CN110433280A - 植物血凝素在制备预防或治疗肥胖药物中的应用 - Google Patents
植物血凝素在制备预防或治疗肥胖药物中的应用 Download PDFInfo
- Publication number
- CN110433280A CN110433280A CN201910859688.1A CN201910859688A CN110433280A CN 110433280 A CN110433280 A CN 110433280A CN 201910859688 A CN201910859688 A CN 201910859688A CN 110433280 A CN110433280 A CN 110433280A
- Authority
- CN
- China
- Prior art keywords
- mouse
- pha
- fat
- treatment
- drug
- 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
- 239000003726 plant lectin Substances 0.000 title claims abstract description 19
- 230000002265 prevention Effects 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000000883 anti-obesity agent Substances 0.000 title abstract description 6
- 229940125710 antiobesity agent Drugs 0.000 title abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 21
- 229940079593 drug Drugs 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 230000004060 metabolic process Effects 0.000 claims abstract description 6
- 239000007924 injection Substances 0.000 claims description 15
- 238000002347 injection Methods 0.000 claims description 15
- 238000010253 intravenous injection Methods 0.000 claims description 2
- 238000010254 subcutaneous injection Methods 0.000 claims description 2
- 239000007929 subcutaneous injection Substances 0.000 claims description 2
- 210000003486 adipose tissue brown Anatomy 0.000 abstract description 24
- 230000004913 activation Effects 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 5
- 230000023852 carbohydrate metabolic process Effects 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- 230000033228 biological regulation Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 56
- 210000004027 cell Anatomy 0.000 description 17
- 230000014509 gene expression Effects 0.000 description 14
- 238000012545 processing Methods 0.000 description 14
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 12
- 229960001031 glucose Drugs 0.000 description 12
- 239000008103 glucose Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 10
- 102000015494 Mitochondrial Uncoupling Proteins Human genes 0.000 description 9
- 108010050258 Mitochondrial Uncoupling Proteins Proteins 0.000 description 9
- 230000000638 stimulation Effects 0.000 description 9
- 239000003651 drinking water Substances 0.000 description 8
- 235000020188 drinking water Nutrition 0.000 description 8
- 210000001789 adipocyte Anatomy 0.000 description 7
- 208000008589 Obesity Diseases 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 235000013305 food Nutrition 0.000 description 6
- 230000006698 induction Effects 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 210000003470 mitochondria Anatomy 0.000 description 6
- 210000000636 white adipocyte Anatomy 0.000 description 6
- 210000000436 anus Anatomy 0.000 description 5
- 210000001593 brown adipocyte Anatomy 0.000 description 5
- 238000007446 glucose tolerance test Methods 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 235000020824 obesity Nutrition 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 210000000577 adipose tissue Anatomy 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000004069 differentiation Effects 0.000 description 4
- 201000007116 gestational trophoblastic neoplasm Diseases 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- 239000012894 fetal calf serum Substances 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- 101710186708 Agglutinin Proteins 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 101710154606 Hemagglutinin Proteins 0.000 description 2
- 102100024594 Histone-lysine N-methyltransferase PRDM16 Human genes 0.000 description 2
- 101000686942 Homo sapiens Histone-lysine N-methyltransferase PRDM16 Proteins 0.000 description 2
- 101001123331 Homo sapiens Peroxisome proliferator-activated receptor gamma coactivator 1-alpha Proteins 0.000 description 2
- 101710146024 Horcolin Proteins 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 101710189395 Lectin Proteins 0.000 description 2
- 108090001090 Lectins Proteins 0.000 description 2
- 102000004856 Lectins Human genes 0.000 description 2
- 101710179758 Mannose-specific lectin Proteins 0.000 description 2
- 101710150763 Mannose-specific lectin 1 Proteins 0.000 description 2
- 101710150745 Mannose-specific lectin 2 Proteins 0.000 description 2
- 101100154912 Mus musculus Tyrp1 gene Proteins 0.000 description 2
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 2
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 2
- 101710176177 Protein A56 Proteins 0.000 description 2
- 101100403108 Schizosaccharomyces pombe (strain 972 / ATCC 24843) mud1 gene Proteins 0.000 description 2
- 239000000910 agglutinin Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000037149 energy metabolism Effects 0.000 description 2
- 201000010063 epididymitis Diseases 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 239000000185 hemagglutinin Substances 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 239000002523 lectin Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 210000004003 subcutaneous fat Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SPFMQWBKVUQXJV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;hydrate Chemical compound O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O SPFMQWBKVUQXJV-BTVCFUMJSA-N 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 101000588298 Homo sapiens Endoplasmic reticulum membrane sensor NFE2L1 Proteins 0.000 description 1
- 101000577547 Homo sapiens Nuclear respiratory factor 1 Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 208000005125 Invasive Hydatidiform Mole Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 102100028744 Nuclear respiratory factor 1 Human genes 0.000 description 1
- 102000023984 PPAR alpha Human genes 0.000 description 1
- 108010028924 PPAR alpha Proteins 0.000 description 1
- 102100028960 Peroxisome proliferator-activated receptor gamma coactivator 1-alpha Human genes 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 108010047620 Phytohemagglutinins Proteins 0.000 description 1
- 108010089814 Plant Lectins Proteins 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000027734 detection of oxygen Effects 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 229960000673 dextrose monohydrate Drugs 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 210000001339 epidermal cell Anatomy 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000010794 food waste Substances 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000010627 oxidative phosphorylation Effects 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000001885 phytohemagglutinin Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 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 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000002918 waste heat Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
Abstract
本发明涉及一种植物血凝素新的药物用途,具体涉及植物血凝素在制备预防或治疗代谢相关疾病药物中的应用,更具体涉及植物血凝素在制备预防或治疗肥胖药物中的应用。本发明充分说明PHA可通过激活棕色脂肪组织活性调控能量代谢从而减少体重的增加,能促进糖代谢,降低脂肪存储,达到防控和/或治疗肥胖的目的,而且与抑制脂肪在肠道内吸收和抑制食欲的药物相比,天然化合物PHA作为减肥药物更容易被肥胖患者接受。本发明为制备预防与治疗和代谢相关疾病药物提供新的方法,应用前景较好。
Description
技术领域
本发明属于医药药物用途技术领域,涉及植物血凝素新的药物用途,具体涉及植物血凝素在制备预防或治疗肥胖药物中的应用。
背景技术
肥胖已逐渐成为全球成年人以及儿童和青少年的一个主要问题,严重威胁身体健康和降低生活质量(NgM.2014)。肥胖与胰岛素抵抗有关,会增加高血压、心血管疾病、2型糖尿病和癌症的风险(Gallagher EJ.2015;Lovren F.2015;Deng T.2016)。肥胖为脂肪组织中脂肪的过度积累,通过脂肪细胞的数量增加和脂肪细胞的大小增加以及脂肪组织功能障碍而发生。研究表明,小型哺乳动物和人类的脂肪细胞主要分为三种类型:WAT(白色脂肪)的白色脂肪细胞中含有单个大的脂滴和少量线粒体,以甘油三酯的形式储存多余热量,BAT(棕色脂肪)的棕色细胞中含有大量线粒体,线粒体内膜中存在ucp1,ucp1可将ATP再生过程中的氧化磷酸化解耦,将以甘油三酯形式存在的能量转化为热能,米色脂肪细胞基础状态下UCP1表达量较低,在寒冷刺激下UCP1水平显著提高,与BAT中的水平相当(CannonB.2004;Wu.2012;JingxinLiu.2018)。棕色和米色脂肪细胞的产热是消耗能量的一种方式,所以可利用棕色脂肪数量的增加及产热增加的方式用于制备预防和治疗肥胖和相关代谢疾病产品。
植物血凝素(phytohemagglutinin,PHA)是一类广泛存在于植物中的豆类凝集素主要存在于子叶中,可使红细胞发生凝集。对原来从植物中发现的,具有凝集红血球作用的物质,而命名的,后来发现了很多具有同样作用的物质,扩大其含义为细胞凝集素中植物来源的总称——植物凝集素(phytoagglutinin,plant agglutinin)或凝集素(lectin)的同义词涵义模糊。PHA是可特异性结合碳水化合物的蛋白质(Irlanda Lagarda-Diaz.2017),具有一个或多个可以与单糖或寡糖特异可逆结合的非催化结构域。植物血凝素最大的特点在于它们能识别糖蛋白和糖脂,特别是细胞膜中复杂结构的糖链,即细胞膜表面决定簇。PHA能促使淋巴细胞转化为淋巴母细胞,继而分裂增殖,释放淋巴因子,并能提高巨噬细胞的吞噬作用。尚能促进骨髓造血功能,提升白细胞;对病毒侵袭的细胞有杀伤作用,并能诱生干扰素。在体外能抑制人体食管癌及肝癌细胞株,对艾氏腹水癌亦有抑制作用,可延长带瘤小鼠的生存期。目前临床用于免疫功能受损引起的疾病,如急性白血病(急淋、急粒)、晚期绒癌及恶性葡萄胎、乳腺癌、肠癌、鼻咽癌、再生障碍性贫血、迁延性肝炎等。
发明内容
有鉴于此,本发明的目的在于提供一种植物血凝素在制备预防或治疗肥胖药物中的应用,本发明阐明了PHA调控棕色脂肪激活及能量代谢的功能,为制备预防与治疗肥胖和代谢相关疾病的药物提供新策略。
为达到上述目的,本发明提供如下技术方案:
1.植物血凝素在制备预防和/或治疗代谢相关疾病的药物中的应用。
进一步,植物血凝素在制备预防和/或治疗肥胖药物中的应用。
进一步,所述药物以植物血凝素12.5-40mg/天剂量范围给予的形式存在。
进一步,所述药物以植物血凝素0.5mg/kg/天剂量范围给予的形式存在。
进一步,所述药物给予的形式为皮下注射或静脉注射。
也可以参照胰岛素泵的形式给予持续的皮下PHA皮下输注,或者采用喷射注射,所述喷射注射是一种无注射针而能使病人接受皮下注射蛋白药物的系统,利用高压使药物液体以喷射出的水柱---“液体针”的形式瞬间穿过表皮细胞,精确无误地渗透入皮下组织,完成注射。
进一步,所述药物的形式为注射剂或注射用无菌粉末。
本发明的有益效果在于:本发明经发明人研究表明在细胞水平,PHA抑制C3H10T1/2细胞WAT分化并诱导白色脂肪细胞棕色化,激活棕色脂肪细胞。动物模型中与对照组相比,经PHA处理的HFD小鼠体温升高,体重增加较少。发明人还发现,与对照组相比,经PHA腹腔注射的HFD小鼠体重、葡萄糖糖耐量、胰岛素敏感性及能量消耗有显著改善。进一步研究发现PHA通过激活棕色脂肪(BAT)功能调控小鼠全身能量代谢,BAT和白色脂肪(WAT)中UCP1及线粒体合成相关基因表达显著增加。所以本发明充分说明PHA可通过激活棕色脂肪组织活性调控能量代谢从而减少体重的增加,能促进糖代谢,降低脂肪存储,达到防控和/或治疗肥胖的目的,而且与抑制脂肪在肠道内吸收和抑制食欲的药物相比,PHA是天然化合物,低剂量无毒副作用能够通过激活棕色脂肪增加能量消耗,最终抑制体重增加,本发明为制备预防与治疗和代谢相关疾病药物提供新的方法,应用前景较好。
附图说明
为了使本发明的目的、技术方案和有益效果更加清楚,本发明提供如下附图进行说明:
图1显示C3H10T1/2细胞(前脂肪细胞)分化模型的建立以及PHA 10(μm)处理C3H10T1/2细胞和未加植物血凝素处理两组细胞分化结果。
图2显示PHA(10μm)处理C3H10T1/2细胞诱导分化棕色脂肪细胞后棕色脂肪细胞标志基因及线粒体生成和功能相关基因mRNA的表达量。
图3显示PHA处理C3H10T1/2细胞UCP1的蛋白表达。
图4显示不同剂量PHA对小鼠体温的影响
图5显示对照组和实验组两组的小鼠在处理时间内的体重变化。
图6显示对照组和实验组两组的小鼠的各器官重量差异。
图7显示对照组和实验组两组的小鼠的白色脂肪对照图。
图8显示对照组和实验组两组小鼠的葡萄糖糖耐受试验的检测结果。
图9显示对照组和实验组两组小鼠的小鼠24h能量代谢结果。
图10显示对照组和实验组两组小鼠的24h饮水量的检测结果。
图11显示对照组和实验组两组小鼠的24h摄食量的检测结果。
图12显示对照组和实验组两组小鼠的4℃寒冷刺激下小鼠的肛门体温变化结果。
图13显示对照组和实验组两组小鼠的棕色脂肪组织中UCP1及线粒体生成和功能相关基因mRNA的表达结果。
图14显示对照组和实验组两组小鼠的棕色脂肪组织免疫组化结果。
具体实施方式
下面将结合附图,对本发明的优选实施例进行详细的描述。实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。
实施例1
小鼠胚胎成纤维细胞C3H10T1/2的培养与诱导分化
C3H10T1/2购买于上海生科院细胞库,将C3H10T1/2细胞接种于含10%FBS胎牛血清的MEM培养基中培养。培养至细胞密度达到80%以上时,胰蛋白酶消化,接种于12孔板,实验组和对照组各6孔重复,以含10%FBS胎牛血清的MEM培养基培养。在细胞生长至完全铺满培养板孔底时更换培养基为含吲哚美辛100μM、胰岛素5μg/mL、地塞米松1μM、IBMX0.5mM以及10%FBS胎牛血清的MEM培养基,培养48h(即诱导分化两天)。接着以胰岛素10μg/mL+10%FBS胎牛血清的MEM培养基培养96h。诱导和分化阶段同时加入10μmPHA处理细胞,对照组是同体积的DMSO。分化6天后将细胞进行油红染色,染色结果如图1所示,PHA能够诱导棕色脂肪细胞形成,而抑制白色脂肪细胞分化。qPCR检测其相关基因表达量,结果表明与对照相比较,PHA能够促进UCP1、PRDM16及线粒体相关基因PGC1α和PPARαmRNA表达(见图2),表达量数据如表1所示。Western blot实验结果显示,PHA处理组细胞在棕色脂肪和白色脂肪细胞分化过程中UCP1蛋白表达量上调(见图3)。这充分说明PHA能够激活BAT并抑制前脂肪细胞(C3H10T1/2)分化成白色脂肪细胞同时诱导其向棕色脂肪细胞转化,激活棕色脂肪。
表1对照组和PHA组各mRNA表达量
实施例2.PHA改善HFD小鼠的肥胖、促进糖代谢
C57BL6小鼠4周大,连续腹腔注射PHA,给药剂量分别为0.1,0.2,0.25,0.5,1mg/kg/day,给药一周后寒冷刺激后测量小鼠肛温(℃),测量数据如表2所示。结果显示,在寒冷刺激后0.1,0.2,0.25mg/kg给药剂量与对照组血凝素处理组相比无显著性差异,0.5mg/kg/day和1mg/kg/day给药剂量在寒冷刺激后与对照组相比小鼠体温升高,结果表明0.5mg/kg可能是激活棕色脂肪产热的最低工作浓度(见图4),后续实验以0.5mg/kg/day进行研究。
表2小鼠肛温
对照组 | PHA | |
1mg/kg | 33.983 | 34.950 |
0.5mg/kg | 34.070 | 34.970 |
0.25mg/kg | 34.229 | 34.433 |
0.2mg/kg | 34.317 | 34.367 |
0.1mg/kg | 34.733 | 34.933 |
购买4周大的C57BL6小鼠,随机分为对照组(10只)和实验组(10只),以高脂(HFD)喂养。每日腹腔注射处理上述两组小鼠。实验组腹腔注射0.05μg/μl PHA,剂量为0.5mg/kg/天,对照组腹腔注射生理盐水,八周后取材。在此期间,每周称重,在给药第四周开始,PHA处理组小鼠体重增加显著低于对照组(见图5和表3)。结果显示PHA处理组小鼠各组织与对照组小鼠相比重量减少。实验结束后取小鼠肝、皮下脂肪、附睾脂肪并称重,各组织数据见表4。实验数据显示,PHA处理组小鼠肝脏及皮下脂肪重量显著低于对照组,附睾脂肪有降低趋势,但无显著性差异(见图6)。图7为两组小鼠白色脂肪(iWAT)拍照结果,显示PHA处理组白色脂肪比对照组白色脂肪小(称重数据见图6和表4)。在给药第7.5周进行葡萄糖耐量实验测试(Glucose tolerance testing,GTT)实验进行。小鼠GTT实验的葡萄糖使用量一般为1.5或者2g/kg,本发明葡萄糖使用量是2g/kg,用生理盐水配置20%的葡萄糖溶液。实验前一天下午5点将小鼠换入干净的笼子禁食,禁食16小时,小鼠保持正常的饮水,至次日上午9点,称取每只小鼠的体重,用血糖仪测定空腹基础血糖,测定值认定为0min的血糖值(操作尽量轻柔,使小鼠不至于过度惊吓);小鼠适应30min之后,将小鼠轻轻抓起,按照标准的腹腔注射操作用1ml注射器给小鼠注射葡萄糖溶液(注射的体积根据小鼠的体重决定,每g体重注射0.01ml。)从注射完毕开始计时,在15min,30min,60min,90min,120min测定每只小鼠各个时间点的血糖值;图8和表5显示对照组和实验组两组小鼠的葡萄糖糖耐受试验的检测结果,GTT结果表明,高脂诱导的小鼠表现出葡萄糖耐受受损,但在PHA处理后糖耐受性显著提高。
表3各组小鼠体重对比
表4各组小鼠组织重量对比
表5各组小鼠GTT测试结果
实施例3.PHA增加能量消耗
耗氧量的检测,小鼠放入代谢笼内,正常给予食物和水,24h后拿出小鼠;摄食量及饮水量的测量,先称量出初始高脂饲料质量及量出饮用水体积,24h后称量出高脂饲料剩余量及量出饮用水剩余量。计算摄食量和饮水量。图9为对照组和实验组两组小鼠的小鼠24h能量代谢结果。耗氧量检测结果表明,在夜晚PHA处理组小鼠与对照组小鼠相比较耗氧量增加。而两组小鼠的摄食量及饮水量并无显著性差异(见图10和图11)。结合实施例1、2的结果表明PHA通过激活棕色脂肪活性增加能量代谢,减少高脂诱导的体重增加,同时维持葡萄糖稳态。本发明在PHA处理第7周4℃寒冷刺激后检测小鼠肛温,寒冷刺激期间小鼠正常摄食和饮水。小鼠肛温结果显示,在寒冷刺激1h对照组和PHA处理组体温无显著性差异(见图12);在寒冷刺激2h和3h后,PHA处理组小鼠体温显著高于对照组(见图12)。
实施例4.PHA激活棕色脂肪活性
实验结束后,取小鼠棕色脂肪组织,采用Trizol法提取棕色脂肪总RNA,qPCR检测棕色脂肪组织内产热相关基因的表达量,各组表达量如表6所示。实验结果显示,PHA处理组小鼠棕色脂肪组织的UCP1、PRDM16、PGC1α、NRF1和Tfarm基因的mRNA表达量显著增加(见图13)。小免疫组化检测结果显示,PHA促进UCP1蛋白表达,如图14所示,图上标尺为50μm。
表6各组小鼠相关基因的表达量
综上所述,图1-14表明了PHA能抑制C3H10T1/2细胞向白色脂肪细胞分化并诱导白色脂肪细胞棕色化激活棕色脂肪细胞。小鼠实验结果表明,PHA通过激活棕色脂肪组织活性和上调线粒体相关基因表达调控能量代谢从而减少体重的增加;PHA维持葡萄糖稳态,降低脂肪存储,达到防控和/或治疗肥胖的目的。本发明为制备预防和/或治疗肥胖等相关代谢疾病药物提供新的方法,有较好的应用前景。
最后说明的是,以上优选实施例仅用以说明本发明的技术方案而非限制,尽管通过上述优选实施例已经对本发明进行了详细的描述,但本领域技术人员应当理解,可以在形式上和细节上对其作出各种各样的改变,而不偏离本发明权利要求书所限定的范围。
Claims (6)
1.植物血凝素在制备预防和/或治疗代谢相关疾病的药物中的应用。
2.根据权利要求1所述的应用,其特征在于,植物血凝素在制备预防和/或治疗肥胖药物中的应用。
3.根据权利要求2所述的应用,其特征在于,所述药物以植物血凝素12.5-40mg/天剂量范围给予的形式存在。
4.根据权利要求3所述的应用,其特征在于,所述药物以植物血凝素0.5mg/kg/天剂量范围给予的形式存在。
5.根据权利要求1-4任一项所述的应用,其特征在于,所述药物给予的形式为皮下注射或静脉注射。
6.根据权利要求1-4任一项所述的应用,其特征在于,所述药物的形式为注射剂或注射用无菌粉末。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910859688.1A CN110433280A (zh) | 2019-09-11 | 2019-09-11 | 植物血凝素在制备预防或治疗肥胖药物中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910859688.1A CN110433280A (zh) | 2019-09-11 | 2019-09-11 | 植物血凝素在制备预防或治疗肥胖药物中的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110433280A true CN110433280A (zh) | 2019-11-12 |
Family
ID=68439918
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910859688.1A Pending CN110433280A (zh) | 2019-09-11 | 2019-09-11 | 植物血凝素在制备预防或治疗肥胖药物中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110433280A (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997049420A1 (en) * | 1996-06-21 | 1997-12-31 | Alizyme Therapeutics Limited | Lectin compositions and uses thereof |
CN101641111A (zh) * | 2007-03-07 | 2010-02-03 | 因德纳有限公司 | 包含用于治疗肥胖症的菜蓟与菜豆提取物的制剂 |
CN104703616A (zh) * | 2012-10-12 | 2015-06-10 | 因德纳有限公司 | 治疗和预防肥胖的制剂 |
-
2019
- 2019-09-11 CN CN201910859688.1A patent/CN110433280A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997049420A1 (en) * | 1996-06-21 | 1997-12-31 | Alizyme Therapeutics Limited | Lectin compositions and uses thereof |
CN1230891A (zh) * | 1996-06-21 | 1999-10-06 | 阿利茨默治疗学有限公司 | 凝集素组合物及其用途 |
CN101641111A (zh) * | 2007-03-07 | 2010-02-03 | 因德纳有限公司 | 包含用于治疗肥胖症的菜蓟与菜豆提取物的制剂 |
CN104703616A (zh) * | 2012-10-12 | 2015-06-10 | 因德纳有限公司 | 治疗和预防肥胖的制剂 |
Non-Patent Citations (1)
Title |
---|
YUNXIA ZHANG ET AL.: ""Phytohemagglutinin ameliorates HFD-induced obesity by increasing energy expenditure"", 《JOURNAL OF MOLECULAR ENDOCRINOLOGY》 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108420854A (zh) | 提高耐力表现的抗疲劳组合物 | |
EP3023104B1 (en) | Recombinant ganoderma lucidum immunomodulatory protein (rlz-8) for use in treating melanoma | |
CN106212858A (zh) | 一种高脂饲料及ⅱ型糖尿病动物模型 | |
CN109568299A (zh) | 氨溴索在制备肿瘤化疗药物增效制剂中用途 | |
CN104352521B (zh) | 制备小牛脾提取物的方法及在抗肿瘤和免疫调节中的应用 | |
CN102106864B (zh) | 淫羊藿苷在制备拮抗髓系衍生抑制性细胞药物中的应用 | |
CN110433280A (zh) | 植物血凝素在制备预防或治疗肥胖药物中的应用 | |
CN113244219A (zh) | 土木香内酯在制备治疗肿瘤恶病质疾病的药物中的应用 | |
CN103977014B (zh) | 一种应用于治疗代谢综合征的药物 | |
CN106820133A (zh) | 一种植物乳杆菌发酵大麦提取物片剂及其制备方法 | |
CN104490942B (zh) | 桑黄作为治疗肿瘤药物的应用 | |
CN110090209A (zh) | 刺芒柄花素在治疗非酒精性脂肪肝中的应用 | |
CN105267191A (zh) | 丙酰胺类化合物的应用 | |
WO2022077276A1 (zh) | 烟酰胺单核苷酸与发酵乳杆菌联合在制备缓解皮肤光老化制剂中的应用 | |
CN104910122B (zh) | 一种芒柄花素衍生物、制备方法及其用途 | |
CN109908167B (zh) | 蒙花苷在制备通过保护肾小管上皮细胞治疗肾脏缺血再灌注损伤药物中的应用 | |
CN106955292A (zh) | 一种治疗食管癌的药物组合物及用途 | |
CN111773324A (zh) | 鲜石斛水提物在制备治疗代谢性疾病药物中的应用 | |
CN101333515A (zh) | 用dcik细胞培养的上清液及其应用 | |
CN105136781A (zh) | 脂肪因子grem2在制备肥胖症治疗药物中的应用 | |
CN111544440A (zh) | 地奥司明及组合物在制备抗肥胖的产品方面中的应用 | |
CN105969725B (zh) | 枸杞红素的用途 | |
KR20100059305A (ko) | 저실자 추출물 함유 피부외용제 조성물 | |
CN106822252A (zh) | 一种具有促进白色脂肪细胞褐色化的中药组合物及其制备方法和应用 | |
CN114642675B (zh) | L-山梨糖在制备治疗肿瘤的药物中的应用 |
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 | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20191112 |