WO2015062167A1 - Metrnl蛋白在制备降血脂降血糖药物中的应用 - Google Patents

Metrnl蛋白在制备降血脂降血糖药物中的应用 Download PDF

Info

Publication number
WO2015062167A1
WO2015062167A1 PCT/CN2014/000949 CN2014000949W WO2015062167A1 WO 2015062167 A1 WO2015062167 A1 WO 2015062167A1 CN 2014000949 W CN2014000949 W CN 2014000949W WO 2015062167 A1 WO2015062167 A1 WO 2015062167A1
Authority
WO
WIPO (PCT)
Prior art keywords
metrnl
mice
fat
protein
application
Prior art date
Application number
PCT/CN2014/000949
Other languages
English (en)
French (fr)
Other versions
WO2015062167A8 (zh
Inventor
缪朝玉
李志勇
王培�
Original Assignee
中国人民解放军第二军医大学
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from CN201310525184.9A external-priority patent/CN103536904B/zh
Priority claimed from CN201310525181.5A external-priority patent/CN103536903B/zh
Application filed by 中国人民解放军第二军医大学 filed Critical 中国人民解放军第二军医大学
Publication of WO2015062167A1 publication Critical patent/WO2015062167A1/zh
Publication of WO2015062167A8 publication Critical patent/WO2015062167A8/zh
Priority to US15/137,606 priority Critical patent/US20160251405A1/en
Priority to US15/729,420 priority patent/US10342852B2/en

