WO2020224649A1 - 含光皮树提取物的制剂及其应用 - Google Patents

含光皮树提取物的制剂及其应用 Download PDF

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WO2020224649A1
WO2020224649A1 PCT/CN2020/089246 CN2020089246W WO2020224649A1 WO 2020224649 A1 WO2020224649 A1 WO 2020224649A1 CN 2020089246 W CN2020089246 W CN 2020089246W WO 2020224649 A1 WO2020224649 A1 WO 2020224649A1
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preparation
liver
extract
glabra
liver fibrosis
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PCT/CN2020/089246
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English (en)
French (fr)
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徐迅迪
刘强
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中南大学湘雅二医院
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Priority to US17/595,060 priority Critical patent/US20220202890A1/en
Publication of WO2020224649A1 publication Critical patent/WO2020224649A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/40—Cornaceae (Dogwood family)
    • 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

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  • the invention belongs to the field of preparations, and relates to the application of extracts of the radix bark.
  • liver fibrosis is part of the pathological development of many chronic liver diseases, such as viral hepatitis, liver damage caused by toxins, alcoholic hepatitis, non-alcoholic hepatitis, etc. As liver fibrosis progresses, it may lead to cirrhosis, portal hypertension, liver decompensation, liver tumors, and even death. More than one million people die from the disease every year, especially for end-stage liver disease, and there is no effective reversing drug. Liver transplantation has become the most effective method, but the shortage of donors has caused many patients to die while waiting. Therefore, drug research and development for such diseases is imminent.
  • the inventor of the present application has conducted research on the anti-fibrosis effect of the extract of the radix bark, and has been verified by experiments to provide a new way to improve liver fibrosis.
  • the present invention provides an anti-hepatic fibrosis preparation, the preparation comprising a radix bark extract.
  • the present invention provides the application of the extract of Guangbark tree in the preparation of anti-liver fibrosis preparations.
  • the glabra tree extract is glabra tree oil; more preferably, the glabra tree oil is a lipid substance extracted from the fruit and seeds of the glabra tree.
  • the liver fibrosis is induced by CCl 4 (carbon tetrachloride).
  • the preparation is food, medicine or health care product.
  • the preparation when the preparation is a medicine, the preparation is administered by oral, injection or intragastric administration; further preferably, the injection is intravenous injection or intraperitoneal injection.
  • the dosage form of the medicine is tablet, capsule, powder injection, injection or aerosol.
  • the drug further includes one or more pharmaceutically acceptable excipients, such as diluents, binders, wetting agents, disintegrants, solvents and/or buffers.
  • pharmaceutically acceptable excipients such as diluents, binders, wetting agents, disintegrants, solvents and/or buffers.
  • the preparation when it is a food or health care product, it also includes one or more pharmacologically acceptable excipients, such as fillers, taste improvers, solvents and/or buffers.
  • pharmacologically acceptable excipients such as fillers, taste improvers, solvents and/or buffers.
  • Those skilled in the art can select appropriate auxiliary materials and amounts according to actual needs to prepare suitable food or health products.
  • the present invention provides a method for anti-liver fibrosis, which includes administering the gladiolus extract or preparation of the present invention to an animal in need, such as a human.
  • the anti-liver fibrosis described in the present invention refers to the prevention, treatment or improvement of liver fibrosis.
  • the preparations containing light bark tree oil provided by the present invention can effectively improve the condition of liver fibrosis and bring a new approach for the treatment of liver fibrosis.
  • Figure 1 Test results of liver function indexes and blood lipid indexes in Example 2, where A is the ALT test result, B is the AST test result, and the above two are liver function indexes.
  • C is the TG test result
  • D is the TC test result
  • E is the HDL-C test result
  • F is the LDL-C test result
  • the above four are the blood lipid indicators.
  • * represents P ⁇ 0.05
  • ** represents P ⁇ 0.01.
  • FIG. 1 Serum liver fiber index test results in Example 2, where A is the PCIII test result, B is the IV-C test result, and C is the LN test result.
  • FIG. 3 Test results of the antioxidant capacity index in Example 2, where A is the SOD test result, B is the MDA test result, and C is the GSH test result.
  • Figure 4 Results of HE staining, Sirius red staining and Masson staining on liver tissues.
  • FIG. 5 Western blot experiment results in Example 2, where A is the detection result of ⁇ -SMA, and B is the detection result of TGF- ⁇ 1.
