CN112334129A - 用于预防和治疗肝病的包含氨基酸的组合物 - Google Patents
用于预防和治疗肝病的包含氨基酸的组合物 Download PDFInfo
- Publication number
- CN112334129A CN112334129A CN201980042577.XA CN201980042577A CN112334129A CN 112334129 A CN112334129 A CN 112334129A CN 201980042577 A CN201980042577 A CN 201980042577A CN 112334129 A CN112334129 A CN 112334129A
- Authority
- CN
- China
- Prior art keywords
- composition
- acid
- use according
- liver disease
- citric acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 89
- 150000001413 amino acids Chemical class 0.000 title claims abstract description 47
- 208000019423 liver disease Diseases 0.000 title claims abstract description 27
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 95
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 51
- 229940024606 amino acid Drugs 0.000 claims abstract description 46
- 235000011090 malic acid Nutrition 0.000 claims abstract description 31
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 30
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000001630 malic acid Substances 0.000 claims abstract description 30
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims abstract description 27
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims abstract description 27
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims abstract description 23
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000004474 valine Substances 0.000 claims abstract description 23
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims abstract description 22
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229960000310 isoleucine Drugs 0.000 claims abstract description 22
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims abstract description 20
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims abstract description 20
- 239000004472 Lysine Substances 0.000 claims abstract description 20
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims abstract description 20
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000004473 Threonine Substances 0.000 claims abstract description 20
- 239000013543 active substance Substances 0.000 claims abstract description 18
- 150000001735 carboxylic acids Chemical class 0.000 claims abstract description 11
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims abstract description 8
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 241000124008 Mammalia Species 0.000 claims abstract description 5
- 230000002265 prevention Effects 0.000 claims abstract description 5
- 235000001014 amino acid Nutrition 0.000 claims description 45
- 239000001384 succinic acid Substances 0.000 claims description 22
- 208000022309 Alcoholic Liver disease Diseases 0.000 claims description 19
- 206010016654 Fibrosis Diseases 0.000 claims description 14
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 13
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 12
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 12
- 230000007882 cirrhosis Effects 0.000 claims description 11
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 11
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 9
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 9
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 9
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 9
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 9
- 229930182817 methionine Natural products 0.000 claims description 9
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 9
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 9
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 8
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 8
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 6
- 235000018417 cysteine Nutrition 0.000 claims description 6
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 6
- 208000010706 fatty liver disease Diseases 0.000 claims description 6
- 206010049287 Lipodystrophy acquired Diseases 0.000 claims description 3
- 208000006454 hepatitis Diseases 0.000 claims description 3
- 231100000283 hepatitis Toxicity 0.000 claims description 3
- 208000006132 lipodystrophy Diseases 0.000 claims description 3
- 239000011782 vitamin Substances 0.000 claims description 3
- 235000013343 vitamin Nutrition 0.000 claims description 3
- 229930003231 vitamin Natural products 0.000 claims description 3
- 229940088594 vitamin Drugs 0.000 claims description 3
- 239000011720 vitamin B Substances 0.000 claims description 3
- 235000019156 vitamin B Nutrition 0.000 claims description 3
- 229930003270 Vitamin B Natural products 0.000 claims description 2
- 239000011691 vitamin B1 Substances 0.000 claims description 2