Links

Images

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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the invention relates to the technical field of medicine, in particular to the application of the Metrin protein in preparing hypolipidemic and hypoglycemic drugs.
  • Metrnl protein is a very new protein, encoded by metrnl gene, the size is about 30kDa, and the amino acid sequence of Metrnl protein is NP_001004431.1. The expression and physiological function of this protein are close to unknown.
  • METRNL is a neuronal survival and growth factor with neuron protection and/or neurogenesis, METRNL protein It can be used to treat diseases, disorders or damage to the nervous system.
  • Diabetes is a group of metabolic diseases characterized by hyperglycemia caused by defective insulin secretion or its biological effects, or both.
  • Hyperglycemia which persists in diabetes, causes chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves.
  • the development of new hypoglycemic drugs has always been a hot spot and focus in drug development.
  • hyperlipidemia is an important factor in the development of metabolic diseases such as type 2 diabetes, impaired glucose tolerance, hypertension and atherosclerosis. Therefore, finding new lipid-lowering drugs may provide new drugs or intervention targets for the treatment of hyperlipidemia.
  • the invention provides the application of the Metrin protein in the preparation of a hypoglycemic or health food.
  • the invention provides the application of the Metrnl protein in preparing a hypolipidemic drug or a health food.
  • the invention also provides a preparation method of a Metrrl fat-specific overexpressing mouse, the method comprising the following steps:
  • the present invention has been experimentally shown to perform a fasting glucose tolerance test in normal mice and Metrnl fat-specific overexpressing mice, that is, intraperitoneal injection of glucose under fasting, and blood glucose will rise rapidly after the mice ingest glucose.
  • a fasting glucose tolerance test in normal mice and Metrnl fat-specific overexpressing mice, that is, intraperitoneal injection of glucose under fasting, and blood glucose will rise rapidly after the mice ingest glucose.
  • the present invention has been experimentally shown that in normal mice and Metrnl fat-specific overexpressing mice, triglyceride is administered intragastrically, and it is found that the blood lipid level of Metrnl fat-specific overexpressing mice is significantly lower than that of normal mice, indicating that Metrnl Protein has the effect of lowering blood lipids.
  • Metrrl protein of the present invention for the preparation of a hypoglycemic or health food is a pharmaceutical composition consisting of the medicinal active ingredient Metrnl protein and a pharmaceutically acceptable adjuvant.
  • the pharmaceutically acceptable excipient refers to a pharmaceutical excipient which is conventional in the pharmaceutical field, wherein a diluent, an excipient such as water, etc.; a binder such as a cellulose derivative, gelatin or polyvinylpyrrolidone; a filler such as starch, etc.
  • a cracking agent such as calcium carbonate or sodium hydrogencarbonate; other adjuvants such as flavoring agents and/or sweeteners may also be added to the composition.
  • the pharmaceutical composition can be prepared into various dosage forms by using Metrerl protein as an active ingredient and pharmaceutically acceptable excipients by a conventional method in the medical field. When used orally, it can be prepared into a conventional solid preparation such as a tablet, a powder or a capsule, etc.; when it is used for injection, it can be prepared as an injection.
  • the active ingredient is present in an amount of from 0.1% to 99.9% by weight, preferably from 0.5% to 90% by weight.
  • the pharmaceutical composition can be used to lower blood sugar levels of hyperlipidemia.
  • the pharmaceutical composition can be used to reduce blood lipids and blood sugar levels of hyperlipidemia. It also has a lowering effect on hyperlipidemia and hyperglycemia caused by other causes.
  • the dosage form can be applied to an individual in need of treatment by intraperitoneal injection, subcutaneous injection, intravenous injection, intramuscular injection, intralymphatic injection, mucosal administration or the like.
  • An individual can be a human or an animal.
  • the dosage is generally 0.01-1000 mg/kg body weight/day, which can be changed according to the age, condition, etc. of the individual. Chemical.
  • the Metrnl protein is a protein having a size of 30 kDa, and the amino acid sequence of the human Metrnl protein is shown in NP_001004431.1.
  • the invention provides the application of the Metrnl protein in the preparation of a hypoglycemic agent, and the Metrnl protein can significantly reduce the increase of blood glucose caused by intraperitoneal injection of glucose. This may be of great significance for the treatment of diabetes.
  • the invention provides the application of the Metrnl protein in the preparation of a hypolipidemic drug, and the Metrin protein can significantly reduce the increase of blood lipid caused by oral high-fat food. This may be of great significance for the treatment of hyperlipidemia.
  • Metrrn protein itself is an endogenous protein of the human body. From the current data, the possible side effects on the human body are small, so the safety as a potential drug is high.
  • FIG 1 shows changes in blood glucose after intraperitoneal injection of glucose in normal mice and Metrnl overexpressing mice.
  • Figure 2 shows changes in blood lipids after administration of triglycerides in normal mice and Metrnl overexpressing mice.
  • mice were purchased from the Shanghai Southern Model Animal Center.
  • the reagents and starting materials used in the present invention are either commercially available or can be prepared by literature methods.
  • the experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer.
  • the plasmid Fabp4-Metrnl can also be produced using commercially available products, such as the Metrln gene.
  • the open reading frame is available from Thermo, Inc., item number MMM1013-202763251.
  • the upstream promoter region of the Fabp4 gene is commercially available from Addgene, Inc., plasmid number 11424.
  • Metrnl fat-specific overexpressing mice can also be commissioned by the Shanghai Southern Model Animal Center.
  • Example 2 Metrnl overexpression can reduce blood glucose elevation caused by intraperitoneal injection of glucose
  • the 22-week-old normal-type mice and the Metanl fat-specific overexpressing mice fed with high-fat diet used the same dose of glucose.
  • the administration method was intraperitoneal injection. The specific method is as follows: :
  • mice were intraperitoneally injected with glucose at a dose of 1 g/kg after fasting for 8 hours. Subsequently, the tail vein blood of the mouse was taken at different time points (see Table 1 at specific time points), and the blood glucose was measured by a fast blood glucose meter (product of Johnson & Johnson, USA).
  • Example 3 Metrnl overexpression can reduce elevated blood lipids caused by oral high fat diets
  • mice and Metrnl fat-specific overexpressing mice of about 12 weeks of age were administered with the same dose of fat milk, as follows:
  • mice were given a 20% medium/long-chain fat emulsion injection (trade name “Li Bao Yuan Ning”, German Berenger Medical Co., Ltd.) for 3 hours after fasting for 3 hours.
  • g body weight blood was taken from the tail vein at different time points, and 10 ul of serum was taken for centrifugation to detect the content of triglyceride.
  • the kit used for the detection of triglyceride was triglyceride sold by Beijing Pulilai Gene Technology Co., Ltd. Blood) Enzymatic assay kit, article number E1003.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Toxicology (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nutrition Science (AREA)
  • Mycology (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Emergency Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