  • any reagents and instruments used in the following examples are conventional reagents and instruments in the art and can be obtained through commercial channels. Any method is a conventional method in the field, and those skilled in the art can implement the method without any doubt and obtain corresponding results according to the content of the embodiments.
  • Light bark tree oil is a lipid substance extracted from the fruits and seeds of the light bark tree (Glossy bark). It mainly contains active ingredients such as oleic acid and linoleic acid. It can treat hyperlipidemia (hypertension, coronary heart disease) , Has a significant effect on lowering cholesterol, among which unsaturated fatty acids have anti-oxidation and improve lipid peroxidation damage.
  • hyperlipidemia hypertension, coronary heart disease
  • the research on the anti-hepatic fibrosis effect of the light bark tree oil has not been reported.
  • the following examples will use the CCl 4 induced liver fibrosis animal model to study the therapeutic effect of the light bark tree oil on liver fibrosis.
  • mice used in the following examples are C57BL/6J mice, provided by Hunan Slack Jingda Experimental Animal Co., Ltd., license number: SCXK (xiang) 2016-0002. The mice are raised in SPF laboratory.
  • the light bark tree oil used comes from Hunan Academy of Forestry; the fatty acid composition of light bark tree oil is mainly oleic acid (35.71%) and linoleic acid (44.49%). Both oleic acid and linoleic acid are unsaturated fatty acids; Benefit factors: phytosterol (1.98mg/g), squalene (0.0324mg/g), vitamin E (0.60556mg/g).
  • CCl 4 (code: C112040), olive oil (code: O108686) were purchased from Aladdin Company, HE staining kit (code: G1120), Sirius red staining kit (code: G1471), Masson tricolor staining kit (code: G1471) : G1340) were purchased from Solarbio.
  • ⁇ -actin (code: 60008.I.AP) was purchased from Proteintech company, and ⁇ -SMA (code: ab32575) and TGF ⁇ 1 (code: ab215715) were purchased from abcam company.
  • Example 1 Laboratory animal grouping and treatment
  • mice were selected, raised in a clean grade, and randomly divided into 4 groups after a 1-week adaptation period, namely:
  • NC Normal group
  • Model group (Model): CCl 4 groups, 5;
  • LDG Low-dose Ligneous tree oil group
  • High-dose clear bark oil group (HDG): CCl 4 + high-dose clear bark oil (2mg/kg) group, 6 animals.
  • CCl 4 is dissolved in olive oil at 20%, intraperitoneally injected twice a week, and the dose is 5 mL/kg.
  • the normal group was injected with the same amount of olive oil.
  • the usage of light bark tree oil is to give the corresponding dose to the stomach every day. After 6 weeks of continuous administration, the mice were sacrificed, and serum and liver samples were collected.
  • Example 1 The serum and liver specimens collected in Example 1 were tested.
  • the test items and test methods are as follows:
  • Liver function indexes and blood lipid indexes were tested by the Laboratory Department of the Second Xiangya Hospital of Central South University;
  • Serum liver fiber indicators were tested by the Laboratory of Infectious Diseases, the Second Xiangya Hospital of Central South University;
  • Antioxidant indicators are tested by the kit of Nanjing Jiancheng Institute of Biological Engineering according to the instructions;
  • Figure 1 A and B show the test results of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which are indicators of liver function. It can be seen from the figure that the levels of ALT and AST in the model group are significantly different from those in the normal group (P ⁇ 0.05), indicating that the model is successful; the serum ALT and AST levels in the low and high-dose groups of the light bark oil are lower In the model group, compared with the model group, the difference was statistically significant (P ⁇ 0.05). It shows that light bark tree oil can protect liver function.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • the detection results of blood lipid indexes are given by C ⁇ F in Figure 1.
  • the model group and the low and high dose group of light bark oil are in triglyceride (TG), total cholesterol (TC), high density
  • HDL-C lipoprotein
  • the content of the model group is higher than that of the normal group
  • the LDL-C content of the high-dose light bark tree oil group was statistically significant compared with the model group (P ⁇ 0.05), see Figure 1F. It shows that high-dose light bark tree oil can reduce serum low-density lipoprotein and help improve blood lipids.
  • Serum liver fiber indicators include type III procollagen (PCIII), laminin (LN) and type IV collagen (IV-C).
