WO2019153816A1 - 木瓜白桦脂酸在制备抗高血压心肌纤维化药物中的应用 - Google Patents

木瓜白桦脂酸在制备抗高血压心肌纤维化药物中的应用 Download PDF

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WO2019153816A1
WO2019153816A1 PCT/CN2018/115185 CN2018115185W WO2019153816A1 WO 2019153816 A1 WO2019153816 A1 WO 2019153816A1 CN 2018115185 W CN2018115185 W CN 2018115185W WO 2019153816 A1 WO2019153816 A1 WO 2019153816A1
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betulinic acid
papaya
myocardial fibrosis
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content
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French (fr)
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吕琳
张国华
吴少瑜
陈凯
全东令
刘馨
庄宇鑫
管怡晴
张静茹
马韵词
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南方医科大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/732—Chaenomeles, e.g. flowering quince

Definitions

  • the invention belongs to the field of biomedical technology, and particularly relates to the application of papaya bile fatty acid in preparing antihypertensive myocardial fibrosis drugs.
  • Myocardial fibrosis is a major cardiac pathological change caused by hypertension and one of the important causes of various cardiovascular events. Therefore, it is important to study the inhibition and reversal of myocardial fibrosis. Recent studies at home and abroad have concluded that the mechanism of myocardial fibrosis is the result of excessive accumulation of collagen fibers in the normal tissue structure of the myocardium, a significant increase in collagen concentration in cardiac tissue, or a change in collagen composition. Most anti-myocardial fibrosis studies focus on drugs.
  • hypertensive myocardial fibrosis is a serious complication in the middle and late stages of hypertension. Unlike simple hypertension and other causes of myocardial fibrosis, conventional antihypertensive drugs and matrix metalloproteinase inhibitors cannot. It can effectively improve myocardial fibrosis while lowering blood pressure, and has certain side effects.
  • traditional Chinese medicine has many unique advantages in the treatment of hypertension. Traditional Chinese medicine has become a hot spot for antihypertensive myocardial fibrosis in improving hypertensive myocardial fibrosis.
  • the object of the present invention is to provide the application of papaya betulinic acid against hypertensive myocardial fibrosis.
  • the main active ingredient extracted from papaya, betulinic acid can be used for preparing antihypertensive myocardial fibrosis drugs, and solving the single-step and side effects of western medicine.
  • Major problems provide a basis for refining the blood pressure of Chinese herbal active ingredients and improving myocardial fibrosis.
  • betulinic acid or a pharmacologically acceptable salt thereof for antihypertensive and/or heart disease.
  • Hypertensive myocardial fibrosis is a serious complication in the middle and late stage of hypertension. Unlike simple hypertension and other causes of myocardial fibrosis, conventional antihypertensive drugs and matrix metalloproteinase inhibitors cannot be treated well at the same time. Lowering blood pressure and improving myocardial fibrosis, and have certain side effects.
  • the experiment of the present invention proves that papain can inhibit the oxidative stress and inflammatory reaction of myocardial tissue and reduce the secretion of collagen while lowering blood pressure, thereby effectively improving cardiac structure and function damage caused by hypertension.
  • papaya can be used for conventional hypertension and heart disease (including myocardial fibrosis of heart disease).
  • betulinic acid can also be extracted from rose apple leaves, birch bark and the like. After the applicant of the present invention verified that papaya fatty acid has the effect of treating hypertension and/or heart disease, it can be reasonably presumed that betulinic acid extracted from other plant sources such as rose apple leaves and birch bark has the same efficacy.
  • betulinic acid can selectively kill human melanoma cells without killing healthy cells; inhibiting HIV-1 infection, etc., but does not mention betulinic acid It has efficacy in high blood pressure or heart disease.
  • the betulinic acid is extracted from the traditional Chinese medicine papaya.
  • the traditional Chinese medicine papaya is the fruit of the Rosaceae plant Chaenomeles speciosa (Sweet) Nakai. In the summer and autumn, the fruit is harvested when it is green and yellow. It is placed in boiling water and burned to the outer skin. It is half-longitudinal and can be used as a medicine.
  • the "Compendium of Materia Medica” records that papaya can phlegm and stagnate evil, and myocardial fibrosis has the characteristics of blood stasis in the TCM syndrome system.
  • the applicant of the present invention takes the traditional Chinese medicine papaya as the research object, studies the active ingredients and curative effects of the traditional Chinese medicine papaya, and concludes that the main active ingredient extracted from papaya, betulinic acid, can be used for the treatment of hypertensive myocardial fibrosis.
  • the traditional Chinese medicine papaya is the fruit of the Rosaceae plant Chaenomeles speciosa (Sweet) Nakai. Unlike the rose apple leaves and birch bark, it is necessary to consume a large number of plant vegetative organs and affect the growth of plants.
  • the traditional Chinese medicine papaya is a fruit, which can be obtained in large quantities without affecting the growth of the plant, and is beneficial for the extraction of papaya fatty acid. Since the extracted papaya betulinic acid is a natural substance, the papaya betulinic acid of the present invention can be applied to medicines and health care products.
  • the heart disease is a hypertensive heart disease.
  • the hypertensive heart disease is hypertensive myocardial fibrosis.
  • the application includes, but is not limited to, the use of drugs and/or health care products.
  • the medicine and/or health care product is a medicine and/or health care product which reduces body systolic blood pressure, increases cardiac ejection fraction and short axis shortening rate.
  • the medicine and/or health care product is a medicine and/or health care product which increases the content of nitric oxide in the blood of the body and reduces the content of endothelin.
  • a pharmaceutical composition wherein the active ingredient in the pharmaceutical composition is betulinic acid or a pharmacologically acceptable salt thereof.
  • the betulinic acid is extracted from the traditional Chinese medicine papaya.
  • the heart disease is a hypertensive heart disease.
  • the hypertensive heart disease is hypertensive myocardial fibrosis.
  • a health care product comprising betulinic acid or a pharmacologically acceptable salt thereof.
  • the betulinic acid is extracted from the traditional Chinese medicine papaya.
  • betulinic acid can be extracted from foodstuffs, it is not a synthetic substance and can be added to health care products within the allowable range.
  • the present invention uses papaya betulinic acid to treat spontaneously hypertensive rats (SHR), and the results show that after 12 weeks of treatment, the blood pressure of each group of SHR is decreased, among which papaya betulinic acid dose groups and Cato
  • the serum endothelin (ET) level in the CAP group was significantly decreased (P ⁇ 0.05); the nitric oxide (NO) level was significantly increased (P ⁇ 0.05); the papaya folic acid in each dose group could reduce the MCP-1
  • the contents of TNF- ⁇ , IL-1, IL-6, CRP and MDA showed that papain can reduce the content of inflammatory factors in myocardial tissue, reduce the damage of oxidative stress on tissues, and enhance the antioxidant capacity of tissues.
  • Myocardial fibrosis was improved by multiple targets; the results of echocardiography showed that papaya high-dose and CAP groups could effectively increase the cardiac ejection fraction (EF%) and short-axis shortening rate (FS%) of SHR; papaya
  • the protein expression levels of TGF- ⁇ , TGF ⁇ R, Smad2/3 and Smad4 in rat myocardium were down-regulated (P ⁇ 0.05), indicating that papain can regulate TGF- ⁇ signaling pathway.
  • the expression level of key target genes improves myocardial fibrosis in SHR.
  • the present invention is a major active ingredient, betulinic acid, extracted from the fruit of natural plants, papaya, which is weaker than Cato in terms of blood pressure reduction. Puli, but it can inhibit the oxidative stress and inflammatory reaction of myocardial tissue and reduce the secretion of collagen while lowering blood pressure, thus effectively improving the structural and functional damage caused by hypertension.
  • the invention can solve the defects that the existing antihypertensive drugs have a single action path and large side effects, and provides a basis for refining the blood pressure of the active ingredients of the traditional Chinese medicine and improving myocardial fibrosis.
  • Figure 1 shows the mass spectrometry results of papaya blood components
  • Figure 2 is a graph of primary mass spectrometry (a) and secondary mass spectrometry (b) corresponding to ion peaks at a retention time of 6.05 min.
  • SHR spontaneously hypertensive rat
  • CS SHR+chaenomeles speciosa
  • the chromatographic conditions were: column: Waters C18 column (50 mm ⁇ 2.1 mm, 5 ⁇ m); mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile (0.1% formic acid); elution gradient: 0-0.5 min (B: 0% - 10%), 0.5 - 1.5 min (B: 10%), 1.5 - 2.5 min (B: 10% - 30%), 2.5 - 4.5 min (B: 30% - 65%), 4.5 -10.5 min (B: 65% - 100%), 10.5-12 min (B: 100%); volume flow rate 0.3 mL ⁇ min-1, column temperature 40 ° C, injection volume 5 ⁇ L.
  • the mass spectrometry conditions were: ion source: H-ESI; positive and negative ion mode, positive ion spray voltage: 3000V; negative ion spray voltage: 2500V; evaporator temperature: 350 °C, scanning mode for full scan, mass scan range m/z 100 -1500.
  • papaya bile acid solution accurately weighed papaya bile acid extract (purchased from Sichuan Weikeqi Biotechnology Co., Ltd.) 250mg, 500mg, 1000mg, dissolved in 0.9% volume of normal saline and fixed to volume 100mL, that is, a solution of 2.5mg/mL, 5mg/mL, 10mg/mL, stored in a refrigerator at 4 °C in the dark.
  • captopril solution ready-to-use, use a mortar to grind the captopril tablets into a powder, accurately weigh 150mg, add 0.9% of normal saline solution and dilute to 100mL, which is 1.5 The mg/mL solution was stored in a refrigerator at 4 ° C in the dark.
  • Captopril is an angiotensin-converting enzyme inhibitor (ACE inhibitor or ACEI) that directly inhibits the production of AT II in the heart while dilating blood vessels to lower blood pressure, and indirectly inhibits cardiac sympathetic nerves.
  • ACE inhibitor an angiotensin-converting enzyme inhibitor
  • the release of catecholamines at the periphery which in turn reduces the activation of alpha or beta receptors by catecholamine transmitters, works together to prevent the development of cardiac hypertrophy, so captopril is used to treat hypertension and certain types of congestive heart Depletion.
  • captopril is considered a breakthrough in drug therapy due to its new mechanism of action and revolutionary development process. Captopril was first produced by Bristol-Myers Squibb under the trade name Capoten.
  • the present invention compares the efficacy of papaya betulinic acid and captopril.
  • the rats in each group were sacrificed. Blood was taken from the tail vein using a 1 ml syringe before sacrifice. The plasma was allowed to stand at room temperature for 4 hours and then centrifuged at 3000 r/min for 10 min. The serum was separated and dispensed in a 1 mL centrifuge tube. Reserve in a refrigerator at -20 °C.
  • Rats were sacrificed immediately after taking blood from the tail vein, and the heart and aorta were quickly dissected and completely separated. After washing, they were divided into two parts, some were placed in 4% paraformaldehyde for storage, and some were placed in liquid nitrogen. Then quickly put it into the -80 ° C refrigerator for later use.
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • EF left ventricular ejection fraction
  • FS fractional shortening
  • Each group was administered for 12 weeks. At the end of the 12th week, blood was taken from the tail vein to measure the levels of nitric oxide (NO), endothelin (ET), aspartate aminotransferase (AST) and lactate dehydrogenase in the serum of each group.
  • NO nitric oxide
  • ET endothelin
  • AST aspartate aminotransferase
  • lactate dehydrogenase lactate dehydrogenase
  • Table 2 The main components of papaya's blood components that can act on hypertensive myocardial fibrosis
  • Betulinic acid, berytidine, and Ethyl oleate have good pharmacokinetic parameters, including oral bioavailability (OB), drugs.
  • Drug-like properties (DL), drug half-life (HL) and human colon adenocarcinoma absorption model score (Caco-2), so betulinic acid, quercetin and ethyl oleate may be The main active ingredient of papaya.
  • the original mass was 457, and the structure was similar to that of amygdalin (molecular mass 457.48), but the TCMSP database showed that the polarity of amygdalin was large, and the oral utilization was small, and the peak appeared at the peak. The polarity is small, so the possibility of apricotin is excluded.
  • the second-order mass spectrum (Fig. 2b) is available.
  • the base peak should be 497.39 and the sub-strong peak 479.45 is 18, which is inferred to be a hydroxyl group dehydration to form a fragment peak.
  • the above parameters are consistent with betulinic acid.
  • the analysis of the blood components of papaya confirmed the prediction results of network pharmacology, indicating that betulinic acid is very likely to be the main active ingredient of papaya.
  • betulinic acid can increase the content of endothelium-lowering factor nitric oxide (NO) in serum and decrease the content of endothelin (ET) in spontaneously hypertensive rats.
  • betulinic acid can effectively lower the heart.
  • the damage specificity indexes were AST, LDH, CK and CK-MB, and the P value was less than 0.01 compared with the SHR group.
  • CSBA-H betulinic acid
  • the present invention uses papaya betulinic acid to treat spontaneously hypertensive rats (SHR), and the results show that after 12 weeks of treatment, the blood pressure of each group of SHR is reduced, among which papaya bile fatty acid dose groups Serum endothelin (ET) levels in captopril (CAP) group were significantly decreased (P ⁇ 0.05); nitric oxide (NO) levels were significantly increased (P ⁇ 0.05); papaya betulinic acid in each dose group could be reduced.
  • the contents of MCP-1, TNF- ⁇ , IL-1, IL-6, CRP and MDA showed that papain can reduce the content of inflammatory cytokines in myocardial tissue, reduce the damage of oxidative stress on tissues, and then enhance the anti-oxidation of tissues.
  • the present invention is a main active ingredient, betulinic acid, extracted from the fruit of the natural plant, papaya, which is weaker than the card in terms of blood pressure reduction. Topley, but it can inhibit the oxidative stress and inflammatory response of myocardial tissue and reduce the secretion of collagen while lowering blood pressure, thus effectively improving the structural and functional damage caused by hypertension.
  • the invention can solve the defects that the existing antihypertensive drugs have a single action path and a large side effect, and provide an experimental basis for further research on the mechanism of papalic acid to interfere with hypertensive myocardial fibrosis.

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Abstract

本发明公开了木瓜白桦脂酸在制备抗高血压心肌纤维化药物中的应用，属于生物医药技术领域。本发明应用木瓜白桦脂酸处理自发性高血压大鼠SHR，结果显示，经12周给药治疗后，各组SHR的血压均有所降低，其中木瓜白桦脂酸各剂量组以及卡托普利CAP组的血清内皮素ET含量显著降低；一氧化氮NO含量显著升高；木瓜白桦脂酸各剂量组可以降低MCP-1、TNF-α、IL-1、IL-6、CRP，MDA的含量，显示木瓜白桦脂酸能够减少心肌组织炎症因子的含量，减少氧化应激对组织的损伤，进而增强组织抗氧化能力，能够通过多靶点改善心肌纤维化。

Description

木瓜白桦脂酸在制备抗高血压心肌纤维化药物中的应用 技术领域
本发明属于生物医药技术领域，具体涉及木瓜白桦脂酸在制备抗高血压心肌纤维化药物中的应用。
背景技术
高血压病是危害我国人民身体健康的常见疾病，而心肌纤维化(Myocardial Fibrosis，MF)是高血压病引起的主要心脏病理改变，也是导致各种心血管事件发生的重要原因之一。因此，研究抑制和逆转心肌纤维化具有重要意义。国内外近年来的研究认为心肌纤维化的机制是心肌的正常组织结构中胶原纤维过量积聚，心脏组织中胶原浓度显著升高或胶原成分发生改变的结果，目前多数抗心肌纤维化研究很注重药物对心肌胶原过度增生方面因素的调控，但近来发现心肌胶原降解异常在致心肌纤维化方面日益显露出重要作用。另一方面，高血压心肌纤维化是高血压中后期一种较为严重的并发症，不同于单纯的高血压和其他原因引起的心肌纤维化，常规的降压药和基质金属蛋白酶抑制剂治疗无法在降低血压的同时有效改善心肌纤维化，且均有一定的副作用。目前，中药在高血压病的治疗中具有很多独特的优势，中医中药对改善高血压心肌纤维化的研究成为抗高血压心肌纤维化的热点。
中医药作为我国的传统文化精髓，很多都是祖祖辈辈靠经验积累起来的东西。中医所用的药材确实在一定程度上可以发挥效用。然而，目前中医药的大部分理论都没有经过西医的科学验证，部分药材在发挥效用的基础上也不免带有一定的毒副作用。所以如何通过科学的实验来验证中药药材中真正起作用的物质，将其提炼出来为人类造福，是一件具有重大意义的事情。
发明内容
本发明的目的在于提供木瓜白桦脂酸抗高血压心肌纤维化的应用，从木瓜中提取的主要活性成分白桦脂酸可用于制备抗高血压心肌纤维化的药物，解决西药降压途径单一、副作用大等问题，为提炼中药活性成分降血压和改善心肌纤维化提供依据。
本发明所采取的技术方案是：
白桦脂酸或其药理学上可接受的盐在抗高血压和/或心脏病中的应用。
中文名称：白桦脂酸；
中文别名：丁子香萜；桦木酸；
英文名称：Betulinic acid；
英文别名：3β-hydroxy-lup-20(29)-ene-28-oic acid.；3-Hydroxylup-20(29)-en-28-oic acid；(1R，3aS，5aR，5bR，7aR，9S，11aR，11bR，13aR，13bR)-9-Hydroxy-1-isopropenyl-5a，5b，8，8，11a-pentamethyl-eicosahydro-cyclopenta[a]chrysene-3a-carboxylic acid；Mairin；
CAS号：472-15-1；
分子式：C 30H 48O 3；
分子量：456.71；
结构式：
Figure PCTCN2018115185-appb-000001
高血压心肌纤维化是高血压中后期一种较为严重的并发症，不同于单纯的高血压和其他原因引起的心肌纤维化，常规的降压药和基质金属蛋白酶抑制剂治疗无法同时很好地降低血压和改善心肌纤维化，且均有一定的副作用。而本发明实验证明木瓜白桦脂酸在降低血压的同时能抑制心肌组织的氧化应激和炎症反应水平，减少胶原蛋白的分泌，因而能有效改善高血压引起的心脏结构和功能损害。加上高血压心肌纤维化同时具有高血压和心脏病中的心肌纤维化的特点，所以可以合理的推测木瓜白桦脂酸也可以用于常规的高血压和心脏病(包括心脏病的心肌纤维化)。
除了木瓜白桦脂酸，白桦脂酸还可以提取自蒲桃树叶、白桦树皮等。经过本发明申请人验证，木瓜白桦脂酸具有治疗高血压和/或心脏病的作用，则可以合理的推测提取自蒲桃树叶、白桦树皮等其他植物来源的白桦脂酸也同等的具有此功效。
现有技术中对于白桦脂酸的研究提及白桦脂酸可以选择性地杀死人类黑色素瘤细胞而不杀伤健康细胞；对HIV-1型感染有抑制作用等，但是并未提及白桦脂酸在高血压或心脏病方面具有功效。
优选的，白桦脂酸提取自中药木瓜。
中药木瓜是蔷薇科植物贴梗海棠Chaenomeles speciosa(Sweet)Nakai的果实。于夏、秋二季果实绿黄时采收，置沸水中烫至外皮灰白色，对半纵剖，晒干即可入药。《本草纲目》中记载木瓜能祛湿痹邪气，而心肌纤维化在中医辨证体系中具有血瘀痰湿的特点。所以本发 明申请人以中药木瓜为研究对象，研究中药木瓜中的活性成分及疗效，并通过实验得出了木瓜中提取的主要活性成分白桦脂酸可用于治疗高血压心肌纤维化的结论。
中药木瓜是蔷薇科植物贴梗海棠Chaenomeles speciosa(Sweet)Nakai的果实。不同于蒲桃树叶、白桦树皮，需要消耗大量的植物营养器官而影响植物的生长。中药木瓜为果实，可以大量获得，且不影响植物的生长，有利于提炼得到木瓜白桦脂酸。因为所提取的木瓜白桦脂酸为天然物质，所以本发明的木瓜白桦脂酸可以适用于药物和保健品。
优选的，心脏病为高血压性心脏病。
优选的，高血压性心脏病为高血压心肌纤维化。
优选的，所述应用包括但不限于在药物和/或保健品的应用。
优选的，所述药物和/或保健品为降低机体收缩压、增加心脏射血分数和短轴缩短率的药物和/或保健品。
优选的，所述药物和/或保健品为增加机体血中一氧化氮含量、降低内皮素含量的药物和/或保健品。
一种药物组合物，所述药物组合物中的有效成分为白桦脂酸或其药理学上可接受的盐。
优选的，白桦脂酸提取自中药木瓜。
优选的，心脏病为高血压性心脏病。
优选的，高血压性心脏病为高血压心肌纤维化。
一种保健品，所述保健品中包含白桦脂酸或其药理学上可接受的盐。
优选的，白桦脂酸提取自中药木瓜。
由于白桦脂酸可以从食材中提取，并非合成的物质，可以在允许的范围内添加到保健品中。
本发明的有益效果是：
本发明应用木瓜白桦脂酸处理自发性高血压大鼠(SHR)，结果显示，经12周给药治疗后，各组SHR的血压均有所降低，其中木瓜白桦脂酸各剂量组以及卡托普利(CAP)组的血清内皮素(ET)含量显著降低(P<0.05)；一氧化氮(NO)含量显著升高(P<0.05)；木瓜白桦脂酸各剂量组可以降低MCP-1、TNF-α、IL-1、IL-6、CRP，MDA的含量，显示木瓜白桦脂酸能够减少心肌组织炎症因子的含量，减少氧化应激对组织的损伤，进而增强组织抗氧化能力，能够通过多靶点改善心肌纤维化；超声心动图的结果显示木瓜白桦脂酸高剂量组和CAP组均可以有效增加SHR的心脏射血分数(EF％)和短轴缩短率(FS％)；木瓜白桦脂酸各剂量组均能下调大鼠心肌组织中TGF-β，TGFβR，Smad2/3及Smad4基因的蛋白表达水 平(P<0.05)，表明木瓜白桦脂酸可以通过调节TGF-β信号通路中关键靶基因的表达量，改善SHR的心肌纤维化。
与现有口服降压药和抗心肌纤维化药物相比，本发明是从天然植物的果实——木瓜中提取的一类主要活性成分白桦脂酸，该成分在降压方面虽弱于卡托普利，但是其在降低血压的同时能抑制心肌组织的氧化应激和炎症反应水平，减少胶原蛋白的分泌，因而能有效改善高血压引起的心脏结构和功能损害。
本发明可以解决现有降压药作用途径单一、副作用较大等缺陷，为提炼中药活性成分降血压和改善心肌纤维化提供依据。
附图说明
图1为木瓜入血成分的质谱结果；
图2为保留时间6.05min时离子峰对应的一级质谱(a)和二级质谱(b)图。
具体实施方式
下面结合具体实施例对本发明做进一步的说明，但不限于此。
实施例1
1、具体的实验步骤
(1)网络药理学预测：
①根据TCMSP中药数据库找出木瓜的主要活性成分；
②从GeneCards数据库中找出与高血压心肌纤维化相关的靶基因；
③将两组靶基因结合起来取交集，并根据口服生物利用度(Oral bioavailability)≥30％、类药效(Drug-like Properties)≥0.18、药物半衰期(Drug half-life)≥4，人结肠腺癌细胞吸收模型评分(Caco-2)≥-0.4等相关药物动力学指标筛选出木瓜入血成分中作用于高血压心肌纤维化的主要成分。
(2)血清药物化学验证：
①将10只12周龄的雄性自发性高血压大鼠随机分为5组，包括自发性高血压大鼠模型组(spontaneous hypertensive rat，SHR)和SHR+木瓜(chaenomeles speciosa，CS)组。SHR+CS组给予中药饮片木瓜(康美中药饮片，批号170551083)的醇提液灌胃，用量为4ml/kg，SHR给予等量的0.9％生理盐水的灌胃处理；
②连续灌胃三天并于末次灌胃3小时后使用1ml注射器从尾静脉取血，血浆于室温静置4小时后3000r/min离心10min，分离血清备用；
③分别取SHR及SHR+CS组血淸各0.5ml，分别加入10μL磷酸，涡旋30s后，上样到 用2ml甲醇、2ml水预活化好的SPE小柱，1ml水淋洗一次，淋洗液弃去，再用2ml甲醇洗脱，收集洗脱液，室温下吹干，加200μL甲醇复溶，4℃、10000rpm离心l0min，取上清液，过滤(滤头φ＝0.22μm)，供LC-MS-MS分析；
④通过Prelude SPLC+TSQ Quantiva LC-MS-MS进样分析，由于木瓜的入血成分在血清中浓度较低，易被血清成分信号等掩盖，在全扫描模式下难以直观地检测出来，故采用提取离子流图的方法对化瘀方的入血成分进行逐一比对分析。正、负离子模式下分别得到SHR组和SHR+CS组血清质谱图谱，然后将SHR组图谱设为背景信息，从SHR+CS组图谱上减去SHR的血清背景信息即得到木瓜入血成分的质谱结果，如图1所示。
其中色谱条件为：色谱柱：Waters C18柱(50mm×2.1mm，5μm)；流动相A：水(0.1％甲酸)，流动相B：乙腈(0.1％甲酸)；洗脱梯度：0-0.5min(B：0％-10％)，0.5-1.5min(B：10％)，1.5-2.5min(B：10％-30％)，2.5-4.5min(B：30％-65％)，4.5-10.5min(B：65％-100％)，10.5-12min(B：100％)；体积流量0.3mL·min-1，柱温40℃，进样量5μL。质谱条件为：离子源：H-ESI；采用正、负离子模式，正离子喷雾电压：3000V；负离子喷雾电压：2500V；蒸发器温度：350℃，扫描方式为全扫描，质量扫描范围m/z 100-1500。
(3)药品溶液的制备：
木瓜白桦脂酸溶液的配制：精密称取木瓜白桦脂酸提取物(购自四川省维克奇生物科技有限公司)250mg、500mg、1000mg，加体积分数为0.9％的生理盐水溶解并定容至100mL，即得2.5mg/mL、5mg/mL、10mg/mL的溶液，避光保存于4℃冰箱中备用。
卡托普利溶液的配置：现用现配，用研钵将卡托普利片研磨成粉末状，精密称取150mg，加体积分数0.9％的生理盐水溶解并定容至100mL，即得1.5mg/mL的溶液，避光保存于4℃冰箱中。
卡托普利(Captopril)是一种血管紧张素转化酶抑制剂(ACE inhibitor或ACEI)，它在扩张血管降低血压的同时能直接抑制心脏局部AT II的生成，另一方面间接抑制心脏交感神经末梢释放儿茶酚胺，继而减少儿茶酚胺递质对α或β受体的激活，通过这两个方面共同作用预防心肌肥厚的发生，因此卡托普利被应用于治疗高血压和某些类型的充血性心力衰竭。作为第一种ACEI类药物，由于其新的作用机制和革命性的开发过程，卡托普利被认为是一个药物治疗上的突破。卡托普利最早由百时美施贵宝公司(Bristol-Myers Squibb)生产，商品名是开博通(Capoten)。
本发明采用木瓜白桦脂酸和卡托普利进行疗效的对比。
(4)动物分组实验及给药
将25只12周龄的雄性自发性高血压大鼠随机分为5组，包括自发性高血压大鼠模型组(spontaneous hypertensive rat，SHR)、卡托普利阳性对照组(Captopril，CAP)、木瓜白桦脂酸低剂量组(Chaenomeles speciosa betulinic acid low，CSBA-L)、木瓜白桦脂酸中剂量组(Chaenomeles speciosa betulinic acid middle，CSBA-M)、木瓜白桦脂酸高剂量组(Chaenomeles speciosa betulinic acid high，CSBA-H)。另外取5只12周龄的雄性WKY大鼠作为正常对照组(Normal control，NC)。具体分组见表1。
表1 各组的试剂内容与浓度
Figure PCTCN2018115185-appb-000002
(5)样品的采集
①血液样品的制备
给药12周后处死各组大鼠取样，处死前使用1ml注射器从尾静脉取血，血浆于室温静置4小时后3000r/min离心10min，分离血清，分装于1mL离心管中，密封保存于-20℃的冰箱中备用。
②组织样品的制备
大鼠尾静脉取血后立刻断颈处死，迅速解剖完整分离出心脏和主动脉，冲洗干净后均分为两部分，一部分置于4％多聚甲醛中保存备用，一部分先置于液氮中，然后迅速放入-80℃冰箱备用。
(6)相关指标的测定
①大鼠血压的测定
在给药期间，每周使用小动物无创尾压仪测量各组大鼠的血压水平变化，包括收缩压(systolic blood pressure，SBP)和舒张压(diastolic blood pressure，DBP)。
②大鼠心脏射血分数和短轴缩短率的测定
在给药期间，每周通过M型超声心动图观察大鼠心脏的长轴切面，检测大鼠的左室射血 分数(ejection fraction，EF)以及左室短轴缩短率(fractional shortening，FS)。心肌纤维化病变会造成心脏左室收缩功能的下降，而EF和FS是临床上判断左室收缩能力的首选指标，因此可以用于评价心肌纤维化的病变程度。
③血清中血压和心肌损伤相关指标的测定
各组给药12周，于12周末尾静脉取血测定各组大鼠血清中的一氧化氮(NO)，内皮素(ET)，天门冬氨酸氨基转移酶(AST)、乳酸脱氢酶(LDH)、肌酸激酶(CK)及同工酶(CKMB)的含量，实验步骤按照相关试剂盒说明书操作。
(7)实验结果
①基于网络药理学，通过TCMSP数据库筛选出木瓜的入血成分中能够作用于高血压心肌纤维化的主要成分，结果见表2。
表2 木瓜的入血成分中能够作用于高血压心肌纤维化的主要成分
Figure PCTCN2018115185-appb-000003
表2结果表明Betulinic acid(白桦脂酸)、Quercitrin(槲皮素)和Ethyl oleate(油酸乙酯)均具有良好的药物动力学指标，包括口服生物利用度(Oral bioavailability，OB)、类药效(Drug-like Properties，DL)、药物半衰期(Drug half-life，HL)和人结肠腺癌细胞吸收模型评分(Caco-2)，因此白桦脂酸、槲皮素和油酸乙酯可能就是木瓜发挥作用的主要活性成分。
②木瓜入血成分的质谱分析如图1所示。图1结果显示，保留时间为6.05min时吸收峰面积最大，提示该峰对应的分子可能是木瓜的主要入血成分。因此对保留时间为6.05min的成分做进一步分析，见图2，一级质谱图(图2a)可得其最大响应为496.28，由于为正离子模式，其有可能为(M+39)，其原质量为457，从数据库查得以上结构与苦杏苷(分子质量为 457.48)相近，但由于TCMSP数据库显示苦杏苷的极性较大，且口服利用小，而此峰出现的出峰时极性较小，故排除苦杏苷的可能。二级质谱(图2b)图可得，其基峰应为497.39与次强峰479.45相差18，则推断其为羟基脱水形成碎片峰，以上参数与白桦脂酸相符。通过木瓜入血成分的分析证实了网络药理学的预测结果，表明白桦脂酸极有可能就是木瓜发挥作用的主要活性成分。
③木瓜白桦脂酸对大鼠血压的影响，结果见表3。
表3 木瓜白桦脂酸对大鼠血压的影响
Figure PCTCN2018115185-appb-000004
Group SBP(mmHg) DBP(mmHg)
WKY 125.32±2.74 93.75±3.87
SHR 189.41±5.21 138.53±3.26
CSBA-L 170.27±3.75 127.41±4.51
CSBA-M 163.57±3.28 122.67±3.05
CSBA-H 156.052±4.05 115.21±2.82
CAP 126.31±2.46 98.18±3.24
表3结果表明，白桦脂酸能有效降低自发性高血压大鼠的收缩压(SBP)和舒张压(DBP)，且效果呈剂量依赖性关系(与SHR组相比P值均小于0.01)，但降压效果不及阳性药卡托普利组。
④木瓜白桦脂酸对大鼠心脏功能的影响，结果见表4。
表4 木瓜白桦脂酸对大鼠心脏功能的影响
Figure PCTCN2018115185-appb-000005
Group EF(％) FS(％)
WKY 80.4±2.88 48.5±2.41
SHR 64±3.24 34.2±2.58
CSBA-L 68.6±2.88 36.7±3.75
CSBA-M 70.1±3.16 39.6±1.93
CSBA-H 75.6±1.74 43.2±2.61
CAP 76.4±2.88 41.5±2.64
表4结果表明白桦脂酸能有效提高自发性高血压大鼠的射血分数(EF)和短轴缩短率(FS)，且与SHR组相比P值均小于0.01，其中白桦脂酸高剂量组(CSBA-H)与阳性药卡托普利组效果接近。
⑤木瓜白桦脂酸对大鼠血清中的一氧化氮(NO)，内皮素(ET)，天门冬氨酸氨基转移酶(AST)、乳酸脱氢酶(LDH)、肌酸激酶(CK)及同工酶(CK-MB)的含量，结果见表5。
表5 木瓜白桦脂酸对各组大鼠血清中NO、ET、AST、LDH、CK和CK-MB水平的影响
Figure PCTCN2018115185-appb-000006
Figure PCTCN2018115185-appb-000007
表5结果表明白桦脂酸能增加自发性高血压大鼠血清中内皮舒张因子一氧化氮(NO)的含量以及降低内皮收缩因子内皮素(ET)的含量；此外，白桦脂酸能有效降低心脏损伤特异性指标AST、LDH、CK和CK-MB的含量，且与SHR组相比P值均小于0.01，其中白桦脂酸高剂量组(CSBA-H)对心脏损伤特异性指标(包括AST、CK和CK-MB)的降低效果与阳性药卡托普利组接近，但对NO的上调和对ET的下调效果与卡托普利组相比仍有一定差 距。
综上，本发明应用木瓜白桦脂酸处理自发性高血压大鼠(SHR)，结果显示，经12周给药治疗后，各组SHR的血压均有所降低，其中木瓜白桦脂酸各剂量组以及卡托普利(CAP)组的血清内皮素(ET)含量显著降低(P<0.05)；一氧化氮(NO)含量显著升高(P<0.05)；木瓜白桦脂酸各剂量组可以降低MCP-1、TNF-α、IL-1、IL-6、CRP，MDA的含量，显示木瓜白桦脂酸能够减少心肌组织炎症因子的含量，减少氧化应激对组织的损伤，进而增强组织抗氧化能力，能够通过多靶点改善心肌纤维化；超声心动图的结果显示木瓜白桦脂酸高剂量组和CAP组均可以有效增加SHR的心脏射血分数(EF％)和短轴缩短率(FS％)；木瓜白桦脂酸各剂量组均能下调大鼠心肌组织中TGF-β，TGFβR，Smad2/3及Smad4基因的蛋白表达水平(P<0.05)，表明木瓜白桦脂酸可以通过调节TGF-β信号通路中关键靶基因的表达量，改善SHR的心肌纤维化。
与现有口服降压药和抗心肌纤维化药物相比，本发明是从天然植物的果实——木瓜中提取的一类主要活性成分白桦脂酸，该成分在降压方面虽梢弱于卡托普利，但是其在降低血压的同时能抑制心肌组织的氧化应激和炎症反应水平，减少胶原蛋白的分泌，因而能有效改善高血压引起的心脏结构和功能损害。
本发明可以解决现有降压药作用途径单一、副作用较大等缺陷，为进一步开发木瓜白桦脂酸干预高血压心肌纤维化的机制研究提供实验依据。

Claims (11)

  1. 白桦脂酸或其药理学上可接受的盐在抗高血压和/或心脏病中的应用。
  2. 根据权利要求1所述的应用，其特征在于：白桦脂酸提取自中药木瓜。
  3. 根据权利要求1所述的应用，其特征在于：心脏病为高血压性心脏病。
  4. 根据权利要求1所述的应用，其特征在于：所述应用包括在药物和/或保健品的应用。
  5. 根据权利要求4所述的应用，其特征在于：所述药物和/或保健品为降低机体收缩压、增加心脏射血分数和短轴缩短率的药物和/或保健品。
  6. 根据权利要求4所述的应用，其特征在于：所述药物和/或保健品为增加机体血中一氧化氮含量、降低内皮素含量的药物和/或保健品。
  7. 一种药物组合物，其特征在于：所述药物组合物中的有效成分为白桦脂酸或其药理学上可接受的盐。
  8. 根据权利要求7所述的药物组合物，其特征在于：白桦脂酸提取自中药木瓜。
  9. 根据权利要求7所述的药物组合物，其特征在于：心脏病为高血压性心脏病。
  10. 一种保健品，其特征在于：所述保健品中包含白桦脂酸或其药理学上可接受的盐。
  11. 根据权利要求10所述的保健品，其特征在于：白桦脂酸提取自中药木瓜。
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CN109674800A (zh) * 2019-02-28 2019-04-26 天津国际生物医药联合研究院 白桦酯酸在制备用于治疗肺纤维化疾病的药物中的应用
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1853637A (zh) * 2005-03-11 2006-11-01 中国药科大学 五环三萜类化合物作为糖原磷酸化酶抑制剂的用途
CN108159054A (zh) * 2018-02-12 2018-06-15 南方医科大学 木瓜白桦脂酸在制备抗高血压心肌纤维化药物中的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1853637A (zh) * 2005-03-11 2006-11-01 中国药科大学 五环三萜类化合物作为糖原磷酸化酶抑制剂的用途
CN108159054A (zh) * 2018-02-12 2018-06-15 南方医科大学 木瓜白桦脂酸在制备抗高血压心肌纤维化药物中的应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FU, JIA-YIN: "Betulinic acid ameliorates endothelium-dependent relaxa- tion in L-NAME-induced hypertensive rats by reducing oxidative stress", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 44, no. 3, 1 September 2011 (2011-09-01), pages 385 - 391, XP028309902, ISSN: 0928-0987 *
JIANG, LING .: "Betulinic acid prevents high glucose-induced expression of extracellular matrix protein in cardiac fibroblasts by inhibiting the TGF-beta 1/Smad signaling pathway", MOLECULAR MEDICINE REPORTS, vol. 16, no. 5, 31 December 2017 (2017-12-31), pages 6320 - 6325, XP055630495, ISSN: 1791-2997 *

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