本发明提供了Metrnl蛋白在制备降血脂、降血糖药物或保健食品中的应用。本发明还提供了Metrnl脂肪特异性过表达小鼠的制备方法。

Description

Metrnl蛋白在制备降血脂降血糖药物中的应用 技术领域
本发明涉及医药技术领域，具体涉及Metrnl蛋白在制备降血脂、降血糖药物方面的应用。
背景技术
Metrnl蛋白是一个非常新的蛋白，由metrnl基因编码，大小为30kDa左右，Metrnl蛋白的氨基酸序列见NP_001004431.1，该蛋白的表达、生理功能近于未知状况。
中国专利申请CN200980137344.4，发明名称为“生长因子METRNL的治疗用途”，申请公布号：CN102164611A，公开了METRNL是一种具有神经元保护和/或神经发生作用的神经生存和生长因子，METRNL蛋白可用于治疗神经系统的疾病、疾患或损害。
糖尿病是一组以高血糖为特征的代谢性疾病，是由于胰岛素分泌缺陷或其生物作用受损，或两者兼有引起。糖尿病时长期存在的高血糖，导致各种组织，特别是眼、肾、心脏、血管、神经的慢性损害、功能障碍。发展新的降血糖药物，一直是药物开发中的一个热点和重点。
大量证据表明高脂血症是引发2型糖尿病、糖耐量异常、高血压及动脉粥样硬化等代谢性疾病的重要因素。因此，找到新的降血脂药物，有可能对于高脂血症的治疗提供新的药物或干预靶点。
目前国内外尚无有关Metrnl蛋白在制备降血脂、降血糖药物方面的文献报道。
发明内容
本发明的目的在于提供Metrnl蛋白的新用途。
本发明提供了Metrnl蛋白在制备降血糖药物或保健食品中的应用。
本发明提供了Metrnl蛋白在制备降血脂药物或保健食品中的应用。
本发明还提供了一种Metrnl脂肪特异性过表达小鼠的制备方法，该方法包括如下步骤：
脂肪特异性构建包含脂肪特异性表达基因Fabp4上游启动子区域与Metrnl基因开放性阅读框的质粒Fabp4-Metrnl，测序正确后，酶切线性化，注射受精卵，移植到假孕母鼠的子宫内，对后代小鼠进行基因组鉴定。挑选转基因成功的子鼠与C57BL6小鼠交配，下一代小鼠中基因组中携带Fabp4-Metrnl的小鼠为Metrnl脂肪特异性过表达小鼠。
本发明经实验显示：在正常型小鼠和Metrnl脂肪特异性过表达小鼠实施空腹糖耐量实验，即在空腹下给予葡萄糖腹腔注射，小鼠摄入葡萄糖后，血糖会很快上升。我们发现：相较正常型小鼠而言，Metrnl脂肪特异性过表达小鼠的血糖水平的上升明显要迟缓，这说明Metrnl蛋白的过表达阻滞了血糖的上升，因此，Metrnl蛋白有降低血糖的作用。
本发明经实验显示：在正常型小鼠和Metrnl脂肪特异性过表达小鼠给予甘油三酯灌胃，发现Metrnl脂肪特异性过表达小鼠的血脂水平明显比正常型小鼠要低，说明Metrnl蛋白有降低血脂的作用。
本发明所述的Metrnl蛋白在制备降血糖药物或保健食品中的应用，所述的药物是由药物活性成分Metrnl蛋白和药学上可接受的辅料组成的药物组合物。
所述的药学上可接受的辅料是指药学领域常规的药物辅料，其中，稀释剂、赋形剂如水等；粘合剂如纤维素衍生物、明胶或聚乙烯吡咯烷酮等；填充剂如淀粉等；崩裂剂如碳酸钙或碳酸氢钠；也可以在组合物中加入其他辅助剂如香味剂和/或甜味剂。
所述的药物组合物可采用医学领域常规的方法，将Metrnl蛋白作为活性成分，与药学上可接受的辅料制成各种剂型。当用于口服时，可将其制备成常规的固体制剂如片剂、粉剂或胶囊剂等；用于注射时，可将其制备成注射液。在各种制剂中，活性成分的重量含量为0.1％～99.9％，优选的重量含量为0.5～90％。
所述的药物组合物可以用于降低高脂血症的血糖水平。所述的药物组合物可以用于降低高脂血症的血脂、血糖水平。对其他原因引起的高血脂、高血糖也有降低作用。
可以按剂型通过腹腔注射、皮下注射、静脉注射、肌肉注射、淋巴结内注射、粘膜用药等途径应用于需要治疗的个体。个体可以是人或动物。剂量一般为0.01～1000mg/公斤体重/天，具体可根据个体的年龄、病情等进行变 化。
本发明中，所述的Metrnl蛋白是一种蛋白质，大小为30kDa，人Metrnl蛋白的氨基酸序列见NP_001004431.1号。
相比于现有技术，本发明的有益效果如下：
本发明提供了Metrnl蛋白在制备降血糖药物方面的应用，Metrnl蛋白可以明显降低因腹腔注射葡萄糖导致的血糖升高。这对于糖尿病的治疗可能具有重大意义。
本发明提供了Metrnl蛋白在制备降血脂药物方面的应用，Metrnl蛋白可以明显降低因口服高脂食物导致的血脂升高。这对于高脂血症的治疗可能具有重大意义。
并且Metrnl蛋白本身是一种人体的内源性蛋白质，从目前的资料来看对人体可能的副作用很小，因此作为潜在药物的安全性很高。
附图说明
图1是正常型小鼠和Metrnl过表达小鼠腹腔注射葡萄糖后的血糖变化情况。
图2是正常型小鼠和Metrnl过表达小鼠甘油三酯灌胃后的血脂变化情况。
具体实施方式
现结合实施例和附图，对本发明作详细描述，但本发明的实施不仅限于此。
正常型小鼠购自上海南方模式动物中心。
本发明所用试剂和原料均市售可得或可按文献方法制备。下列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：Metrnl脂肪特异性过表达小鼠的制备
脂肪特异性构建包含脂肪特异性表达基因Fabp4上游启动子区域与Metrnl基因开放性阅读框的质粒Fabp4-Metrnl，测序正确后，酶切线性化，注射受精卵，移植到假孕母鼠的子宫内，对后代小鼠进行基因组鉴定。挑选转基因成功的子鼠与C57BL6小鼠交配，下一代小鼠中基因组中携带Fabp4-Metrnl的为实验组，未携带的为对照组。
质粒Fabp4-Metrnl，也可以使用直接市购的商品制得，如Metrnl基因的 开放性阅读框可购自Thermo公司，货号MMM1013-202763251。Fabp4基因上游启动子区域可购自Addgene公司，质粒编号11424。
Metrnl脂肪特异性过表达小鼠也可委托上海南方模式动物中心构建。
实施例2：Metrnl过表达可以降低因腹腔注射葡萄糖导致的血糖升高
对高脂饲料(Research Diets公司，货号D12492)饲养16周的22周龄的正常型小鼠和Metrnl脂肪特异性过表达小鼠均使用相同剂量的葡萄糖，给药方法为腹腔注射，具体方法如下：
上述22周龄小鼠，禁食8小时后，于腹腔注射葡萄糖，剂量为1g/kg。随后在不同的时间点(具体的时间点见表1)取小鼠的尾部静脉血，用快速血糖仪(美国强生公司产品)测出血糖。
结果表明，腹腔注射葡萄糖在Metrnl脂肪特异性过表达小鼠上导致的血糖升高作用要显著低于在正常型小鼠上的作用，详见表1和图1。
表1.Metrnl脂肪特异性过表达可抑制腹腔注射葡萄糖导致的血糖升高
Figure PCTCN2014000949-appb-000001
*表示Metrnl脂肪特异性过表达小鼠+腹腔注射葡萄糖与对照组相比较，有统计学差异(P＜0.05)；**表示Metrnl脂肪特异性过表达小鼠+腹腔注射葡萄糖与对照组相比较，有显著的统计学差异(P＜0.01)。
实施例3：Metrnl过表达可以降低因口服高脂食物导致的血脂升高
对约12周龄的正常型小鼠和Metrnl脂肪特异性过表达小鼠均使用相同剂量的脂肪乳灌胃，具体方法如下：
上述12周龄小鼠，禁食3小时后，给予20％的中/长链脂肪乳注射液(商品名为“力保肪宁”，德国贝朗医疗有限公司)灌胃，剂量为10ul/g体重，在不同的时间点尾静脉取血，血液离心后取10ul血清用于检测甘油三酯的含量，甘油三酯检测所用试剂盒为北京普利莱基因技术有限公司销售的甘油三酯(血液)酶法测定试剂盒，货号E1003。
结果表明，脂肪乳灌胃在Metrnl脂肪特异性过表达小鼠上导致的血脂升高要显著低于在正常型小鼠上的作用，详见表2与图2。
表2.Metrnl抑制血中甘油三酯的升高
Figure PCTCN2014000949-appb-000002
*表示Metrnl脂肪特异性过表达小鼠+脂肪乳灌胃与对照组相比较，有统计学差异(P＜0.05)；**表示Metrnl脂肪特异性过表达小鼠+脂肪乳灌胃与对照组相比较，有显著的统计学差异(P＜0.01)。
以上已对本发明创造的较佳实施例进行了具体说明，但本发明创造并不限于所述实施例，熟悉本领域的技术人员在不违背本发明创造精神的前提下还可作出种种的等同的变型或替换，这些等同的变型或替换均包含在本申请权利要求所限定的范围内。

Claims (4)

  1. Metrnl蛋白在制备降血糖药物或保健食品中的应用。
  2. 根据权利要求1所述的Metrnl蛋白在制备降血糖药物或保健食品中的应用，其特征在于，所述的应用是指降低高脂血症的血糖水平。
  3. Metrnl蛋白在制备降血脂药物或保健食品中的应用。
  4. 一种Metrnl脂肪特异性过表达小鼠的制备方法，其特征在于，该方法包括如下步骤：
    构建包含脂肪特异性表达基因Fabp4上游启动子区域与Metrnl基因开放性阅读框的质粒Fabp4-Metrnl，测序正确后，酶切线性化，注射受精卵，移植到假孕母鼠的子宫内，对后代小鼠进行基因组鉴定；挑选转基因成功的子鼠与C57BL6小鼠交配，下一代小鼠中基因组中携带Fabp4-Metrnl的小鼠为Metrnl脂肪特异性过表达小鼠。
PCT/CN2014/000949 2013-10-29 2014-10-27 Metrnl蛋白在制备降血脂降血糖药物中的应用 WO2015062167A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US15/137,606 US20160251405A1 (en) 2013-10-29 2016-04-25 Application of metrnl protein in preparing hypolipidemic, hypoglycemic medicine
US15/729,420 US10342852B2 (en) 2013-10-29 2017-10-10 Methods of reducing blood glucose or triglyceride levels by administration of METRNL protein

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201310525184.9A CN103536904B (zh) 2013-10-29 2013-10-29 Metrnl蛋白在制备降血糖药物方面的应用
CN201310525181.5A CN103536903B (zh) 2013-10-29 2013-10-29 Metrnl蛋白在制备降血脂药物方面的应用
CN201310525184.9 2013-10-29
CN201310525181.5 2013-10-29

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/137,606 Continuation US20160251405A1 (en) 2013-10-29 2016-04-25 Application of metrnl protein in preparing hypolipidemic, hypoglycemic medicine

Publications (2)

Publication Number Publication Date
WO2015062167A1 true WO2015062167A1 (zh) 2015-05-07
WO2015062167A8 WO2015062167A8 (zh) 2015-12-30

Family

ID=53003220

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/000949 WO2015062167A1 (zh) 2013-10-29 2014-10-27 Metrnl蛋白在制备降血脂降血糖药物中的应用

Country Status (2)

Country Link
US (2) US20160251405A1 (zh)
WO (1) WO2015062167A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102016204700A1 (de) 2016-03-22 2017-09-28 Universität Rostock Rekombinante Herstellung von Subfatin
CN109420158A (zh) * 2017-09-01 2019-03-05 上海风劲生物医药科技有限公司 Metrnl抗血栓用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102164611A (zh) * 2008-07-24 2011-08-24 Ns基因公司 生长因子metrnl的治疗用途
CN103536903A (zh) * 2013-10-29 2014-01-29 中国人民解放军第二军医大学 Metrnl蛋白在制备降血脂药物方面的应用
CN103536904A (zh) * 2013-10-29 2014-01-29 中国人民解放军第二军医大学 Metrnl蛋白在制备降血糖药物方面的应用
WO2014116556A2 (en) * 2013-01-25 2014-07-31 Dana-Farber Cancer Institute, Inc. Compositions and methods for regulating thermogenesis and muscle inflammation using metrnl and metrn

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK0639225T3 (da) * 1992-04-30 2003-02-17 Innogenetics Nv Nye polypeptider og peptider, nucleinsyrer, der koder for dem, og deres anvendelse i området tumorterapi, inflammation eller immunologi

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102164611A (zh) * 2008-07-24 2011-08-24 Ns基因公司 生长因子metrnl的治疗用途
WO2014116556A2 (en) * 2013-01-25 2014-07-31 Dana-Farber Cancer Institute, Inc. Compositions and methods for regulating thermogenesis and muscle inflammation using metrnl and metrn
CN103536903A (zh) * 2013-10-29 2014-01-29 中国人民解放军第二军医大学 Metrnl蛋白在制备降血脂药物方面的应用
CN103536904A (zh) * 2013-10-29 2014-01-29 中国人民解放军第二军医大学 Metrnl蛋白在制备降血糖药物方面的应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HERTZEL, A.V. ET AL.: "Increased lipolysis in transgenic animals overexpressing the epithelial fatty acid binding protein in adipose cells", JOURNAL OF LIPID RESEARCH, vol. 43, no. 12, 1 December 2002 (2002-12-01), pages 2106 *
ZHANG, WEIZHEN ET AL.: "Effect of Des-acyl Ghrelin on Adiposity and Glucose Metabolism", ENDOCRINOLOGY, vol. 149, no. 9, 5 June 2008 (2008-06-05), pages 4710 *
ZHU, JIN'GAI: "Construction and phenotype analysis of adipose tissue-specific PID1 expression transgenic mice", CHINA DOCTORAL DISSERTATIONS FULL-TEXT DATABASE (ELECTRONIC JOURNALS, 15 January 2013 (2013-01-15), pages 13 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102016204700A1 (de) 2016-03-22 2017-09-28 Universität Rostock Rekombinante Herstellung von Subfatin
CN109420158A (zh) * 2017-09-01 2019-03-05 上海风劲生物医药科技有限公司 Metrnl抗血栓用途

Also Published As

Publication number Publication date
US10342852B2 (en) 2019-07-09
WO2015062167A8 (zh) 2015-12-30
US20180030102A1 (en) 2018-02-01
US20160251405A1 (en) 2016-09-01

Similar Documents

Publication Publication Date Title
JP2005068060A (ja) ラクトフェリンを含有する医薬組成物ならびに加工食品の製造法
CN115969802A (zh) 含吡非尼酮缓释组合物用于治疗和逆转人脂肪性肝炎的药物用途
US20240307337A1 (en) Method Of Treatment Of Obesity
JP6445686B2 (ja) ジペノサイド７５の抗糖尿病効果
JP6444515B2 (ja) タウリンのコロナウイルス属及び／又はロタウイルス属のウィルスにより引き起こされる疾患の予防及び／又は治療における応用
WO2015062167A1 (zh) Metrnl蛋白在制备降血脂降血糖药物中的应用
CN103536904B (zh) Metrnl蛋白在制备降血糖药物方面的应用
CN103536903B (zh) Metrnl蛋白在制备降血脂药物方面的应用
CN104306370A (zh) 用于保肝治疗的药物组合物及其制备方法
JP2010111646A (ja) 潰瘍性大腸炎治療剤
KR101671008B1 (ko) TNP(N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 식욕억제용 약학적 조성물
KR100732614B1 (ko) 복어 추출물을 포함하는 비만 또는 당뇨성 질환의 예방또는 치료용 약학 조성물
TWI364286B (en) Compositions for diabetes treatment and prophylaxis
JP2001048794A (ja) 桑の葉由来粉末およびカキ由来粉末の混合物を含むｎｉｄｄｍ治療用の医薬組成物および健康食品
JP6437183B2 (ja) 肝機能改善剤
WO2022061962A1 (zh) 一种l型氨基酸转运蛋白抑制剂或拮抗剂有效干预糖尿病的方法
WO2022113693A1 (ja) 筋ジストロフィー治療剤、中心静脈栄養用組成物、筋組織の炎症抑制剤および筋ジストロフィーの抗炎症用食品組成物
TWI846645B (zh) 光色素用於製備治療或改善非酒精性脂肪性肝病及肥胖症之組合物的用途
CN112641779B (zh) Gw441756在制备预防和/或治疗脂肪肝药物中的应用
JP2011032256A (ja) 薬用ニンジンを始めとしたサポニン含有生薬服用時に生じるメンゲン反応の防止及び生薬の吸収性を増大させる製法（生薬の有効成分を鶏卵タンパクに吸収させる方法）による医薬組成物及び健康食品
JP2010265186A (ja) 貧血予防用組成物
JP2008031154A (ja) 血糖低下剤
JP2004215562A (ja) 飲食物用添加剤、医薬組成物、ｇｌｕｔ４トランスロケート剤及びトランスロケート方法
CN110051820A (zh) 一种用于肝病患者的组合物及其应用
JP6418911B2 (ja) Ｇｌｐ−１分泌促進剤

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14857086

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 14857086

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 14857086

Country of ref document: EP

Kind code of ref document: A1