  • PCIII type III procollagen
  • LN laminin
  • IV-C type IV collagen
  • A, B, and C of Figure 2 compared with the normal group, the mouse serum PCIII, IV-C and LN levels increased significantly in the model group (P ⁇ 0.05); To a certain extent, the contents of serum PCIII and IV-C in mice were reduced (P ⁇ 0.01); the high-dose bark tree oil group could significantly reduce the contents of serum PCIII, IV-C and LN (P ⁇ 0.01). It shows that the light bark tree oil can reduce the serum indexes related to liver fiber, which indicates that the light bark tree oil can reduce the liver fibrosis induced by CCl 4 in mice.
  • the antioxidant capacity indicators include superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH).
  • SOD superoxide dismutase
  • MDA malondialdehyde
  • GSH glutathione
  • the mouse liver tissue was stained with HE according to the conventional steps, and the results are shown in row 1 of Figure 4.
  • the normal group the liver cells are arranged radially with the central vein as the center, and the structure of the liver lobules is normal, and no liver cell degeneration and inflammation are seen Cell infiltration;
  • Model group Hepatic cords are arranged disorderly, visible fibrous septum formation, collagen proliferation, liver cell swelling and degeneration, most of which are fatty degeneration, mostly distributed around the boundary plate, with inflammatory cell infiltration in the interstitium;
  • high dose Light bark tree oil group: the liver lobule structure exists, there are a small amount of fibrous septa, a small amount of hepatocyte fatty degeneration, and mild inflammatory cell infiltration;
  • low-dose bark tree oil shows fibrous septum formation, collagen proliferation is more obvious, hepatocyte swelling, interstitial There was moderate inflammation infiltration.
  • the light bark tree oil can improve the damage of liver cells in mice and reduce liver inflammation.
  • the mouse liver tissue was subjected to Sirius red staining (Sirius red) and Masson staining microscopic examination, and the results are shown in the second and third rows of Figure 4.
  • Sirius red staining Sirius red
  • Masson staining microscopic examination the results are shown in the second and third rows of Figure 4.
  • the normal group only a small amount of collagen was seen in the portal area; in the model group, collagen was obviously proliferated, forming a complete fibrous interval, and the normal lobular structure was destroyed.
  • the high-dose light bark oil group a small amount of collagen proliferation and a small amount of fibrous interstitial formation can be seen, indicating that light bark oil can reduce the formation of liver fibrosis; low-dose light bark oil shows more obvious collagen proliferation, incomplete fibrous interspace formation, and liver The leaflet structure is slightly damaged.
  • TGF- ⁇ is an important regulator of liver fibrosis, so it is also a biomarker of liver fibrosis, and it is located in the cytoplasm.
  • the up-regulation of ⁇ -SMA expression is a characteristic manifestation of hepatic stellate cell activation and therefore is a biomarker of liver fibrosis.
  • ⁇ -SMA is located in fibroblasts and smooth muscle cells.
  • the protein of the liver of each group was extracted, and western blotting experiment was performed.
  • the results showed that compared with the normal group, the expression levels of ⁇ -SMA and TGF- ⁇ 1 protein in the liver of the model group increased, and the difference was significant; low-dose light bark oil
  • the expression level of ⁇ -SMA and TGF- ⁇ 1 protein in the liver of the group was slightly lower than that of the model group; the expression level of ⁇ -SMA and TGF- ⁇ 1 protein in the liver of the high-dose light bark oil group was significantly lower than that of the model group, and the difference was significant (see Figure 5A) , 5B).
  • the light bark tree oil can reduce the mouse liver fibrosis index ⁇ -SMA in a dose-dependent manner, and can reduce the factor TGF- ⁇ 1 that promotes the formation of liver fibrosis in a dose-dependent manner.