- 239000011726 vitamin B6 Substances 0.000 claims description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims 2
- 229930003451 Vitamin B1 Natural products 0.000 claims 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims 1
- 229960003495 thiamine Drugs 0.000 claims 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 claims 1
- 235000010374 vitamin B1 Nutrition 0.000 claims 1
- 235000019158 vitamin B6 Nutrition 0.000 claims 1
- 229940011671 vitamin b6 Drugs 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 116
- 210000004027 cell Anatomy 0.000 description 29
- 210000004185 liver Anatomy 0.000 description 23
- 235000015165 citric acid Nutrition 0.000 description 22
- 235000005772 leucine Nutrition 0.000 description 22
- 229960003136 leucine Drugs 0.000 description 22
- 235000014393 valine Nutrition 0.000 description 19
- 229960004295 valine Drugs 0.000 description 19
- 235000014705 isoleucine Nutrition 0.000 description 18
- 230000004900 autophagic degradation Effects 0.000 description 17
- 235000018977 lysine Nutrition 0.000 description 16
- 229960003646 lysine Drugs 0.000 description 16
- 235000011044 succinic acid Nutrition 0.000 description 16
- 229960002898 threonine Drugs 0.000 description 16
- 235000008521 threonine Nutrition 0.000 description 16
- 102100020814 Sequestosome-1 Human genes 0.000 description 12
- 108020004414 DNA Proteins 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 150000005693 branched-chain amino acids Chemical class 0.000 description 7
- 210000003494 hepatocyte Anatomy 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 235000002374 tyrosine Nutrition 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 235000014304 histidine Nutrition 0.000 description 6
- 235000006109 methionine Nutrition 0.000 description 6
- 235000008729 phenylalanine Nutrition 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 6
- 239000004475 Arginine Substances 0.000 description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 5
- 101150080431 Tfam gene Proteins 0.000 description 5
- 230000035508 accumulation Effects 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 5
- 230000037354 amino acid metabolism Effects 0.000 description 5
- 230000000692 anti-sense effect Effects 0.000 description 5
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 5
- 235000009697 arginine Nutrition 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 230000037213 diet Effects 0.000 description 5
- 230000006676 mitochondrial damage Effects 0.000 description 5
- 208000007848 Alcoholism Diseases 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- -1 mitochondrial damage Chemical compound 0.000 description 4
- 239000003642 reactive oxygen metabolite Substances 0.000 description 4
- 230000009469 supplementation Effects 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- 102100030840 AT-rich interactive domain-containing protein 4B Human genes 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000004930 Fatty Liver Diseases 0.000 description 3
- 206010019708 Hepatic steatosis Diseases 0.000 description 3
- 101000792935 Homo sapiens AT-rich interactive domain-containing protein 4B Proteins 0.000 description 3
- 101000588298 Homo sapiens Endoplasmic reticulum membrane sensor NFE2L1 Proteins 0.000 description 3
- 101000577547 Homo sapiens Nuclear respiratory factor 1 Proteins 0.000 description 3
- 101000644537 Homo sapiens Sequestosome-1 Proteins 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 102100028744 Nuclear respiratory factor 1 Human genes 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- 102000017946 PGC-1 Human genes 0.000 description 3
- 108700038399 PGC-1 Proteins 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 230000003176 fibrotic effect Effects 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 210000005228 liver tissue Anatomy 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 230000008437 mitochondrial biogenesis Effects 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 231100000241 scar Toxicity 0.000 description 3
- 235000004400 serine Nutrition 0.000 description 3
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101001123331 Homo sapiens Peroxisome proliferator-activated receptor gamma coactivator 1-alpha Proteins 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 102100028960 Peroxisome proliferator-activated receptor gamma coactivator 1-alpha Human genes 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 201000007930 alcohol dependence Diseases 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000035622 drinking Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000005182 global health Effects 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 231100000753 hepatic injury Toxicity 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 235000020888 liquid diet Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 230000004898 mitochondrial function Effects 0.000 description 2
