN201910030979.XA patent/CN110468061B/zh active Active
- 2019-01-14 CN CN202110013498.5A patent/CN113151036A/zh active Pending
- 2019-05-08 CA CA3104023A patent/CA3104023C/en active Active
- 2019-05-08 JP JP2021513739A patent/JP7119220B2/ja active Active
- 2019-05-08 EP EP19799157.3A patent/EP3792343A4/en active Pending
- 2019-05-08 US US17/054,433 patent/US20210322490A1/en active Pending
- 2019-05-08 WO PCT/KR2019/005518 patent/WO2019216649A1/ko active Application Filing
- 2019-05-08 CA CA3099906A patent/CA3099906C/en active Active
- 2019-05-08 AU AU2019267042A patent/AU2019267042B8/en active Active
- 2019-05-08 KR KR1020190053963A patent/KR102148223B1/ko active IP Right Grant
- 2019-05-09 TW TW108116028A patent/TWI791111B/zh active
- 2019-05-09 TW TW110103672A patent/TWI791190B/zh active
-
2020
- 2020-11-12 US US17/096,031 patent/US20210138003A1/en active Pending
- 2020-11-23 AU AU2020277103A patent/AU2020277103B2/en active Active
-
2021
- 2021-01-19 JP JP2021006383A patent/JP7119143B2/ja active Active
Non-Patent Citations (1)
Title |
---|
期刊 Wei Hongyun ET AL: "Antitumor mechanisms of bifidobacteria (Review)", Oncology Letters, vol. 16, 10 May 2018, pages 3-8. |
Also Published As
Publication number | Publication date |
---|---|
US20210138003A1 (en) | 2021-05-13 |
CN110468061B (zh) | 2024-03-08 |
CA3099906A1 (en) | 2019-11-14 |
TW202016291A (zh) | 2020-05-01 |
AU2020277103B2 (en) | 2022-11-03 |
JP2021522866A (ja) | 2021-09-02 |
WO2019216649A9 (ko) | 2019-12-05 |
AU2019267042A8 (en) | 2022-10-06 |
CA3099906C (en) | 2024-01-16 |
EP3792343A4 (en) | 2022-06-22 |
AU2019267042B2 (en) | 2022-03-31 |
JP2021129553A (ja) | 2021-09-09 |
CN110468061A (zh) | 2019-11-19 |
WO2019216649A1 (ko) | 2019-11-14 |
JP7119143B2 (ja) | 2022-08-16 |
EP3792343A1 (en) | 2021-03-17 |
KR20190129739A (ko) | 2019-11-20 |
AU2019267042A1 (en) | 2020-12-03 |
AU2019267042B8 (en) | 2022-10-06 |
CA3104023C (en) | 2024-01-30 |
JP7119220B2 (ja) | 2022-08-16 |
CA3104023A1 (en) | 2019-11-14 |
CN113151036A (zh) | 2021-07-23 |
US20210322490A1 (en) | 2021-10-21 |
AU2020277103A1 (en) | 2020-12-17 |
TW202118864A (zh) | 2021-05-16 |
TWI791111B (zh) | 2023-02-01 |
KR102148223B1 (ko) | 2020-08-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI791190B (zh) | 具有預防或治療癌症的效果的新穎菌株 | |
KR101889281B1 (ko) | 다양한 기능성을 가진 신규 유산균 및 이의 용도 | |
TWI726303B (zh) | 乳酸乳球菌gen3013菌株及包含其之用於預防或治療癌症之組合物 | |
KR102040117B1 (ko) | 비피도박테리움 비피덤 mg731 균주 및 이를 포함하는 암의 예방 또는 치료용 조성물 | |
KR101494279B1 (ko) | 지방세포 분화 유도에 관여하는 유전자의 발현을 억제함으로써 지방세포 분화 억제 효능을 갖는 락토바실러스 플란타룸 케이와이1032 및 이를 유효성분으로 함유하는 제품 | |
Luo et al. | Preventive effect of Lactobacillus reuteri on melanoma | |
JP7489045B2 (ja) | 抗腫瘍効果増強剤 | |
KR101951919B1 (ko) | 도파민 분비 증진 기능이 있는 신규한 락토바실러스 루테리 atg-f4 균주, 이를 함유하는 정신질환의 예방 또는 치료용 조성물 | |
US11285179B2 (en) | Method for preventing or treating movement disorders with lactic acid bacterium | |
JP2023540711A (ja) | 抗癌活性を有するラクトバチルス・プランタルム微生物、それを含む組成物、及びそれを利用した癌の予防方法または治療方法 | |
KR20110052808A (ko) | 균체외 다당을 생성하고 건강기능성 효과를 갖는 신규한 락토바실러스 파라카제이 | |
JP2015502410A (ja) | ポリポーシスおよび結腸直腸癌を低減する方法 | |
KR101109746B1 (ko) | 균체외 다당을 생성하고 건강기능성 효과를 갖는 신규한 페디오코커스 펜토사세우스 | |
CN113337440A (zh) | 一株唾液乳杆菌mg-587及其应用 | |
KR101050307B1 (ko) | 암 세포 증식 억제 효과 및 면역 증강 효과를 가진비피도박테리움 아돌레센티스 spm0212의 부탄올 추출물,이를 포함하는 약학적 조성물 및 이의 용도 | |
KR101823459B1 (ko) | 헬리코박터 파이로리에 대한 항균활성과 응집력을 갖는 락토바실러스 파라카제이 hp7 및 이를 유효성분으로 함유하는 제품 | |
Rolny et al. | Lactobacillus delbrueckii subsp lactis CIDCA 133 modulates response of human epithelial and dendritic cells infected with Bacillus cereus. | |
KR102668292B1 (ko) | 신규한 락토바실러스 퍼멘텀 atg-v5 균주 또는 이를 포함하는 면역증강용 조성물 | |
KR20120034444A (ko) | 지방세포 분화 유도에 관여하는 유전자의 발현을 억제함으로써 지방세포 분화 억제 효능을 갖는 락토바실러스 가세리 에이치와이7021 및 이를 유효성분으로 함유하는 제품 | |
TR2021021242A2 (tr) | Yeni̇ lacti̇planti̇baci̇llus plantarum suşunun kolon kanseri̇, rahi̇mağzi kanseri̇ ve meme kanseri̇ni̇n önlenmesi̇ ve/veya tedavi̇si̇nde kullanimi |