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Abstract

本发明提供了一种含光皮树提取物的制剂及其应用，所述光皮树提取物如光皮树油。本发明提供的含有光皮树提取物的制剂能够有效改善肝脏纤维化的情况，为肝脏纤维化的治疗带来新途径。

Description

含光皮树提取物的制剂及其应用 技术领域
本发明属于制剂领域，涉及光皮树提取物的应用。
背景技术
我国是肝脏慢性疾病大国。肝脏纤维化是很多肝脏慢性疾病的病理发展过程的一环，例如病毒性肝炎、毒素导致的肝损伤、酒精性肝炎、非酒精性肝炎等。随着肝脏纤维化的进展，可能导致肝硬化、门静脉高压、肝脏功能失代偿、肝脏肿瘤，甚至死亡。每年有超过一百万人因此病死亡，特别是对终末期肝病，尚无有效的逆转药物。肝移植成了最有效的方法，然而供体不足使很多病人在等待的过程中死亡。因此，针对此类疾病的药物研发迫在眉睫。
发明内容
本申请发明人对光皮树提取物的抗纤维化作用进行了研究，经实验验证，提供一种改善肝脏纤维化的新方式。
在第一个方面，本发明提供一种抗肝脏纤维化的制剂，所述制剂包括光皮树提取物。
在第二个方面，本发明提供光皮树提取物在制备抗肝脏纤维化制剂中的应用。
优选地，所述光皮树提取物是光皮树油；更优选地，所述光皮树油是从光皮树的果实和种子中萃取出的脂质物质。
优选地，所述肝脏纤维化是由CCl 4(四氯化碳)诱导的。
优选地，所述制剂是食品、药物或保健品。
优选地，所述制剂是药物时，所述制剂为口服、注射或灌胃途径给药；进一步优选地，所述注射为静脉注射或腹腔注射。
优选地，所述药物的剂型为片剂、胶囊剂、粉针、注射剂或气雾剂。
优选地，所述药物还包括一种或多种制药学上可接受的辅料，如稀释剂、粘合剂、润湿剂、崩解剂、溶剂和/或缓冲剂等。本领域技术人员可以根据实际需要选择合适的辅料和量，以制备适用的药物。
优选地，当所述制剂是食品或保健品时，还包括一种或多种制剂学上可接受的辅料，如填充剂、口味改善剂、溶剂和/或缓冲剂等。本领域技术人员可以根据实际需要选择合适的辅料和量，以制备适用的食品或保健品。
在第三个方面，本发明提供抗肝脏纤维化方法，包括对需要的动物，如人，施用本发明的光皮树提取物或制剂。
在第四个方面，提供本发明的光皮树提取物或制剂在抗肝脏纤维化中的应用。
优选地，本发明所述的抗肝脏纤维化指预防、治疗肝脏纤维化或改善肝脏纤维化状态。
本发明的提供的含有光皮树油的制剂能够有效改善肝脏纤维化的情况，为肝脏纤维化的治疗带来新途径。
附图说明
图1：实施例二中肝功能指标、血脂指标检测结果，其中A为ALT检测结果，B为AST检测结果，以上二者为肝功能指标。C为TG检测结果，D为TC检测结果，E为HDL-C检测结果，F为LDL-C检测结果，以上四者为血脂指标。其中，*代表P＜0.05；**代表P＜0.01。
图2：实施例二中的血清肝纤指标检测结果，其中，A为PCIII检测结果，B为IV-C检测结果，C为LN检测结果。
图3：实施例二中的抗氧化能力指标检测结果，其中，A为SOD检测结果，B为MDA检测结果，C为GSH检测结果。
图4：对肝脏组织分别进行HE染色、天狼星红染色和Masson染色的结果。
图5：实施例二中的蛋白质印记实验结果，其中A为α-SMA检测结果，B为TGF-β1检测结果。
具体实施方式
以下将结合具体实施例来说明本发明的内容，但本发明的范围不限于此。任何基于本发明思路的技术方案均落入本发明的范围内。
如果没有特殊说明，以下实施例中使用的任何试剂和仪器均是本领域常规试剂和仪器，可以通过商购途径获得。任何方法均是本领域常规方法，本领域技术人员根据实施例内容可以毫无疑义地实施本方法并获得对应的结果。
光皮树油是从光皮树(光皮梾木)果实和种子中萃取出的脂质物质，主要含油酸和亚油酸等活性成分，可治疗高脂血症(高血压、冠心病)，对降低胆固醇有显著效果，其中不饱和脂肪酸具有抗氧化和改善脂质过氧化损伤的作用。但现在光皮树油抗肝脏纤维化作用研究尚未见报道。为了观察光皮树油的 抗纤维化作用，以下实施例将采用CCl 4诱发的肝纤维化动物模型，研究光皮树油对肝纤维化的治疗作用。
以下实施例中使用的小鼠为C57BL/6J小鼠，由湖南斯莱克景达实验动物有限公司提供，许可证号：SCXK(湘)2016-0002。小鼠饲养于SPF级实验室。
使用的光皮树油来自湖南省林业科学院；光皮树油脂肪酸组成以油酸(35.71％)和亚油酸(44.49％)为主，油酸和亚油酸都属于不饱和脂肪酸；另含有益因子：植物甾醇(1.98mg/g)、鲨烯(0.0324mg/g)、维生素E(0.60556mg/g)。
CCl 4(编号：C112040)、橄榄油(编号：O108686)购自阿拉丁公司，HE染色试剂盒(编号：G1120)、天狼星红染色试剂盒(编号：G1471)、Masson三色染色试剂盒(编号：G1340)均购自Solarbio公司。β-肌动蛋白(编号：60008.I.AP)购自Proteintech公司，α-SMA(编号：ab32575)和TGFβ1(编号：ab215715)购自abcam公司。
实施例一：实验动物分组及处理
选取小鼠，清洁级饲养,1周适应期后随机分为4组，分别为：
正常组(NC)：橄榄油对照组，7只；
模型组(Model)：CCl 4组，5只；
低剂量光皮树油组(LDG)：CCl 4+低剂量光皮树油(0.5mg/kg)组，6只；
高剂量光皮树油组(HDG)：CCl 4+高剂量光皮树油(2mg/kg)组，6只。
以上后三组的CCl 4给药为：CCl 4以20％溶解于橄榄油，每周2次腹腔注射，剂量为5mL/kg。正常组注射等量橄榄油。光皮树油用法为按相应剂量每天灌胃处理。持续给药6周后处死小鼠，收集血清及肝脏标本。
实施例二：测试项目
对实施例一收集到的血清和肝脏标本进行检测，检测项目和检测方法如下：
肝功能指标、血脂指标由中南大学湘雅二医院检验科检测；
血清肝纤指标由中南大学湘雅二医院传染科实验室检测；
抗氧化指标采用南京建成生物工程研究所试剂盒按说明书方法检测；
小鼠肝脏切片的染色均是根据相应染色试剂盒说明书方法进行染色；
使用蛋白质印迹法检测蛋白表达水平。
检测结果见表1，具体说明如下所示：
2.1肝功能指标
图1的A和B显示了肝功能指标谷丙转氨酶(ALT)、谷草转氨酶(AST)的检测结果。由图可知，模型组ALT、AST的含量与对正常组比较差异有统计学意义(P＜0.05)，说明造模成功；光皮树油的低、高剂量组血清ALT、AST含量均低于模型组，与模型组比较，差异有统计学意义(P＜0.05)。说明光皮树油可以保护肝功能。
2.2血脂指标
血脂指标的检测结果由图1的C～F给出，其中，与正常组比较，模型组和光皮树油的低、高剂量组在甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白(HDL-C)的含量这三项无明显差别(P＞0.05)，见图1C、1D、1E；关于低密度脂蛋白(LDL-C)这项，模型组的含量高于正常组含量，同时高剂量光皮树油组的LDL-C含量与模型组相比有统计学意义(P＜0.05)，见图1F。说明高剂量光皮树油可以降低血清低密度脂蛋白，有利于改善血脂情况。
2.3血清肝纤指标
血清肝纤指标包括III型前胶原(PCIII)、层黏蛋白(LN)和IV型胶原(IV-C)。如图2的A、B和C所示，模型组与正常组比较，小鼠血清PCIII、IV-C和LN含量明显升高增加(P<0.05)；低剂量光皮树油组可在一定程度上降低小鼠血清PCIII和IV-C含量(P<0.01)；高剂量光皮树油组能明显降低血清PCIII、IV-C和LN含量(P<0.01)。说明光皮树油可以降低肝纤相关的血清指标，表明光皮树油可以减轻CCl 4诱导的小鼠肝脏纤维化情况。
2.4抗氧化能力指标
抗氧化能力指标包括超氧化物歧化酶(SOD)、丙二醛(MDA)、谷胱甘肽(GSH)。由图3B可知，模型组的肝脏MDA含量高于正常组，同时光皮树油高、低剂量组的MDA低于模型组(P＜0.05)。由图3A和C可知，模型组的肝脏SOD、GSH含量低于正常组，同时光皮树油高、低剂量组的SOD、GSH高于模型组(P＜0.05)。说明CCl 4诱导小鼠肝脏纤维化可以减轻小鼠肝脏的抗氧化能力，而光皮树油可以增强肝脏纤维化小鼠肝脏的抗氧化能力。
2.5小鼠肝脏HE染色
将小鼠肝脏组织按照常规步骤进行HE染色，结果如图4第1行所示，其中，正常组：肝细胞以中央静脉为中心呈放射状排列，肝小叶结构正常，未见肝细胞变性及炎症细胞浸润；模型组：肝索排列紊乱，可见明显纤维间隔形成，胶原明显增生，肝细胞明显肿胀变性，其中多为脂肪变性，多分布于界板周围，间质内见炎症细胞浸润；高剂量光皮树油组：肝小叶结构存在，有少量纤维间隔，少量肝细胞脂肪变性，轻度炎细胞浸润；低剂量光皮树油可见纤维间隔形成，胶原增生较明显，肝细胞肿胀，间质内见中度炎症浸润。
由图可见，光皮树油可以改善小鼠肝细胞受损情况，同时减轻肝脏炎症。
2.6小鼠肝脏天狼星红染色、Masson染色
将小鼠肝脏组织进行天狼星红染色(Sirius red)和Masson染色镜检，结果如图4的第2行和第3行所示。正常组仅汇管区见少量胶原；模型组胶原明显增生，形成完整的纤维间隔，正常小叶结构被破坏。高剂量光皮树油组可见少量胶原增生，少量纤维间隔形成，说明光皮树油可以减轻肝纤维化的形成；低剂量光皮树油可见胶原增生较明显，不完整的纤维间隔形成，肝小叶结构稍破坏。
2.7小鼠肝脏α-SMA(α-平滑肌激动蛋白)、TGF-β1(转化生长因子β1)的蛋白表达水平
TGF-β是肝脏纤维化的重要调节因子，因此也是肝脏纤维化的生物标记物，它定位于细胞质。α-SMA的表达上调是肝脏星形细胞激活的特征性表现，因此是肝脏纤维化的生物标记。α-SMA定位于成纤维细胞、平滑肌细胞。
提取各组小鼠肝脏的蛋白，进行蛋白质印记实验，结果显示，与正常组相比模型组小鼠肝脏α-SMA和TGF-β1蛋白表达水平增高，差异具有显著性；低剂量光皮树油组肝脏α-SMA和TGF-β1蛋白表达水平较模型组稍降低；高剂量光皮树油组肝脏α-SMA和TGF-β1蛋白表达水平较模型组明显降低，差异具有显著性(见图5A、5B)。
说明光皮树油可以剂量依赖性降低小鼠肝纤指标α-SMA，并且可剂量依赖性降低促进肝纤维化形成的因子TGF-β1。
Figure PCTCN2020089246-appb-000001
Figure PCTCN2020089246-appb-000002
Figure PCTCN2020089246-appb-000003

Claims (10)

  1. 光皮树提取物在制备抗肝脏纤维化制剂中的应用。
  2. 根据权利要求1所述的应用，其中，所述光皮树提取物是光皮树油；优选地，所述光皮树油是从光皮树的果实和种子中萃取出的脂质物质。
  3. 根据权利要求1或2所述的应用，其中，所述制剂是食品、药物或保健品。
  4. 根据权利要求3所述的应用，其中，所述制剂是药物时，所述制剂为口服、注射或灌胃途径给药；优选地，所述注射为静脉注射或腹腔注射。
  5. 根据权利要求4所述的应用，其中，所述药物的剂型为片剂、胶囊剂、粉针、注射剂或气雾剂；优选地，所述药物还包括一种或多种制药学上可接受的辅料。
  6. 根据权利要求3所述的应用，其中，当所述制剂是食品或保健品时，还包括一种或多种制剂学上可接受的辅料，如填充剂、口味改善剂、溶剂和/或缓冲剂。
  7. 根据权利要求1～6任一项所述的应用，其中，所述抗肝脏纤维化指预防、治疗肝脏纤维化或改善肝脏纤维化状态。
  8. 根据权利要求1～6任一项所述的应用，其中，所述肝脏纤维化是由CCl 4诱导的。
  9. 一种抗肝脏纤维化的制剂，所述制剂包括光皮树提取物。
  10. 根据权利要求9所述的制剂，其中，所述光皮树提取物是光皮树油；优选地，所述制剂是食品、药物或保健品。
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