- 230000009456 molecular mechanism Effects 0.000 description 2
- 210000003463 organelle Anatomy 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 235000013930 proline Nutrition 0.000 description 2
- PUIBPGHAXSCVRF-QHFGJBOXSA-N prostaglandin C1 Chemical compound CCCCC[C@H](O)\C=C\C1=CCC(=O)[C@@H]1CCCCCCC(O)=O PUIBPGHAXSCVRF-QHFGJBOXSA-N 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000007863 steatosis Effects 0.000 description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- 101150102163 ATG7 gene Proteins 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 1
- 102000004072 Beclin-1 Human genes 0.000 description 1
- 108090000524 Beclin-1 Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 208000017667 Chronic Disease 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
- 206010017533 Fungal infection Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102100037919 Insulin-like growth factor 2 mRNA-binding protein 2 Human genes 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- BVHLGVCQOALMSV-JEDNCBNOSA-N L-lysine hydrochloride Chemical compound Cl.NCCCC[C@H](N)C(O)=O BVHLGVCQOALMSV-JEDNCBNOSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 108020005196 Mitochondrial DNA Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000001907 Mushroom Poisoning Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 101710183293 Respiration factor 1 Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 208000026594 alcoholic fatty liver disease Diseases 0.000 description 1
- 229940009533 alpha-ketoglutaric acid Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229960005260 amiodarone Drugs 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 238000011225 antiretroviral therapy Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007961 artificial flavoring substance Substances 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000004961 autolysosome Anatomy 0.000 description 1
- 210000004957 autophagosome Anatomy 0.000 description 1
- 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 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000010805 cDNA synthesis kit Methods 0.000 description 1
- 108010033929 calcium caseinate Proteins 0.000 description 1
- 235000019577 caloric intake Nutrition 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000002032 cellular defenses Effects 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 230000004640 cellular pathway Effects 0.000 description 1
- 230000004098 cellular respiration Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000003081 coactivator Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000004149 ethanol metabolism Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 208000024386 fungal infectious disease Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003897 hepatic stem cell Anatomy 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000006372 lipid accumulation Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000010831 paired-sample T-test Methods 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- ZWBAMYVPMDSJGQ-UHFFFAOYSA-N perfluoroheptanoic acid Chemical compound OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F ZWBAMYVPMDSJGQ-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000009979 protective mechanism Effects 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- 150000003445 sucroses Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 235000021119 whey protein Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
- A61K31/51—Thiamines, e.g. vitamin B1
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
用于在哺乳动物中预防和/或治疗肝病的用途的组合物，所述组合物包含活性剂，所述活性剂包含氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸和羧酸柠檬酸、琥珀酸、苹果酸。
Description
技术领域
本说明书总体上涉及包含氨基酸的组合物。更具体地，本说明书涉及用于预防和/或治疗肝病的包含氨基酸的组合物。
背景技术
肝病属于由多种不利的环境条件例如如寄生虫和病毒、药物、毒性物质、酒精中毒和抽烟引起的最频繁发生的疾病。其通常是出现恶化临床特征的慢性疾病。慢性肝病的特征在于：肝实质随时间逐渐破坏，具有炎性响应和脂肪积累，具有纤维化损伤和细胞转化的活化，导致在许多情况下的癌症发生。因此，肝病可包括脂肪变性、纤维化、肝硬化和肝细胞癌作为肝的进行性临床紊乱。肝硬化是急性和慢性肝病的结果，并且特征在于：肝组织被纤维化瘢痕组织和再生性结节替代，导致肝功能的进行性丧失。纤维化和结节性再生导致肝的正常微观小叶结构丧失。纤维化代表由例如感染、炎症、损伤以及甚至愈合造成的瘢痕组织生长。随时间推移，纤维化瘢痕组织缓慢替代正常的功能性肝组织，导致流向肝的血液量降低，使得肝不能充分处理血流中存在的营养物、激素、药物和毒物。肝硬化更常见的原因包括酒精中毒、丙型肝炎病毒感染、毒素的摄入，并且还存在许多其他可能的原因。如下所提及的，演变为肝硬化并且可能演变为癌症的流行病学上最相关的障碍是体脂增加和相关肝脂肪积累。这种脂肪积累可归因于两种主要的临床状况：酒精滥用和肥胖。
过量和长期饮酒可导致酒精性肝病(alcoholic liver disease，ALD)，这是一个主要的全球健康问题。ALD的病理特征在长时间内发展，包括肝脂肪变性、脂肪性肝炎、肝硬化直至癌症。
乙醇发病机制是由多种因素导致的。早期事件例如线粒体损伤、活性氧物类(reactive oxygen species，ROS)生成和脂肪积累显示是乙醇代谢的直接结局，并且是ALD与非酒精性肝病或NAFLD(见下文)之间的共同特征(Mantena et al.2008)。
尚未充分了解针对酒精有害作用的细胞防御机制。为消化细胞蛋白质和细胞器以获得能量或消除受损细胞结构的重要降解细胞途径的自噬被认为在ALD中发挥作用，但是对这些机制的了解仍然是零碎的(Lin et al.2015)。自噬显示在肝细胞和非实质细胞(即，巨噬细胞和肝干细胞)二者中均发挥关键作用，影响胰岛素敏感性、脂质积累、肝细胞损伤和固有免疫应答。
最近对小鼠和细胞模型的研究表明，急性乙醇摄入激活了肝中的自噬(Ding etal.2010；Ni et al.2013；Lin et al.2013)。
相比之下，慢性乙醇中毒显示抑制了肝自噬(Thomes et al.2015；Cho etal.2014)。对自噬的抑制已显示加剧了小鼠中乙醇驱动的脂肪变性和肝损伤(Ding etal.2010；Ni et al.2013；Lin et al.2013)。
相反地，自噬的药理学促进显示减轻了乙醇驱动的肝脂肪变性和肝损伤(Lin etal.2013)。作为结果，自噬被视为针对乙醇的细胞毒性作用的保护机制，并且已显现为用于开发ALD的治疗剂的靶标。
如前所提及的，肝病的第二大主要原因是肥胖，肥胖在发达国家广泛扩散且也在发展中国家在流行病学上日益增加，并且引起所谓的非酒精性脂肪性肝病或NAFLD。向着脂肪性肝炎、肝硬化和肝癌的进展在全球范围内日益增加出现。涉及这种病症的生物化学和分子机制与ALD中通常描述的那些重叠。
由于氨基酸代谢改变是与饮酒和肥胖发生二者相关联的肝病的一个标志，其特别地以循环支链氨基酸(branched-chain amino acid，BCAA)的水平降低为特征(Charlton,2006)，人们对开发基于氨基酸补充的新治疗方法作为肝病治疗越来越感兴趣。
发明内容
本说明书的目的是提供在肝病的预防和治疗中有效的新的基于氨基酸的组合物。
根据本说明书，上述目的由于在所附权利要求书中特别提及的主题而实现，所附权利要求书被理解为构成本公开内容的主要部分。
本说明书的一个实施方案提供了用于在哺乳动物中治疗肝病的组合物，该组合物包含活性剂，所述活性剂包含氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸和羧酸柠檬酸、琥珀酸、苹果酸。
在一个或更多个实施方案中，组合物的活性剂还包含选自组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、半胱氨酸和酪氨酸的一种或更多种氨基酸。
在一个优选实施方案中，肝病可选自酒精性肝病(ADL)、非酒精性肝病(NAFDL)脂肪营养不良、肝炎、肝硬化、肝细胞癌(hepatocellular carcinoma，HCC)。
本公开内容的另一个实施方案提供了在哺乳动物中治疗肝病的方法，该方法包括：选择包含活性剂的组合物，所述活性剂包含氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸和羧酸柠檬酸、琥珀酸和苹果酸；施用组合物以在哺乳动物中治疗肝病。
附图说明
现将参照附图仅以实例的方式描述本发明，在附图中：
-图1示出了作为用不同的基于氨基酸的组合物和乙醇(EtOH)处理9天的HepG2细胞中mRNA水平示出的基因表达(*P值<0.05和**P<0.01，相对于CTRL细胞)。
-图2示出了用不同的基于氨基酸的组合物和EtOH处理9天的HepG2细胞中的p62蛋白质水平(*P值<0.05和**P<0.01，相对于CTRL细胞；#P值<0.05，相对于经EtOH处理的细胞)。
具体实施方式
在以下描述中，给出了许多具体细节以提供对一些实施方案的透彻理解。这些实施方案可在没有一个或更多个具体细节的情况下，或者用其他方法、组分、材料等来实施。在另一些情况下，未详细地示出或描述公知的结构、材料或操作以避免使实施方案的一些方面混淆。
在本说明书通篇提及的“一个实施方案”意指与该实施方案相关描述的特定的特征、结构或特性包括在至少一个实施方案中。因此，在本说明书通篇多处出现的短语“在一个实施方案中”不一定全部是指同一个实施方案。此外，在一个或更多个实施方案中，可以以任何合适的方式对特定的特征、结构或特性进行组合。本文中提供的标题仅是为了方便，并不解释实施方案的范围或含义。
酒精性肝病(ALD)和非酒精性脂肪性肝病(NAFLD)是主要的全球健康问题，其特征在于：在长时间内的病理特征发展，包括肝脂肪变性、脂肪性肝炎、肝硬化，直至癌症。
乙醇发病机制中的早期事件例如如线粒体损伤、活性氧物类(ROS)生成和脂肪积累是ALD与NAFLD之间的共同特征。
另外，氨基酸代谢改变已显示是肝病的一个区别性特征，其特征在于低的循环支链氨基酸(BCAA)水平，并且BCAA补充当被开处方为维持治疗时显示与肝硬化并发症频率降低相关(Charlton 2006)。
本申请的发明人发现，通过向包含亮氨酸、异亮氨酸、缬氨酸、苏氨酸和赖氨酸的组合的组合物添加特定的羧酸，可实现抵抗肝病例如如ALD和NAFLD的高有效性。
本文中公开的组合物已显示恢复了由乙醇诱导的改变的氨基酸代谢，并因此防止自噬，所述组合物包含与三种羧酸组合的氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸作为活性剂，所述三种羧酸是三羧酸循环的底物，包括特定量的柠檬酸、琥珀酸和苹果酸。在线粒体基质中进行的三羧酸循环(tricarboxylic acid cycle，TCA循环)(也称为克雷布斯循环(Krebs cycle)和柠檬酸循环)是细胞呼吸的第二阶段，细胞呼吸是通过其活细胞在存在氧的情况下分解有机燃料分子以收获其生长和分裂所需的能量的三阶段过程。
包含上述活性剂的组合物以及包含含有另一些特定氨基酸(列于下表1中)的上述活性剂的组合物比不含这样的特定羧酸的类似氨基酸组合物显著更有效。
在一个或更多个实施方案中，在本文中公开的组合物中，柠檬酸、琥珀酸和苹果酸的总量与氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸的总量之间的重量比为0.05至0.3，优选0.1至0.25。
在一个或更多个实施方案中，活性剂还可包含选自组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、半胱氨酸和酪氨酸的一种或更多种氨基酸。
在一个或更多个实施方案中，组合物中包含的羧酸由柠檬酸、琥珀酸和苹果酸组成。
在另一个实施方案中，本文中公开的组合物的活性剂还可包括天冬氨酸和/或鸟氨酸L-α酮戊二酸(OKG)。
根据一个实施方案，该组合物包含活性剂，该活性剂由以下组成：亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸、组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、半胱氨酸和任选地酪氨酸，以及柠檬酸、琥珀酸、和苹果酸，所述氨基酸是组合物中包含的仅有氨基酸。柠檬酸、琥珀酸和苹果酸可以是组合物中包含的仅有羧酸。
在另一个实施方案中，该组合物可包含相对于活性剂重量的按重量计35％至65％，优选按重量计42％至56％的量的氨基酸异亮氨酸、亮氨酸和缬氨酸。
在一个或更多个实施方案中，亮氨酸与柠檬酸之间的重量比为5至1，优选2.50至3.50。
在另一个实施方案中，柠檬酸的重量或摩尔量高于苹果酸和琥珀酸各自的重量或摩尔量。优选地，柠檬酸的重量或摩尔量高于苹果酸加琥珀酸的重量或摩尔总量。在另一个实施方案中，柠檬酸与苹果酸和琥珀酸的总和之间的重量比为1.0至4.0，优选1.5至2.5。在一个优选实施方案中，柠檬酸：苹果酸：琥珀酸重量比为10:1:1至2:1.5:1.5，优选7:1:1至1.5:1:1，更优选5:1:1至3:1:1。在一个优选实施方案中，柠檬酸：苹果酸：琥珀酸重量比为4:1:1。
根据本公开内容的一些实施方案，优选的异亮氨酸：亮氨酸摩尔比为0.2至0.7，优选0.30至0.60，和/或优选的缬氨酸：亮氨酸重量比为0.2至0.70，优选0.30至0.65。
在另一个实施方案中，苏氨酸：亮氨酸摩尔比为0.10至0.90，优选0.20至0.70，和/或赖氨酸：亮氨酸重量比为0.20至1.00，优选0.40至0.90。
在一个优选实施方案中，柠檬酸、苹果酸、琥珀酸的总摩尔量与甲硫氨酸、苯丙氨酸、组氨酸和色氨酸的总摩尔量之间的比率高于1.35。
在一个或更多个实施方案中，柠檬酸、苹果酸、琥珀酸的总和与支链氨基酸亮氨酸、异亮氨酸、缬氨酸的总和之间的重量比为0.1至0.4，优选0.15至0.35。
在另一个实施方案中，支链氨基酸亮氨酸、异亮氨酸、缬氨酸加苏氨酸和赖氨酸的总重量量高于三种羧酸例如柠檬酸、苹果酸和琥珀酸的总重量量。优选地，单一羧酸(柠檬酸、琥珀酸或苹果酸)的重量量小于单一氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸和赖氨酸各自的重量量。
在另一个实施方案中，赖氨酸和苏氨酸的总摩尔量高于三种羧酸柠檬酸、琥珀酸、苹果酸的总摩尔量。优选地，三种羧酸柠檬酸、琥珀酸、苹果酸的总摩尔量与赖氨酸和苏氨酸的总摩尔量之间的比率为0.1至0.7，优选0.15至0.55。
在一个或更多个实施方案中，本文中公开的组合物还包含维生素，其优地选自维生素B，例如为维生素B1和/或维生素B6。
在本公开内容的另一个实施方案中，该组合物可包含碳水化合物、添加剂和/或矫味物质。
在一个优选实施方案中，该组合物专用于预防和/或治疗选自以下的肝病：脂肪性肝病、脂肪营养不良、肝炎、肝硬化、肝细胞癌(HCC)。
在一个或更多个实施方案中，肝病是脂肪性肝病。脂肪性肝病可由饮酒引起(酒精性脂肪性肝病，ALD)。
在一个或更多个实施方案中，脂肪性肝病是非酒精性脂肪性肝病(NFLD)。
在一个或更多个实施方案中，脂肪性肝病可由以下引起：药物或毒素，例如如胺碘酮(amiodarone)、甲氨喋呤(methotrexate)、地尔硫卓(diltiazem)、高效抗逆转录病毒治疗、糖皮质激素、他莫昔芬(tamoxifen)、蕈中毒(mushroom poisoning)。
此外，特别是在制备根据本公开内容的组合物且特别是活性剂时，优选地避免氨基酸精氨酸。另外，本文中公开的组合物优选避免的另一些氨基酸可以是丝氨酸、脯氨酸、丙氨酸。这样的氨基酸在组合物中在一定浓度或化学计量比下可起反作用或甚至有害。
本申请中公开的氨基酸可被相应的可药用衍生物(即，盐)替代。
如在下文中显而易见的是，根据本公开内容的组合物的施用在预防和/或治疗肝病方面特别有效。
在一个优选实施方案中，所公开的组合物可用于治疗酒精性肝病(ALD)。
根据另一个实施方案，氨基酸组合物可包含可药用赋形剂，如例如蛋白质、维生素、碳水化合物、天然和人工甜味剂和/或矫味物质。在一个优选实施方案中，可药用赋形剂可选自乳清蛋白、麦芽糊精、果糖、酪蛋白钙、鱼油、三氯蔗糖、蔗糖酯、维生素D3、B族维生素。
对于经口使用，根据本说明书的组合物可以为片剂、胶囊剂、颗粒剂、凝胶剂、可胶凝散剂或散剂的形式。
关于由组合物提供的多种氨基酸的量及其之间的比例的另外说明包含在所附权利要求书中，其构成本文中关于本发明提供的技术教导的主要部分。
实施例
表1示出了在体外对肝细胞(HepG2细胞)和在体内对乙醇消耗大鼠测试的两种不同的基于氨基酸的组合物，如下所公开的。
以下称为“BCAAem”的组合物包含含有氨基酸亮氨酸、赖氨酸、异亮氨酸、缬氨酸、苏氨酸、半胱氨酸、组氨酸、苯丙氨酸、甲硫氨酸、酪氨酸、色氨酸的活性剂。
称为“阿尔法5m(α5m)”的组合物包含含有相同氨基酸加柠檬酸、琥珀酸和苹果酸的活性剂。
表1
上表1的组合物可首先通过用0.8筛筛选所有组分来制备。为了获得预混合物，将每种成分(以按总量的重量计<10％的量)与一部分L-赖氨酸HCl一起放入聚乙烯袋中，以获得总组合物的10％重量。然后将袋手动摇动5分钟。然后将预混合物与其余成分一起装载在混合器(Planetaria)中，并在120rpm下混合15分钟的时间，以获得均匀的最终组合物。
方法
动物与处理
实验方案是根据1986年11月24日的欧洲共同体理事会指令(EuropeanCommunities Council Directive)(86/609/EEC)和意大利卫生部(Italian Ministry ofHeath)批准和实施的，并且符合国家动物保护指南(The National Animal ProtectionGuidelines)。
来自Charles River(Calco,Como,Italy)的雄性Wistar大鼠(3月龄)用于下文中公开的实验分析。
将动物单独圈养在干净的聚丙烯笼中，并分为六组：
1)配对喂养组(配对喂养CTRL，n＝6)用对照流质饮食喂养，其中乙醇(EtOH)被等热量的麦芽糖葡聚糖替代；
2)EtOH组(EtOH，n＝7)用包含EtOH的Lieber-DeCarli流质饮食随意喂养[逐渐提高EtOH的量，在1周之后达到36％热量摄入，对应于6.2％(体积/体积)的终浓度]；
3)BCAAem组(BCAAem，n＝6)，其用对照流质饮食喂养，其中EtOH被等热量的麦芽糖葡聚糖替代，并补充有提供1.5g/kg/天BCAAem的支链氨基酸组合物(表1中的“BCAAem”)；
4)α5组(α5m，n＝6)，其用对照流质饮食喂养，其中EtOH被等热量的麦芽糖葡聚糖替代，并补充有提供1.5g/kg/天的氨基酸组合物(表1中的“α5m”)；
5)EtOH加BCAAem组(EtOH+BCAAem，n＝7)，其用包含EtOH和BCAAem组合物的Lieber-DeCarli流质饮食随意喂养；以及
6)EtOH加α5m组(EtOH+α5m，n＝7)，其用包含EtOH和α5m组合物的Lieber-DeCarli流质饮食随意喂养。
样品制备
对肝(n＝4只动物/组)进行称重，在冷甲醇：水(v/v，1:1)中匀化，并根据Want etal.(Want et al.2013)提取。将经真空干燥的样品混悬在甲醇：1mM TDFHA＝1:1的120μl/50mg组织中，并在4℃下以16,000g离心10分钟。将2μl上清液(surnatant)直接上样到UPLC质谱仪上，并如下报道进行分析。使用三种不同的方法对每个样品进行四个技术重复。
色谱和肝中氨基酸定量
标准氨基酸购自Sigma(Milan,Italy)。每种氨基酸储备溶液均在水中以1mg/ml制备，稀释至终浓度3pmol/μl，并通过注射器以10μl/分钟直接注入TripleTOF 5600+质谱仪(AB Sciex,Milan,Italy)。因此，针对每种氨基酸优化了去簇电位(declusteringpotential，DP)和碰撞能量(collision energy，CE)。
接下来，基于DP和CE值制备三种氨基酸混合物：MIX 1，包含苏氨酸、天冬酰胺、酪氨酸和丝氨酸，并用DP：30V，CE：15V进行分析；MIX 2，包含甘氨酸、丙氨酸、亮氨酸、异亮氨酸、缬氨酸、脯氨酸、组氨酸、甲硫氨酸、天冬氨酸、谷氨酰胺和苯丙氨酸，并用DP：40V，CE：15V进行分析；以及MIX 3，包含谷氨酸、赖氨酸、精氨酸和色氨酸，并用DP：80V，CE：18V进行分析。
源参数为：气体1：33psi，气体2：58psi，帘气：25psi，温度：500℃，以及ISVF(离子喷雾电压浮动(IonSpray Voltage Floating))：5500V。
为了获得校准曲线，将三种混合物的不同量(10、33、50、100、200、400pm ol)的技术一式四份物在使用UPLC 1290(Agilent Technologies Italia,Cernusco sulNaviglio,Milan,Italy)进行UPLC分离之后注入质谱仪中。色谱柱来自Waters，AcquityHSS T3 C18 2.1x 100mm，1.7μm，同时流动相为A：水中的1mM TDFHA(十三氟庚酸)；B：乙腈中的1mM TDFHA。B在4分钟中从12.5％到26.5％随后在3.5分钟中从26.5％升至92％的梯度用于分离所有氨基酸，其中流速为0.35ml/分钟，并且柱温为65℃，如所述(Le et al.,2014)。
自动进样器设置为4℃。使用色谱峰面积和加权回归(除天冬酰胺、酪氨酸、缬氨酸和谷氨酸拟合至1/x2之外所有化合物为1/x)通过MultiQuant软件2.1版(SCIEX)绘制校准曲线。通过使色谱峰面积与来源于外部运行的校准标准品的色谱峰面积相关联并针对组织(mg)进行归一化，获得大鼠肝样品中每种氨基酸的定量值(pmol)。
细胞培养与处理
人HCC HepG2细胞购自美国典型培养物保藏中心(American Type CultureCollection)(HB-8065；ATCC,Manassas,VA)。在具有5％CO2的气氛中，在37℃下，在补充有10％胎牛血清、青霉素(100U/mL)和链霉素(100μg/mL)的RPMI-1640培养基中常规培养细胞。每个75cm2烧瓶(Corning Inc.,Corning,NY)接种200万个HepG2细胞。
在接种之后六小时，单独或组合添加75mM(0.34％)EtOH和1％BCAAem或α5m。将未经处理的细胞平板接种作为对照。每隔24小时，分别用具有或不具有EtOH和BCAAem或α5m的新鲜培养基替换对照烧瓶和处理烧瓶二者中的培养基。在接种之后四天，将细胞胰蛋白酶化并以每个烧瓶200万个活细胞接种到新的烧瓶中，并且每天更换培养基，如前所述(Pochareddy et al.2012)。在分开过程之后五天(总共9天，具有或不具有EtOH、BCAAem或α5m、或EtOH加BCAAem或α5m)，收获细胞如下所报道用于不同的测定。
定量RT-PCR分析
如所述(Tedesco et al.2008)进行定量RT-PCR反应，并用iQ SybrGreenISuperMix(Bio-Rad；Segrate,Italy)在iCycler iQ实时PCR检测系统(Bio-Rad)上运行。
简言之，使用
组织微型试剂盒(Qiagen,Milan,Italy)从组织中分离RNA。使用iScriptTM cDNA合成试剂盒(Bio-Rad Laboratories,Segrate,Italy)合成cDNA。
使用来自Premier Biosoft International的Beacon Designer 2.6软件设计引物(序列在下表2中报道)。将可检测到多种转录本时的循环数(阈值循环，CT)与TBP的循环数进行比较，称为ΔCT。将基因相对水平表示为2-(ΔΔCT)，其中ΔΔCT等于经EtOH-或BCAAem-或CAA混合物处理的大鼠(或处理的HepG2细胞)的ΔCT减去对照大鼠(或未经处理的HepG2细胞)的ΔCT。
表2
Ta退火温度(℃)；登录号PGC-1α：NM_013261；登录号Tfam：NM_009360.4；登录号NRF1:NM_005011；登录号Cytc：JF919224.1；登录号TBP：NG_051572用于使基因表达归一化。
Western印迹分析
在存在蛋白酶和磷酸酶抑制剂混合物(Sigma Aldrich,Milan,Italy)的情况下用T-PER哺乳动物蛋白质提取试剂(Pierce,ThermoScientific,Rockford,USA)如制造商所述从肝获得蛋白质提取物。通过二辛可宁酸蛋白质测定(BCA,Pierce,Euroclone,Milan,Italy)测量蛋白质含量，并在还原条件下在SDS-PAGE上运行50μg蛋白质。然后将分离的蛋白质电泳转移到硝酸纤维素膜(Bio-Rad Laboratories,Segrate,Italy)上。目标蛋白质用特异性抗体：抗p62和抗α-肌动蛋白(全部均来自Cell Signaling,Euroclone,Milan,Italy)显现，每种抗体均以1:1000稀释。使用辣根过氧化物酶缀合的抗兔或抗小鼠免疫球蛋白在室温下检测免疫染色1小时。使用SuperSignal底物(Pierce,Euroclone,Milan,Italy)测量蛋白质的量，并用IMAGEJ软件图像分析仪通过密度测量法进行定量。
统计学分析
对于所有基因表达数据，使用双侧配对样品t检验比较对照细胞与经处理细胞之间的值。P值<0.05被认为具有统计学显著性。
结果
组合物α5m比BCAAem组合物更有效地恢复因EtOH消耗而受损的肝线粒体生物发生
和功能
评价了BCAAem和α5m组合物改善由于EtOH暴露而受损的线粒体生物发生和功能的能力。为了研究参与BCAAem和α5m组合物发挥作用的分子机制，使用了肝EtOH毒性的体外模型。
为此，在有或没有BCAAemα5m组合物的情况下将肝HepG2细胞暴露于75mM EtOH，持续9天。与未经处理的对照细胞中相比，增殖物激活受体γ辅激活子1α(PGC-1α)、核呼吸因子-1(nuclear respiratory factor-1，NRF-1)、线粒体DNA转录因子A(Tfam)和cyt c mRNA水平在暴露于75mM EtOH持续9天的HepG2细胞中不变或略微更低(图1)。
然而，相对于未经处理细胞和经EtOH处理细胞，施用BCAAem和α5m组合物9天提高了PGC-1α和Tfam mRNA水平(图1)。
值得注意的是，α5m组合物改善肝线粒体生物发生标志物的效力在统计学上高于BCAAem的效力。
自噬分析
自噬流可通过将数种标志物进行组合来推断，所述标志物包括p62/SQSTM1蛋白质水平以及LC3II/LC3I比、Beclin1和Atg7、以及4EBP1磷酸化(Klionsky et al.,2016)。p62/SQSTM1已显示并入自噬体中并在自溶酶体中降解。因此，降低的p62/SQSTM1蛋白质水平指示自噬提高(Klionsky et al.2016)。
如本申请的图2中所示，p62蛋白质水平在暴露于75mM EtOH持续9天的HepG2细胞中低于未经处理的对照细胞中。
然而，在施用BCAAem或α5m组合物9天之后，相对于未经处理细胞和经EtOH处理细胞的p62水平，p62蛋白质水平更高。
同样在这种情况下，α5m组合物的效力在统计学上高于BCAAem组合物的效力。
肝氨基酸定量
如上所公开的，改变的氨基酸代谢，具体地低循环BCAA水平，已显示是酒精性肝病的一个区别性特征(Charlton,2006)。
以下提供的数据指代BCAAem或α5m组合物对慢性EtOH消耗大鼠的肝中氨基酸代谢的作用。
为此目的，使用色谱分析测量消耗单独或与受试组合物组合的EtOH的大鼠的肝组织中的游离氨基酸水平。
如表3中所报道的，补充BCAAem和α5m组合物对精氨酸、亮氨酸和色氨酸的水平无效。相比之下，EtOH消耗导致肝中这些氨基酸的水平降低。
令人感兴趣的是，在EtOH消耗大鼠中施用BCAAem和α5m组合物防止了精氨酸、亮氨酸和色氨酸降低。
此外，暴露于含EtOH饮食的小鼠的肝中的异亮氨酸、丝氨酸、酪氨酸和缬氨酸浓度较低。
尽管BCAAem补充不能阻止其下降，但α5m补充反而也能有效防止EtOH诱导的异亮氨酸和缬氨酸降低。
其余氨基酸的浓度在各组之间不具有统计学差异。
这些结果与α5m组合物与BCAAem组合物相比在使EtOH消耗大鼠的肝样品中BCAA水平重新正常化方面的特定能力相一致。
表3
值被报道为平均值±SD(pmol/mg组织)，n＝4只动物/组；*相对于CTRL组，P<0.05；#相对于EtOH组，P值<0.05。
总之，体外和体内结果表明，饮食补充包含活性剂的组合物在预防暴露于EtOH的肝细胞的线粒体损伤方面是显著有效的，该活性剂包含亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸、柠檬酸、琥珀酸和苹果酸的组合。
这种作用还伴随着通过EtOH暴露而提高(即，p62蛋白质水平降低)的自噬降低(即，p62蛋白质水平提高)。
EtOH本身可增强自噬以补偿EtOH毒性以及特别是线粒体损伤，线粒体损伤在暴露于酒精的肝细胞中和消耗酒精的动物的肝中明显。
事实上，自噬是旨在消除功能异常细胞器(包括线粒体)的细胞机制。当肝细胞暴露于酒精并且线粒体功能降低时，提高的自噬，如本申请中也公开的，可用于消除功能异常的线粒体。
本文中公开的氨基酸组合物能够防止线粒体损伤，使得细胞不需要自噬来维持其活力功能，所述组合物包含亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸与柠檬酸、琥珀酸和苹果酸的组合。因此，自噬降低(如由本申请中所示的p62蛋白质水平提高所示)。
此外，并且最重要的是，已发现所公开的组合物在恢复EtOH消耗大鼠的肝中的游离BCAA、精氨酸和色氨酸浓度方面非常有效。
值得注意的是，初步结果表明，本文中公开的包含亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸与柠檬酸、琥珀酸和苹果酸的组合的氨基酸组合物还能够减小暴露于高脂肪饮食(high-fat diet，HFD，60％热量来自脂肪)6个月的小鼠的肝细胞中脂滴的直径，该小鼠是广泛使用的NAFLD小鼠模型。总而言之，这些结果强烈支持以下观点：本文中公开且在酒精依赖性肝毒性方面具有活性的氨基酸组合物可在预防NAFLD发生和恶化方面是健康的。
由前述内容显而易见的是，根据本公开内容的组合物可用于预防和/或治疗在全球范围内影响大量成年人群且增加社会成本的肝病。
参考文献
Charlton M.(2006)作为用于肝病的治疗的富含支链氨基酸的补充剂(Branched-Chain Amino Acid Enriched Supplements as Therapy for Liver Disease).J Nutr136:295S-298S.
Cho HI,Choi JW,Lee SM(2014)自噬体-溶酶体融合受损导致慢性乙醇诱导性肝损伤(Impairment of autophagosome-lysosome fusion contributes to chronicethanol-induced liver injury).Alcohol 48:717–725.
Cooper GM和Hausman RE(2009)细胞.分子方法.生物能和代谢.线粒体、叶绿体和过氧化物酶体(La cellula.Un approccio molecolare.Bioenergetica emetabolismo.Mitocondri,cloroplasti e perossisomi).Piccin 11:432-468.
Ding WX,Li M,Chen X,Ni HM,Lin CW,Gao W,Lu B,Stolz DB,Clemens DL,YinXM(2010)自噬降低了小鼠中急性乙醇诱导性肝毒性和脂肪变性(Autophagy reducesacute ethanol-induced hepatotoxicity and steatosis in mice).Gastroenterology139:1740–1752.
Jung CH,Ro S-H,Cao J,Otto NM,Kim D-H(2010)自噬的mTOR调节(mTORregulation of autophagy).FEBS Lett 584:1287–1295.
Klionsky DJ等(2016)用于监测自噬的测定的使用和说明指南(第3版)(Guidelines for the use and interpretation of assays for monitoring autophagy(3rd edition)).Autophagy 12:1–222.
Lin CW,Zhang H,Li M,Xiong X,Chen X,Chen X,Dong XC,Yin XM(2013)自噬的药理学促进减轻了小鼠的酒精性和非酒精性脂肪性肝病中的脂肪变性和损伤(Pharmacological promotion of autophagy alleviates steatosis and injury inalcoholic and non-alcoholic fatty liver conditions in mice).J Hepatol 58:993–999.
Lin Wang,Bilon Khambu,Hao Zhang,Xiao-Ming Yin(2015)酒精性肝病中的自噬，由饮酒触发的自食(Autophagy in alcoholic liver disease,self-eatingtriggered by drinking).Clinics and research in hepatology andgastroenterology 39,S2-S6.
Le A,Ng A,Kwan T,Cusmano-Ozog K,Cowan TM.(2014)用于通过液相色谱-串联质谱(LC-MS/MS)定量分析未衍生化氨基酸的迅速、灵敏方法(A rapid,sensitive methodfor quantitative analysis of underivatized amino acids by liquidchromatography-tandem mass spectrometry(LC-MS/MS)).J Chromatogr B AnalytTechnol Biomed Life Sci 944:166-174.
Mantena SK,King AL,Andringa KK,Eccleston HB和Bailey SM(2008)酒精和肥胖诱导的脂肪性肝病的发病机制中的线粒体功能障碍和氧化应激(Mitochondrialdysfunction and oxidative stress in the pathogenesis of alcohol-and obesity-induced fatty liver diseases).Free Radical Biology and Medicine 44:1259-1272.
Ni H-M,Du K,You M,Ding W-X(2013)FoxO3a在酒精诱导的自噬和肝毒性中的关键作用(Critical role of FoxO3a in alcohol-induced autophagy andhepatotoxicity).Am J Pathol 183:1815–1825.
Pochareddy S,Edenberg HJ.(2012)慢性酒精暴露改变了HepG2细胞中的基因表达(Chronic alcohol exposure alters gene expression in HepG2 cells).AlcoholClin Exp Res 36:1021-1033.
Tedesco L,Valerio A,Cervino C,Cardile A,Pagano C,Vettor R,Pasquali R,Carruba MO,Marsicano G,Lutz B,Pagotto U,和Nisoli E.(2008)大麻素1型受体阻断在白色脂肪细胞中通过内皮型一氧化氮合酶表达促进线粒体生物发生(Cannabinoid type1receptor blockade promotes mitochondrial biogenesis through endothelialnitric oxide synthase expression in white adipocytes).Diabetes 57:2028-2036.
Thomes PG,Trambly CS,Fox HS,Tuma DJ,Donohue TM Jr(2015)急性和慢性乙醇施用以不同方式调节肝自噬和转录因子EB(Acute and chronic ethanol administrationdifferentially modulate hepatic autophagy and transcription factor EB).Alcohol Clin Exp Res 39:2354–2363.https://doi.org/10.1111/acer.12904.
Valerio A,D'Antona G,Nisoli E.(2011)支链氨基酸、线粒体生物发生和健康跨度：演变观点(Branched-chain amino acids,mitochondrial biogenesis,andhealthspan:an evolutionary perspective).Aging 3:464-478.
Want EJ,Masson P,Michopoulos F,Wilson ID,Theodoridis G,Plumb RS,Shockcor J,Loftus N,Holmes E,Nicholson JK.(2013)通过UPLC-MS的动物和人组织的全局代谢谱分析(Global metabolic profiling of animal and human tissues via UPLC-MS).Nat Protoc 8:17-32.
序列表
<110> Professional Dietetics
<120> 用于治疗肝病的组合物
<130> BWO21147
<160> 10
<170> BiSSAP 1.3.6
<210> 1
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> PGC1α正义5' - 3'
<400> 1
gaccccagag tcaccaaatg ac 22
<210> 2
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> PGC1α反义5' - 3'
<400> 2
ttggttggct ttatgaggag ga 22
<210> 3
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> Tfam正义5' - 3'
<400> 3
agattggggt cgggtcac 18
<210> 4
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> Tfam反义5' - 3'
<400> 4
gacaacttgc caagacagat g 21
<210> 5
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> NRF1正义5' - 3'
<400> 5
actcgtgtgg gacagcaagc 20
<210> 6
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> NRF1反义5' - 3'
<400> 6
atggtgagag gcggcagttc 20
<210> 7
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> Cytc正义5'-3'
<400> 7
cgttgtgcca gcgactaaaa a 21
<210> 8
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> Cytc反义3'-5'
<400> 8
ttccgcccaa agagacca 18
<210> 9
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> TBP正义5'-3'
<400> 9
aggcaccaca gctcttccac 20
<210> 10
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> TBP反义5'-3'
<400> 10
cccagaactc tccgaagctg 20
Claims (14)
1.用于在哺乳动物中预防和/或治疗肝病的用途的组合物，所述组合物包含活性剂，所述活性剂包含氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸和羧酸柠檬酸、琥珀酸、苹果酸。
2.根据权利要求1所述用途的组合物，其中柠檬酸、苹果酸、琥珀酸的总量与亮氨酸、异亮氨酸、缬氨酸、赖氨酸、苏氨酸的总量之间的重量比为0.05至0.3，优选0.1至0.25。
3.根据前述权利要求中任一项所述用途的组合物，其中柠檬酸、苹果酸、琥珀酸的总量与亮氨酸、异亮氨酸、缬氨酸的总量之间的重量比为0.1至0.4，优选0.15至0.35。
4.根据前述权利要求中任一项所述用途的组合物，其中柠檬酸与苹果酸和琥珀酸的总和之间的重量比为1.0至4.0，优选1.5至2.5。
5.根据前述权利要求中任一项所述用途的组合物，其中柠檬酸：苹果酸：琥珀酸重量比为10:1:1至2:1.5:1.5，优选7:1:1至1.5:1:1，更优选5:1:1至3:1:1。
6.根据前述权利要求中任一项所述用途的组合物，其中所述活性剂还包含选自组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、酪氨酸、半胱氨酸的至少一种氨基酸。
7.根据前述权利要求中任一项所述用途的组合物，其中所述活性剂还包含组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、半胱氨酸和任选地酪氨酸。
8.根据前述权利要求中任一项所述用途的组合物，其中柠檬酸、苹果酸、琥珀酸的总摩尔量与甲硫氨酸、苯丙氨酸、组氨酸和色氨酸的总摩尔量之间的比率高于1.35。
9.根据前述权利要求中任一项所述用途的组合物，其中三种羧酸柠檬酸、琥珀酸、苹果酸的总摩尔量与赖氨酸和苏氨酸的总摩尔量之间的比率为0.10至0.70，优选0.15至0.55。
10.根据前述权利要求中任一项所述用途的组合物，其中柠檬酸的重量或摩尔量高于苹果酸和琥珀酸二者的总重量或总摩尔量。
11.根据前述权利要求中任一项所述用途的组合物，其中亮氨酸与柠檬酸之间的重量比为5至1，优选2.50至3.50。
12.根据前述权利要求中任一项所述用途的组合物，其中所述组合物还包含一种或更多种维生素，优选地选自维生素B，更优选为维生素B1和/或维生素B6。
13.根据权利要求1至12中任一项所述用途的组合物，其中所述肝病选自脂肪性肝病、脂肪营养不良、肝炎、肝硬化、肝细胞癌(HCC)。
14.根据权利要求13所述用途的组合物，其中所述肝病选自酒精性肝病(ALD)和非酒精性脂肪性肝病(NAFLD)。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT102018000006725A IT201800006725A1 (it) | 2018-06-27 | 2018-06-27 | Composizioni comprendenti aminoacidi per l'uso nella prevenzione e nel trattamento di malattie epatiche |
| IT102018000006725 | 2018-06-27 | ||
| PCT/IB2019/052694 WO2020003013A1 (en) | 2018-06-27 | 2019-04-02 | Compositions comprising amino acids for use in the prevention and treatment of liver diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112334129A true CN112334129A (zh) | 2021-02-05 |
Family
ID=63491976
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201980042577.XA Pending CN112334129A (zh) | 2018-06-27 | 2019-04-02 | 用于预防和治疗肝病的包含氨基酸的组合物 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US20210260011A1 (zh) |
| EP (1) | EP3586837B1 (zh) |
| JP (1) | JP7347744B2 (zh) |
| KR (1) | KR20210025611A (zh) |
| CN (1) | CN112334129A (zh) |
| AU (1) | AU2019293293A1 (zh) |
| BR (1) | BR112020026431A2 (zh) |
| CA (1) | CA3104839A1 (zh) |
| CL (1) | CL2020003209A1 (zh) |
| CY (1) | CY1124030T1 (zh) |
| DK (1) | DK3586837T3 (zh) |
| EA (1) | EA202092749A1 (zh) |
| ES (1) | ES2858355T3 (zh) |
| IT (1) | IT201800006725A1 (zh) |
| LT (1) | LT3586837T (zh) |
| MX (1) | MX2020013471A (zh) |
| PH (1) | PH12020552254A1 (zh) |
| PL (1) | PL3586837T3 (zh) |
| RS (1) | RS61613B1 (zh) |
| SG (1) | SG11202012297XA (zh) |
| WO (1) | WO2020003013A1 (zh) |
| ZA (1) | ZA202007834B (zh) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT201700087359A1 (it) | 2017-07-28 | 2019-01-28 | Professional Dietetics Spa | Composizioni comprendenti amino acidi per l'uso nel trattamento di malattie associate a disfunzione mitocondriale |
| IT201700087376A1 (it) | 2017-07-28 | 2019-01-28 | Professional Dietetics Spa | Composizioni comprendenti amino acidi per l'uso nel trattamento di malattie associate a disfunzione mitocondriale |
| IT202000000454A1 (it) * | 2020-01-13 | 2021-07-13 | Professional Dietetics Spa | Composizioni comprendenti amino acidi per la prevenzione e il trattamento del cancro |
| WO2022266480A1 (en) * | 2021-06-17 | 2022-12-22 | Axcella Health Inc. | Methods of predicting liver fat content and uses thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007049818A1 (ja) * | 2005-10-27 | 2007-05-03 | Ajinomoto Co., Inc. | 抗脂肪肝、抗肥満及び抗高脂血症用組成物 |
| WO2016179657A1 (en) * | 2015-05-11 | 2016-11-17 | Newcastle Innovation Limited | Amino acid supplementation |
| US20170143679A1 (en) * | 2013-04-19 | 2017-05-25 | Bioventures, Llc | Methods for improving muscle and heart function |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007161642A (ja) | 2005-12-14 | 2007-06-28 | Kyowa Hakko Kogyo Co Ltd | アルコール性肝障害抑制剤 |
| US20130084378A1 (en) * | 2011-09-30 | 2013-04-04 | Daesang Corporation | Amino acid seasoning compositions comprising l-glutamic acid and l-lysine |
| US10226441B2 (en) | 2014-12-09 | 2019-03-12 | Nihon Sizen Hakkoh Co., Ltd. | Aging inhibitor |
-
2018
- 2018-06-27 IT IT102018000006725A patent/IT201800006725A1/it unknown
-
2019
- 2019-04-02 PL PL19166892T patent/PL3586837T3/pl unknown
- 2019-04-02 KR KR1020217002459A patent/KR20210025611A/ko not_active Application Discontinuation
- 2019-04-02 US US17/255,887 patent/US20210260011A1/en active Pending
- 2019-04-02 SG SG11202012297XA patent/SG11202012297XA/en unknown
- 2019-04-02 MX MX2020013471A patent/MX2020013471A/es unknown
- 2019-04-02 RS RS20210318A patent/RS61613B1/sr unknown
- 2019-04-02 BR BR112020026431-8A patent/BR112020026431A2/pt unknown
- 2019-04-02 EP EP19166892.0A patent/EP3586837B1/en active Active
- 2019-04-02 WO PCT/IB2019/052694 patent/WO2020003013A1/en active Application Filing
- 2019-04-02 AU AU2019293293A patent/AU2019293293A1/en active Pending
- 2019-04-02 LT LTEP19166892.0T patent/LT3586837T/lt unknown
- 2019-04-02 CA CA3104839A patent/CA3104839A1/en active Pending
- 2019-04-02 EA EA202092749A patent/EA202092749A1/ru unknown
- 2019-04-02 ES ES19166892T patent/ES2858355T3/es active Active
- 2019-04-02 DK DK19166892.0T patent/DK3586837T3/da active
- 2019-04-02 JP JP2020568462A patent/JP7347744B2/ja active Active
- 2019-04-02 CN CN201980042577.XA patent/CN112334129A/zh active Pending
-
2020
- 2020-12-10 CL CL2020003209A patent/CL2020003209A1/es unknown
- 2020-12-15 ZA ZA2020/07834A patent/ZA202007834B/en unknown
- 2020-12-22 PH PH12020552254A patent/PH12020552254A1/en unknown
-
2021
- 2021-03-22 CY CY20211100249T patent/CY1124030T1/el unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007049818A1 (ja) * | 2005-10-27 | 2007-05-03 | Ajinomoto Co., Inc. | 抗脂肪肝、抗肥満及び抗高脂血症用組成物 |
| US20170143679A1 (en) * | 2013-04-19 | 2017-05-25 | Bioventures, Llc | Methods for improving muscle and heart function |
| WO2016179657A1 (en) * | 2015-05-11 | 2016-11-17 | Newcastle Innovation Limited | Amino acid supplementation |
Non-Patent Citations (1)
| Title |
|---|
| 吕少仿: "中国酒文化", 30 September 2015, 华中科技大学出版社, pages: 136 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CA3104839A1 (en) | 2020-01-02 |
| JP2021529731A (ja) | 2021-11-04 |
| ZA202007834B (en) | 2021-10-27 |
| AU2019293293A1 (en) | 2021-01-14 |
| EP3586837A1 (en) | 2020-01-01 |
| PL3586837T3 (pl) | 2021-09-13 |
| KR20210025611A (ko) | 2021-03-09 |
| DK3586837T3 (da) | 2021-03-01 |
| SG11202012297XA (en) | 2021-01-28 |
| PH12020552254A1 (en) | 2021-08-16 |
| CY1124030T1 (el) | 2022-05-27 |
| EA202092749A1 (ru) | 2021-06-23 |
| CL2020003209A1 (es) | 2021-06-04 |
| US20210260011A1 (en) | 2021-08-26 |
| JP7347744B2 (ja) | 2023-09-20 |
| EP3586837B1 (en) | 2020-12-23 |
| IT201800006725A1 (it) | 2019-12-27 |
| BR112020026431A2 (pt) | 2021-03-30 |
| MX2020013471A (es) | 2021-02-18 |
| RS61613B1 (sr) | 2021-04-29 |
| ES2858355T3 (es) | 2021-09-30 |
| LT3586837T (lt) | 2021-05-10 |
| WO2020003013A1 (en) | 2020-01-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7347744B2 (ja) | 肝疾患の予防および治療に使用されるアミノ酸を含む組成物 | |
| US11602511B2 (en) | Amino acid compositions and methods for the treatment of liver diseases | |
| Demiroren et al. | Protective effects of L-carnitine, N-acetylcysteine and genistein in an experimental model of liver fibrosis | |
| Faheem et al. | Hepatoprotective effect of cranberry nutraceutical extract in non-alcoholic fatty liver model in rats: Impact on insulin resistance and Nrf-2 expression | |
| Yang et al. | Study on urine metabolic profiling and pathogenesis of hyperlipidemia | |
| Suguro et al. | Combinational applicaton of silybin and tangeretin attenuates the progression of non-alcoholic steatohepatitis (NASH) in mice via modulating lipid metabolism | |
| JP5109134B2 (ja) | 病態モデル実験動物、病態モデル実験動物の作出方法及び病態モデル実験動物の利用方法。 | |
| US20210275479A1 (en) | Compositions and methods for the reduction or treatment of insulin resistance and metabolic conditions | |
| US10265298B2 (en) | Method of increasing the bioavailability of silybin | |
| WO2016203499A1 (en) | Synergistic beverage composition | |
| Lin et al. | Differential action of TGR5 agonists on GLP-2 secretion and promotion of intestinal adaptation in a piglet short bowel model | |
| Xu et al. | Milk‑derived hexapeptide PGPIPN prevents and attenuates acute alcoholic liver injury in mice by reducing endoplasmic reticulum stress | |
| Zhao et al. | Bicyclol alleviates signs of BDL-induced cholestasis by regulating bile acids and autophagy-mediated HMGB1/p62/nrf2 pathway | |
| Bian et al. | Celastrol confers ferroptosis resistance via AKT/GSK3β signaling in high-fat diet-induced cardiac injury | |
| AU2021276402A1 (en) | Use of terpenoids in the treatment or prevention of fibrotic diseases | |
| Liu et al. | Integration of pharmacodynamics and metabolomics reveals the therapeutic effects of 6-acetylacteoside on ovariectomy-induced osteoporosis mice | |
| Widayati et al. | The combination of high fat diet and monosodium glutamate altering adipogenesis, brain resistin and serum cortisol level in female rat | |
| Li et al. | Myricanol improves metabolic profiles in dexamethasone induced lipid and protein metabolism disorders in mice | |
| Shirako | Structure and biological activities of hydrophobic short chain pyroglutamyl peptides in fermented foods and food protein hydrolysates | |
| Men et al. | Metabolomics and targeted amino acid analysis reveal the liver protective effect of arginyl-fructosyl-glucose from red ginseng on acute liver injury in mice |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |