JP5109134B2 - 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。 - Google Patents
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。 Download PDFInfo
- Publication number
- JP5109134B2 JP5109134B2 JP2008528727A JP2008528727A JP5109134B2 JP 5109134 B2 JP5109134 B2 JP 5109134B2 JP 2008528727 A JP2008528727 A JP 2008528727A JP 2008528727 A JP2008528727 A JP 2008528727A JP 5109134 B2 JP5109134 B2 JP 5109134B2
- Authority
- JP
- Japan
- Prior art keywords
- experimental animal
- group
- model experimental
- liver
- disease state
- 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.)
- Active
Links
- 238000010171 animal model Methods 0.000 title claims description 116
- 230000001575 pathological effect Effects 0.000 title claims description 69
- 238000000034 method Methods 0.000 title claims description 44
- 238000004519 manufacturing process Methods 0.000 title claims description 19
- 206010021143 Hypoxia Diseases 0.000 claims description 94
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 78
- 208000004930 Fatty Liver Diseases 0.000 claims description 75
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 70
- 239000001301 oxygen Substances 0.000 claims description 69
- 229910052760 oxygen Inorganic materials 0.000 claims description 69
- 241001465754 Metazoa Species 0.000 claims description 65
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 61
- 208000010706 fatty liver disease Diseases 0.000 claims description 61
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 61
- 210000004369 blood Anatomy 0.000 claims description 57
- 239000008280 blood Substances 0.000 claims description 57
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 54
- 230000001146 hypoxic effect Effects 0.000 claims description 48
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 47
- 201000010099 disease Diseases 0.000 claims description 43
- 230000007954 hypoxia Effects 0.000 claims description 32
- 230000036961 partial effect Effects 0.000 claims description 27
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 22
- 108010054147 Hemoglobins Proteins 0.000 claims description 17
- 102000001554 Hemoglobins Human genes 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 238000001727 in vivo Methods 0.000 claims description 17
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 17
- 238000011161 development Methods 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 230000007246 mechanism Effects 0.000 claims description 15
- 208000018875 hypoxemia Diseases 0.000 claims description 11
- 238000011160 research Methods 0.000 claims description 9
- 238000004458 analytical method Methods 0.000 claims description 8
- 241000283984 Rodentia Species 0.000 claims description 6
- 238000012216 screening Methods 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 239000013543 active substance Substances 0.000 claims description 5
- 230000003449 preventive effect Effects 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- 230000037396 body weight Effects 0.000 claims description 3
- 230000000069 prophylactic effect Effects 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 60
- 210000004185 liver Anatomy 0.000 description 58
- 238000009395 breeding Methods 0.000 description 41
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 40
- 206010016654 Fibrosis Diseases 0.000 description 38
- 230000007882 cirrhosis Effects 0.000 description 37
- 230000001488 breeding effect Effects 0.000 description 36
- 239000002504 physiological saline solution Substances 0.000 description 36
- 238000011282 treatment Methods 0.000 description 24
- 235000005911 diet Nutrition 0.000 description 23
- 230000037213 diet Effects 0.000 description 23
- 235000010288 sodium nitrite Nutrition 0.000 description 20
- 208000006454 hepatitis Diseases 0.000 description 19
- 230000001965 increasing effect Effects 0.000 description 18
- 230000007170 pathology Effects 0.000 description 18
- 241000700159 Rattus Species 0.000 description 17
- 238000007912 intraperitoneal administration Methods 0.000 description 17
- 241000282414 Homo sapiens Species 0.000 description 16
- 150000003254 radicals Chemical class 0.000 description 16
- 230000000384 rearing effect Effects 0.000 description 16
- 108010061951 Methemoglobin Proteins 0.000 description 15
- 210000002966 serum Anatomy 0.000 description 15
- 210000003494 hepatocyte Anatomy 0.000 description 14
- 230000004761 fibrosis Effects 0.000 description 13
- 238000000804 electron spin resonance spectroscopy Methods 0.000 description 12
- 210000003470 mitochondria Anatomy 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 230000001939 inductive effect Effects 0.000 description 11
- 208000005135 methemoglobinemia Diseases 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- VCUVETGKTILCLC-UHFFFAOYSA-N 5,5-dimethyl-1-pyrroline N-oxide Chemical compound CC1(C)CCC=[N+]1[O-] VCUVETGKTILCLC-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- 206010008909 Chronic Hepatitis Diseases 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 230000007423 decrease Effects 0.000 description 9
- 230000003247 decreasing effect Effects 0.000 description 9
- 230000008021 deposition Effects 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 230000002440 hepatic effect Effects 0.000 description 9
- 231100000283 hepatitis Toxicity 0.000 description 9
- 235000009200 high fat diet Nutrition 0.000 description 9
- 239000000411 inducer Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 8
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- 230000007850 degeneration Effects 0.000 description 8
- 230000037149 energy metabolism Effects 0.000 description 8
- 230000008595 infiltration Effects 0.000 description 8
- 238000001764 infiltration Methods 0.000 description 8
- 210000004698 lymphocyte Anatomy 0.000 description 8
- 210000003240 portal vein Anatomy 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 206010061218 Inflammation Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 208000037821 progressive disease Diseases 0.000 description 7
- 230000000750 progressive effect Effects 0.000 description 7
- 230000035882 stress Effects 0.000 description 7
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 7
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 6
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 6
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 6
- 206010067125 Liver injury Diseases 0.000 description 6
- 230000002950 deficient Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 229920002674 hyaluronan Polymers 0.000 description 6
- 229960003160 hyaluronic acid Drugs 0.000 description 6
- 230000017074 necrotic cell death Effects 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 241000282412 Homo Species 0.000 description 5
- 238000013231 NASH rodent model Methods 0.000 description 5
- 230000017531 blood circulation Effects 0.000 description 5
- 239000001569 carbon dioxide Substances 0.000 description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 235000013376 functional food Nutrition 0.000 description 5
- 230000002427 irreversible effect Effects 0.000 description 5
- 230000003908 liver function Effects 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 230000036542 oxidative stress Effects 0.000 description 5
- 208000007232 portal hypertension Diseases 0.000 description 5
- 102000009027 Albumins Human genes 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 206010003445 Ascites Diseases 0.000 description 4
- 101000856500 Bacillus subtilis subsp. natto Glutathione hydrolase proenzyme Proteins 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241000700157 Rattus norvegicus Species 0.000 description 4
- 210000001715 carotid artery Anatomy 0.000 description 4
- 229960001231 choline Drugs 0.000 description 4
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 230000001086 cytosolic effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000003745 diagnosis Methods 0.000 description 4
- 231100000234 hepatic damage Toxicity 0.000 description 4
- 208000007386 hepatic encephalopathy Diseases 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 230000008818 liver damage Effects 0.000 description 4
- 208000019423 liver disease Diseases 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 3
- 108010082126 Alanine transaminase Proteins 0.000 description 3
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 3
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 3
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 3
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 3
- 102000003914 Cholinesterases Human genes 0.000 description 3
- 108090000322 Cholinesterases Proteins 0.000 description 3
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 3
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 3
- 238000001061 Dunnett's test Methods 0.000 description 3
- 208000000624 Esophageal and Gastric Varices Diseases 0.000 description 3
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 3
- 206010062713 Haemorrhagic diathesis Diseases 0.000 description 3
- 206010019668 Hepatic fibrosis Diseases 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 108010094028 Prothrombin Proteins 0.000 description 3
- 102100027378 Prothrombin Human genes 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 102000007562 Serum Albumin Human genes 0.000 description 3
- 108010071390 Serum Albumin Proteins 0.000 description 3
- 206010041660 Splenomegaly Diseases 0.000 description 3
- 206010056091 Varices oesophageal Diseases 0.000 description 3
- 238000000540 analysis of variance Methods 0.000 description 3
- 230000000975 bioactive effect Effects 0.000 description 3
- 239000003114 blood coagulation factor Substances 0.000 description 3
- 229940019700 blood coagulation factors Drugs 0.000 description 3
- 229940048961 cholinesterase Drugs 0.000 description 3
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 3
- 208000024170 esophageal varices Diseases 0.000 description 3
- 201000010120 esophageal varix Diseases 0.000 description 3
- 208000030304 gastrointestinal bleeding Diseases 0.000 description 3
- 208000031169 hemorrhagic disease Diseases 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 210000005228 liver tissue Anatomy 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 235000016709 nutrition Nutrition 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 230000008506 pathogenesis Effects 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 229940039716 prothrombin Drugs 0.000 description 3
- 201000002859 sleep apnea Diseases 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- 206010011703 Cyanosis Diseases 0.000 description 2
- 238000004435 EPR spectroscopy Methods 0.000 description 2
- 208000032274 Encephalopathy Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 101710107035 Gamma-glutamyltranspeptidase Proteins 0.000 description 2
- 101710173228 Glutathione hydrolase proenzyme Proteins 0.000 description 2
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-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
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000003975 animal breeding Methods 0.000 description 2
- 210000003445 biliary tract Anatomy 0.000 description 2
- 235000019577 caloric intake Nutrition 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- NLEBIOOXCVAHBD-QKMCSOCLSA-N dodecyl beta-D-maltoside Chemical compound O[C@@H]1[C@@H](O)[C@H](OCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 NLEBIOOXCVAHBD-QKMCSOCLSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 102000006640 gamma-Glutamyltransferase Human genes 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 150000003278 haem Chemical class 0.000 description 2
- 231100000753 hepatic injury Toxicity 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000002350 laparotomy Methods 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 210000002311 liver mitochondria Anatomy 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- UMFJAHHVKNCGLG-UHFFFAOYSA-N n-Nitrosodimethylamine Chemical compound CN(C)N=O UMFJAHHVKNCGLG-UHFFFAOYSA-N 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 2
- 150000002826 nitrites Chemical class 0.000 description 2
- 235000021062 nutrient metabolism Nutrition 0.000 description 2
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 230000003405 preventing effect Effects 0.000 description 2
- 238000001243 protein synthesis Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 208000007082 Alcoholic Fatty Liver Diseases 0.000 description 1
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 108010001202 Cytochrome P-450 CYP2E1 Proteins 0.000 description 1
- 102100024889 Cytochrome P450 2E1 Human genes 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- QQZWEECEMNQSTG-UHFFFAOYSA-N Ethyl nitrite Chemical compound CCON=O QQZWEECEMNQSTG-UHFFFAOYSA-N 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 239000004158 L-cystine Substances 0.000 description 1
- 235000019393 L-cystine Nutrition 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical group ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 201000002451 Overnutrition Diseases 0.000 description 1
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 description 1
- GVVWEQQBBATYME-UHFFFAOYSA-L [Na+].[Na+].[O-]N=O.[O-]N=O Chemical compound [Na+].[Na+].[O-]N=O.[O-]N=O GVVWEQQBBATYME-UHFFFAOYSA-L 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 208000026594 alcoholic fatty liver disease Diseases 0.000 description 1
- 208000010002 alcoholic liver cirrhosis Diseases 0.000 description 1
- CAMXVZOXBADHNJ-UHFFFAOYSA-N ammonium nitrite Chemical compound [NH4+].[O-]N=O CAMXVZOXBADHNJ-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- GJTDJAPHKDIQIQ-UHFFFAOYSA-L barium(2+);dinitrite Chemical compound [Ba+2].[O-]N=O.[O-]N=O GJTDJAPHKDIQIQ-UHFFFAOYSA-L 0.000 description 1
- 238000010876 biochemical test Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- AJAFRMGZWFDZAS-UHFFFAOYSA-M cesium;nitrite Chemical compound [Cs+].[O-]N=O AJAFRMGZWFDZAS-UHFFFAOYSA-M 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000002554 disease preventive effect Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- APNSGVMLAYLYCT-UHFFFAOYSA-N isobutyl nitrite Chemical compound CC(C)CON=O APNSGVMLAYLYCT-UHFFFAOYSA-N 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012317 liver biopsy Methods 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- BLLFVUPNHCTMSV-UHFFFAOYSA-N methyl nitrite Chemical compound CON=O BLLFVUPNHCTMSV-UHFFFAOYSA-N 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 244000309715 mini pig Species 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- CSDTZUBPSYWZDX-UHFFFAOYSA-N n-pentyl nitrite Chemical compound CCCCCON=O CSDTZUBPSYWZDX-UHFFFAOYSA-N 0.000 description 1
- 208000001797 obstructive sleep apnea Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000020823 overnutrition Nutrition 0.000 description 1
- 230000004783 oxidative metabolism Effects 0.000 description 1
- QVGXLLKOCUKJST-BJUDXGSMSA-N oxygen-15 atom Chemical compound [15O] QVGXLLKOCUKJST-BJUDXGSMSA-N 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000004304 potassium nitrite Substances 0.000 description 1
- 235000010289 potassium nitrite Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- KAOQVXHBVNKNHA-UHFFFAOYSA-N propyl nitrite Chemical compound CCCON=O KAOQVXHBVNKNHA-UHFFFAOYSA-N 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000005457 triglyceride group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5082—Supracellular entities, e.g. tissue, organisms
- G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Environmental Sciences (AREA)
- Cell Biology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biotechnology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Animal Behavior & Ethology (AREA)
- Zoology (AREA)
- Animal Husbandry (AREA)
- Biodiversity & Conservation Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
脂肪肝担持実験動物の調製は下記手順によって実施した。
1)実験動物
Wistar系ラット (清水実験動物)6週齢から実験飼育を開始した。12時間(7:00-19:00)の明暗、50〜60%湿度および23℃の環境下で自由摂餌・自由飲水の各条件により飼育した。
非アルコール性脂肪肝動物の作製:
飼料は通常のMF飼料(オリエンタル酵母)またはコリン欠乏高脂肪飼料(8.000% ビタミンフリーカゼイン, 37.950% ラード, 48.375% シュークロース, 4.000% ハーパーミネラル, 1.050% ビタミン混合, 0.625% L-シスチン w/w、 オリエンタル酵母、以下CDHF飼料と記載)を用い飼育した。
MF飼料またはCDHF飼料のいずれかの給餌により1ヶ月間飼育後、エーテル麻酔下に開腹し摘出した肝臓中Triglyceride含量(mg/g肝湿重量)は、MF飼育群で12.1±1.1、CDHF飼育群で45.0±5.0で、中性脂肪の肝臓への沈着が有意に(p<0.01)惹き起こされていることが判明した。
上述の給餌および処置後ラットから採取した肝臓について、ホルマリン固定肝組織のヘマトキシリン・エオジン染色組織の光学顕微鏡観察により、MF飼料給餌飼育によるラット肝臓では規則正しい肝細胞索列を有する正常肝組織が観察された。同期間のCDHF給餌による飼育ラットの肝臓の大部分の肝細胞に大滴性脂肪性変化が認められた。前項の中性脂肪沈着に関する検討と本項目の病理組織学的検討結果から非アルコール性脂肪肝動物の形成されることを確認した。
肝障害を反映する生化学的マーカー即ち肝実質細胞質内酵素(AST : Aspartate aminotransferase、ALT:Alanine aminotransferase)の血中への逸脱:前述の肝臓摘出前に門脈から採血した試料の血漿に関してAST(KU/mL)については、MF飼育群で53.2±6.2、CDHF飼料群で66.2±8.1で有意に(p<5%)上昇し、ALT(KU/mL)については、MF飼育群で13.9±1.6、CDHF飼料群で17.6±2.3で有意差は認められなかった。
前述の肝臓摘出前に門脈から採血した試料の血漿に関してヒアルロン酸濃度を測定し肝線維化を検討した。ヒアルロン酸濃度(ng/ml 血漿)は、MF飼料群で87.9±7.1、CDHF飼料群で89.9±9.9で有意差は認められなかった。
亜硝酸ナトリウム投与による血中メトヘモグロビン形成と血中酸素分圧低下:MF飼料またはCDHF飼料にて各群8匹を1ヶ月間飼育後予備飼育後、各々を等分2群に分け1群4匹の4群に分け予備飼育期間と同じ飼料による継続飼育を行うと共に、以降、亜硝酸液ナトリウム液投与により惹起させたメトヘモグロビン血症による低酸素ストレス負荷試験を開始した。即ち、MF飼料またはCDHF飼料給餌ラットへ50 mg/kg/日 亜硝酸液ナトリウムの生理的食塩液又は等容量の生理的食塩液の腹腔内投与を施した。
前述のMF飼料またはCDHF飼料にて各群4匹を1ヶ月間飼育後予備飼育後、予備飼育期間と同じ飼料による継続飼育を行うと共に、以降、ヒドロキシルアミン液投与により惹起させたメトヘモグロビン血症による低酸素ストレス負荷を開始した。即ち、MF飼料またはCDHF飼料給餌ラットへ50 mg/kg/日 ヒドロキシルアミンの生理的食塩液による溶解後pH7.4に調整液又は等容量の生理的食塩液の腹腔内投与を施した。
上述のMF飼料又はCDHF飼料にて飼育ラットへの50 mg/kg/日 ヒドロキシルアミン液の腹腔内投与処置による群表記は以降、対照+ヒドロキシルアミン群、NASH-ヒドロキシルアミン群の各々により示す。なお、正常対照群およびCDHF群は実施例1の該項に記した。
低酸素環境下飼育と血中酸素分圧低下:通常空気中ケージ内環境でMF飼料またはCDHF飼料にて各群8匹を1ヶ月間予備飼育後、各々を等分2群に分け1群4匹の4群に分け予備飼育期間と同じ飼料による継続飼育を行うと共に、以降、通常空気中での飼育あるいは飼育ケージに混合気体を送気し低酸素環境を形成して、低酸素状態に動物を暴露させて飼育した。即ち、MF飼料またはCDHF飼料給餌ラットを各二群に分け、MF飼料給餌群とCDHF飼料給餌群の各1群は通常空気中ケージで飼育を行った。また、別のMF飼料給餌群とCDHF飼料給餌群の各1群に窒素、酸素および二酸化炭素を送気するケージで飼育し、下記組成(窒素79.01%以上、酸素20.95%以下、二酸化炭素0.04%以上)下で飼育した。
実験動物や飼育方法などの条件は実施例3に準じ、脂肪肝担持実験動物の作製は高脂肪飼料(37.950% ラード, 48.375% シュークロース, 4.000% ハーパーミネラル, 1.050% ビタミン混合, 0.625% L-シスチン w/w、 オリエンタル酵母、以下高脂肪飼料と記載)を用い、シュークロース添加水を与えて飼育した。2ヵ月以上飼育することで行った。
高脂肪飼料給餌により3ヶ月間飼育後、エーテル麻酔下に開腹し摘出した肝臓中Triglyceride含量(mg/g肝湿重量)は、MF飼育群で12.1±1.1、CDHF飼育群で26.0±5.2で、中性脂肪の肝臓への沈着が有意に(p<0.05)惹き起こされていることが判明した。
Claims (12)
- 脂肪肝担持実験動物に対し、亜硝酸塩および/又はヒドロキシルアミンを、投与量として1日当たり30〜70mg/kg体重、投与期間として3〜16週間、より好ましくは4〜12週間投与することで、メトヘモグロビンを形成させ血中酸素分圧を108ヘクトパスカル未満に低下させた生体内低酸素状態を与えることにより作出される非アルコール性脂肪性肝炎の生化学的特徴及び/又は病理組織学的特徴を維持した病態モデル実験動物(ヒトを除く)。
- 上記病態モデル実験動物は、医学研究用実験動物であることを特徴とする請求項1に記載の病態モデル実験動物。
- 上記医学研究用動物がげっ歯類であることを特徴とする請求項2に記載の病態モデル実験動物。
- 上記げっ歯類がマウス又はラットであることを特徴とする請求項3に記載の病態モデル実験動物。
- 脂肪肝担持実験動物に対し、亜硝酸塩および/又はヒドロキシルアミンを、投与量として1日当たり30〜70mg/kg体重、投与期間として3〜16週間、より好ましくは4〜12週間投与することで、メトヘモグロビンを形成させ血中酸素分圧を108ヘクトパスカル未満に低下させた生体内低酸素状態を与えることにより非アルコール性脂肪性肝炎の生化学的特徴及び/又は病理組織学的特徴を維持した病態モデル実験動物(ヒトを除く)を作出する病態モデル実験動物の作出方法。
- 上記病態モデル実験動物は、医学研究用実験動物であることを特徴とする請求項5に記載の病態モデル実験動物の作出方法。
- 上記医学研究用動物がげっ歯類であることを特徴とする請求項6に記載の病態モデル実験動物の作出方法。
- 上記げっ歯類がマウス又はラットであることを特徴とする請求項7に記載の病態モデル実験動物の作出方法。
- 請求項1乃至4のいずれか1項に記載の病態モデル実験動物を非アルコール性脂肪性肝炎の重症化予防剤開発に供することを特徴とする病態モデル実験動物の利用方法。
- 請求項1乃至4のいずれか1項に記載の病態モデル実験動物を非アルコール性脂肪性肝炎の治療剤開発に供することを特徴とする病態モデル実験動物の利用方法。
- 請求項1乃至4のいずれか1項に記載の病態モデル実験動物を非アルコール性脂肪性肝炎を指標とした生理活性物質のスクリーニングに供することを特徴とする病態モデル実験動物の利用方法。
- 請求項1乃至4のいずれか1項に記載の病態モデル実験動物を低酸素血症に伴う生活習慣病の発症機構の解析及び重症化予防剤開発並びに治療剤開発及び治療法の開発に用いることを特徴とする病態モデル実験動物の利用方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008528727A JP5109134B2 (ja) | 2006-08-10 | 2007-02-13 | 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。 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006218825 | 2006-08-10 | ||
JP2006218825 | 2006-08-10 | ||
JP2008528727A JP5109134B2 (ja) | 2006-08-10 | 2007-02-13 | 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。 |
PCT/JP2007/052477 WO2008018191A1 (fr) | 2006-08-10 | 2007-02-13 | Animal expérimental en tant que modèle pathologique, procédé de production de l'animal expérimental, et procédé d'utilisation dudit animal expérimental |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2008018191A1 JPWO2008018191A1 (ja) | 2009-12-24 |
JP5109134B2 true JP5109134B2 (ja) | 2012-12-26 |
Family
ID=39032731
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008528727A Active JP5109134B2 (ja) | 2006-08-10 | 2007-02-13 | 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。 |
Country Status (3)
Country | Link |
---|---|
US (1) | US20100189647A1 (ja) |
JP (1) | JP5109134B2 (ja) |
WO (1) | WO2008018191A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107197823A (zh) * | 2017-06-20 | 2017-09-26 | 遵义医学院 | 一种非酒精性脂肪肝的大鼠模型建立方法 |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010048710A1 (en) * | 2008-10-31 | 2010-05-06 | Neurodyn, Inc. | Neurotoxic sterol glycosides |
JP2014209849A (ja) * | 2011-07-25 | 2014-11-13 | 株式会社ヤクルト本社 | Nashモデル動物 |
JP2017221121A (ja) * | 2016-06-13 | 2017-12-21 | 学校法人 日本歯科大学 | 非アルコール性脂肪性肝疾患の非ヒトモデル動物 |
US20200115682A1 (en) * | 2017-04-03 | 2020-04-16 | Deborah Lynn GREENE NGUYEN | Use of Engineered Liver Tissue Constructs for Modeling Liver Disorders |
JP7316765B2 (ja) * | 2018-05-23 | 2023-07-28 | オリエンタル酵母工業株式会社 | 薬剤を投与することなく、非アルコール性脂肪肝炎モデル動物を作出するための飼料および非アルコール性脂肪肝炎モデル動物の作出方法 |
JP2020072658A (ja) * | 2019-09-30 | 2020-05-14 | 学校法人 日本歯科大学 | 非アルコール性脂肪性肝疾患の非ヒトモデル動物 |
US20230097470A1 (en) | 2021-08-23 | 2023-03-30 | Chirogate International Inc. | Processes and intermediates for the preparations of carboprost and carboprost tromethamine, and carboprost tromethamine prepared therefrom |
CN114258991A (zh) * | 2021-12-30 | 2022-04-01 | 广西师范大学 | 一种高效构建小鼠肥胖模型的高脂饲料及造模方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2580669A1 (en) * | 2004-09-17 | 2006-03-23 | Banyu Pharmaceutical Co., Ltd. | Pathologic model animal for nonalcoholic steatohepatitis |
-
2007
- 2007-02-13 US US12/377,045 patent/US20100189647A1/en not_active Abandoned
- 2007-02-13 JP JP2008528727A patent/JP5109134B2/ja active Active
- 2007-02-13 WO PCT/JP2007/052477 patent/WO2008018191A1/ja active Application Filing
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107197823A (zh) * | 2017-06-20 | 2017-09-26 | 遵义医学院 | 一种非酒精性脂肪肝的大鼠模型建立方法 |
Also Published As
Publication number | Publication date |
---|---|
WO2008018191A1 (fr) | 2008-02-14 |
JPWO2008018191A1 (ja) | 2009-12-24 |
US20100189647A1 (en) | 2010-07-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
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。 | |
Freemerman et al. | Myeloid Slc2a1-deficient murine model revealed macrophage activation and metabolic phenotype are fueled by GLUT1 | |
Miethke et al. | Pharmacological inhibition of apical sodium‐dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice | |
Hammoutene et al. | A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis | |
Nehra et al. | Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis | |
Dubuquoy et al. | Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis | |
Sahai et al. | Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin | |
Vinciguerra et al. | PTEN down-regulation by unsaturated fatty acids triggers hepatic steatosis via an NF-κBp65/mTOR-dependent mechanism | |
Denk et al. | Animal models of NAFLD from the pathologist's point of view | |
Klöting et al. | Insulin-sensitive obesity | |
Hansotia et al. | Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure | |
Huang et al. | Adipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling | |
Valerio et al. | TNF-α downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents | |
Wooton-Kee et al. | Elevated copper impairs hepatic nuclear receptor function in Wilson’s disease | |
Wu et al. | The role of hepassocin in the development of non-alcoholic fatty liver disease | |
Zadjali et al. | SOCS2 deletion protects against hepatic steatosis but worsens insulin resistance in high‐fat‐diet‐fed mice | |
Kucukoglu et al. | High‐fat diet triggers Mallory‐Denk body formation through misfolding and crosslinking of excess keratin 8 | |
Patankar et al. | Genetic ablation of Cyp8b1 preserves host metabolic function by repressing steatohepatitis and altering gut microbiota composition | |
EP3586837B1 (en) | Compositions comprising amino acids for use in the prevention and treatment of liver diseases | |
Pichon et al. | Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations | |
Altınova et al. | Reduced serum acylated ghrelin levels in patients with hyperthyroidism | |
Andren-Sandberg et al. | Second Giessen International Workshop on Interactions of Exocrine and Endocrine Pancreatic Diseases | |
Miethke et al. | Pharmacological inhibition of ASBT changes bile composition and blocks progression of sclerosing cholangitis in mdr2 knockout mice | |
Bianchi et al. | Impaired insulin-mediated amino acid plasma disappearance in non-alcoholic fatty liver disease: a feature of insulin resistance | |
AU2019240210B2 (en) | Liver protectant compositions and therapeutic applications |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A529 | Written submission of copy of amendment under section 34 (pct) |
Free format text: JAPANESE INTERMEDIATE CODE: A5211 Effective date: 20081212 |
|
A80 | Written request to apply exceptions to lack of novelty of invention |
Free format text: JAPANESE INTERMEDIATE CODE: A80 Effective date: 20081204 |
|
AA64 | Notification of invalidation of claim of internal priority (with term) |
Free format text: JAPANESE INTERMEDIATE CODE: A241764 Effective date: 20090417 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090511 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20100115 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20100115 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120618 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120809 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20120906 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |