WO2021135798A1 - 桑皮苷a及其衍生物在制备保护肠道屏障的药物中的应用 - Google Patents

桑皮苷a及其衍生物在制备保护肠道屏障的药物中的应用 Download PDF

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WO2021135798A1
WO2021135798A1 PCT/CN2020/133474 CN2020133474W WO2021135798A1 WO 2021135798 A1 WO2021135798 A1 WO 2021135798A1 CN 2020133474 W CN2020133474 W CN 2020133474W WO 2021135798 A1 WO2021135798 A1 WO 2021135798A1
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mice
derivatives
drugs
mulberroside
intestinal barrier
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孔令东
李建梅
孙洋
郁蓉
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南京大学
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

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  • the invention relates to the application of mulberryside A and its derivatives in the preparation of drugs for protecting the intestinal barrier, and belongs to the technical field of medicine.
  • the intestine is the part where organisms are in direct contact with the external environment, including various microorganisms and food. It has the functions of absorbing nutrients, electrolytes, and water. It is very important for maintaining the body's homeostasis and preventing the invasion of pathogens and harmful substances.
  • the intestinal barrier is a physical and immune defense barrier between the external environment and the internal environment of the organism. It is composed of a variety of elements. Intestinal flora plays a vital role in maintaining human health.
  • Mulberry glycoside A is a chemical substance with a molecular formula of C 26 H 32 O 14 , which is an active ingredient of stilbene glycosides in mulberry bark and mulberry branches. Studies have shown that mulberryside A has antitussive and asthmatic, inhibiting tyrosinase and antioxidant activities, but there are no reports about mulberryside A regulating intestinal flora disorders and inhibiting neuroinflammation.
  • the purpose of the present invention is to provide an application of Morusin A and its derivatives in the preparation of drugs for protecting the intestinal barrier.
  • the present invention tested the effect of Moringoside A and its derivatives on the neuroinflammation in the hippocampus of high-fructose diet mice, the effect of Moringoside A and its derivatives on the intestinal barrier damage of high-fructose diet mice and its effect on high-fructose diet mice. Effects of Fructose Diet on Intestinal Flora Disorders in Mice. It was found that Morusin A and its derivatives can significantly inhibit the activation of central microglia, the levels of inflammatory factors (interleukin (IL)-1 ⁇ , IL-6, TNF- ⁇ ) and neuron loss in the hippocampus of mice on a high-fructose diet.
  • IL interleukin
  • mulberryside A and its derivatives can be used to prepare drugs for the prevention and/treatment of central nervous system inflammation and related neurodegenerative diseases caused by intestinal barrier damage, and can reshape high
  • the intestinal flora disorder caused by the fructose diet is used to prepare drugs for regulating the intestinal flora disorder.
  • mulberryside A and its derivatives are the active ingredients, and the derivatives are resveratrol and oxidized resveratrol Retrol.
  • the protection of the intestinal barrier includes inhibiting the inflammation of the central nervous system caused by the damage of the intestinal barrier and regulating the disturbance of the intestinal flora.
  • the medicine of the present invention includes Morusin A or its derivatives, and a pharmaceutically acceptable carrier.
  • the pharmaceutical dosage form of the present invention is a solid preparation or a liquid preparation.
  • the medicament of the present invention is usually used in an intragastric administration mode, but other administration modes can also be adopted, and the administration dosage is 5-40 mg/kg.
  • the beneficial effects of the present invention discloses the new use of Moringoside A and its derivatives in the preparation of drugs for protecting the intestinal barrier.
  • the present invention proves through pharmacological experiments that Moringoside A and its derivatives can protect the intestinal tract
  • the barrier function can be used to prepare drugs for the prevention and/treatment of central nervous system inflammation and related neurodegenerative diseases caused by intestinal barrier damage, and can reshape the intestinal flora disorder caused by high fructose diet and improve the intestinal barrier damage , Used to prepare drugs for regulating intestinal flora disorders.
  • Figure 1 shows the mRNA expression levels of the inflammatory factor TNF- ⁇ in the hippocampus of mice in different treatment groups in Example 1;
  • Figure 2 shows the mRNA expression levels of the inflammatory factor IL-1 ⁇ in the hippocampus of mice in different treatment groups in Example 1;
  • Figure 3 shows the mRNA expression level of IL-6, an inflammatory factor, in the hippocampus of mice in different treatment groups in Example 1;
  • Figure 4 is a transmission electron micrograph of the ileum and colon tissues of mice in different treatment groups in Example 2;
  • FIG. 5 shows the serum endotoxin levels of mice in different treatment groups in Example 2.
  • Figure 6 shows the expression levels of ZO-1 protein in the colon of mice in different treatment groups in Example 2;
  • Figure 7 shows the expression levels of the colonic tight junction protein occludin of mice in different treatment groups in Example 2;
  • Figure 8 shows the relative abundance of pathogenic bacteria Helicobacter and Mucispirillum in the feces of mice in different treatment groups in Example 3;
  • Figure 9 shows the content of short-chain fatty acids in the feces of mice in different treatment groups in Example 3.
  • the mulberryside A and resveratrol in the present invention can be extracted in a laboratory or purchased as high-purity products.
  • the Morusin A and resveratrol used in the following examples were purchased from Chengdu Pusi Biotechnology Co., Ltd., but are not limited thereto.
  • Example 1 The effect of mulberryside A on neuroinflammation in the hippocampus of mice on a high fructose diet
  • the normal group was given ordinary feed, and the model group was given fructose-containing feed. Other feeding conditions were the same in the two groups.
  • the model group continued to be fed with fructose feed, while the mulberryside A administration group and the resveratrol administration group were fed with fructose feed, the mulberryside A or resveratrol was made into a suspension with normal saline and then injected Stomach administration, once a day by gavage. After 8 weeks of administration, the treated mice were quickly removed from the hippocampus on an ice table, RNA was extracted, and real-time fluorescent quantitative PCR method was used to detect the expression levels of inflammatory factors IL-1 ⁇ , IL-6, and TNF- ⁇ .
  • FIG. 1 The mRNA expression levels of inflammatory factors TNF- ⁇ , IL-1 ⁇ , and IL-6 in the hippocampus of mice in different treatment groups are shown in Figure 1, Figure 2 and Figure 3, respectively.
  • C represents the normal group
  • F represents the fructose model group
  • M1 represents the 20mg/kg mulberryside A administration group
  • M2 represents the 40mg/kg mulberryside A administration group
  • R represents the 20mg/kg white Veratrol administration group.
  • Example 2 The effect of mulberryside A on the intestinal barrier damage of high-fructose diet mice
  • the model group continued to be fed with fructose feed, while the mulberryside A administration group and the resveratrol administration group were fed with fructose feed, the mulberryside A or resveratrol was made into a suspension with normal saline and then injected Stomach administration, once a day by gavage.
  • the mice were anesthetized and the blood was collected, and the serum endotoxin (LPS) level was detected by a limulus kit; the mice ileum and colon tissues of the mice were quickly taken on the ice table, and the intestines were observed by transmission electron microscopy.
  • the ultrastructural changes of epithelial cells were detected by Western blot method to detect the expression levels of colonic tight junction proteins occludin and ZO-1 protein in each group.
  • FIG. 5 The results of serum endotoxin levels of mice in different treatment groups are shown in Figure 5, the results of colonic ZO-1 protein expression levels are shown in Figure 6, and the results of tight junction protein occludin expression levels are shown in Figure 7.
  • C represents the normal group
  • F represents the fructose model group
  • M1 represents the 20mg/kg mulberryside A administration group
  • M2 represents the 40mg/kg mulberryside A administration group
  • R represents the 20mg/kg mulberry glycoside A administration group.
  • Retrol administration group the results of serum endotoxin levels of mice in different treatment groups are shown in Figure 5, the results of colonic ZO-1 protein expression levels are shown in Figure 6, and the results of tight junction protein occludin expression levels are shown in Figure 7.
  • C represents the normal group
  • F represents the fructose model group
  • M1 represents the 20mg/kg mulberryside A administration group
  • M2 represents the 40mg/kg mulberryside A administration group
  • R represents the 20
  • Example 3 The effect of mulberryside A on the disturbance of intestinal flora in mice fed with high fructose diet
  • the model group continued to be fed with fructose feed, while the mulberryside A administration group and the resveratrol administration group were fed with fructose feed, the mulberryside A or resveratrol was made into a suspension with normal saline and then injected Stomach administration, once a day by gavage. After 8 weeks of administration, fresh feces of each group of mice were taken for 16S rRNA sequencing analysis of fecal flora, and the content of short-chain fatty acids was detected by gas chromatography.
  • FIG 8 The relative abundance results of the pathogenic bacteria Helicobacter and Mucispirillum in the feces of mice in different treatment groups are shown in Figure 8, and the results of short-chain fatty acid content are shown in Figure 9, where C represents the normal group, F represents the fructose model group, and M2 represents 40mg/kg mulberry. A administration group, R represents the 20mg/kg resveratrol administration group.
  • Figure 8A is the relative abundance of the pathogen Helicobacter
  • Figure 8B is the relative abundance of the pathogen Mucispirillum
  • 9-1 is the acetic acid content
  • Figure 9-2 is the propionic acid content
  • Figure 9-3 Is the butyric acid content.

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Abstract

一种桑皮苷A及其衍生物白藜芦醇在制备保护肠道屏障的药物中的新应用，所述药物中，桑皮苷A或其衍生物为活性成分。通过药理实验研究了桑皮苷A及其衍生物对高果糖饮食小鼠海马区神经炎症的影响、对高果糖饮食小鼠肠道屏障损伤的影响以及对高果糖饮食小鼠肠道菌群紊乱的影响，发现了桑皮苷A及其衍生物可明显抑制高果糖饮食小鼠中枢小胶质细胞活化和炎症因子水平，证实了桑皮苷A及其衍生物具有保护肠道屏障的作用，可用于制备预防和/治疗由肠道屏障损伤引起的中枢神经炎症及相关的神经退行性疾病药物，并且可重塑高果糖饮食引起的肠道菌群紊乱，用于制备调节肠道菌群紊乱的药物。

Description

桑皮苷A及其衍生物在制备保护肠道屏障的药物中的应用 技术领域
本发明涉及桑皮苷A及其衍生物在制备保护肠道屏障的药物中的应用，属于医药技术领域。
背景技术
随着人们生活水平的提高和饮食结构的改变，饮食果糖摄入量特别是含有高果糖玉米糖浆的软饮料摄入量逐年增加。近十年来，临床研究和实验证据显示高果糖饮食容易引起肠道菌群紊乱和中枢神经炎症。
肠道是生物体与外界环境包括各类微生物和食物等直接接触的部位，它具有吸收营养、电解质和水等作用，对维持机体稳态、防止病原体和有害物质入侵非常重要。肠道屏障是外界环境和生物体内环境之间的物理和免疫防御屏障，它由多种要素共同构成。肠道菌群对维持人类健康起到了至关重要的作用，在正常生理条件下，它们能促进肠道免疫系统生长发育，调节肠道上皮细胞生长分化和维持肠道屏障功能；并能通过发酵或代谢纤维素等难消化的物质，为宿主提供能量以及维生素、氨基酸等必需营养物质，还能通过竞争生态位防止病原微生物定植。大量研究发现，高果糖饮食会导致肠道屏障损伤，从而引起肠道菌群紊乱和中枢神经炎症，并导致神经退行性疾病。
目前，尚无有效的保护肠道屏障的药物。
桑皮苷A是一种化学物质，分子式是C 26H 32O 14，是桑白皮、桑枝中一种二苯乙烯苷类活性成分。研究表明桑皮苷A具有镇咳平喘、抑制酪氨酸酶以及抗氧化等活性，但目前尚未见有关桑皮苷A调节肠道菌群紊乱和抑制神经炎症的报道。
发明内容
本发明的目的是提供一种桑皮苷A及其衍生物在制备保护肠道屏障的药物中的应用。
本发明通过药理实验测试桑皮苷A及其衍生物对高果糖饮食小鼠海马区神经炎症的影响、桑皮苷A及其衍生物对高果糖饮食小鼠肠道屏障损伤的影响以及对高果糖饮食小鼠肠道菌群紊乱的影响。发现了桑皮苷A及其衍生物可明显抑制高果糖饮食小鼠中枢小胶质细胞活化、炎症因子(白介素(IL)-1β、IL-6、TNF-α)水平和海马区神经元丢失，证实了桑皮苷A及其衍生物具有保护肠道屏障的作用，可用于制备预防和/治疗由肠道屏障损伤引起的中枢神经 炎症及相关的神经退行性疾病药物，并且可重塑高果糖饮食引起的肠道菌群紊乱，用于制备调节肠道菌群紊乱的药物。
本发明的技术方案如下：
桑皮苷A及其衍生物在制备保护肠道屏障的药物中的应用,所述药物中，桑皮苷A或其衍生物为活性成分，所述衍生物为白藜芦醇、氧化白藜芦醇。
所述保护肠道屏障包括抑制由肠道屏障损伤引起的中枢神经炎症和调节肠道菌群紊乱。
本发明所述的药物包括桑皮苷A或其衍生物，以及药学上可接受的载体。
本发明所述的药物剂型为固体制剂或液体制剂。
本发明的药物通常以灌胃给药方式使用，也可以采用其它给药方式，给药用量为5-40mg/kg。
本发明的有益效果：本发明公开了桑皮苷A及其衍生物在制备保护肠道屏障的药物中的新用途，本发明通过药理实验证实了桑皮苷A及其衍生物具有保护肠道屏障的作用，可用于制备预防和/治疗由肠道屏障损伤引起的中枢神经炎症及相关的神经退行性疾病药物，并且可重塑高果糖饮食引起的肠道菌群紊乱，改善肠道屏障损伤，用于制备调节肠道菌群紊乱的药物。
附图说明
图1为实施例1中不同处理组小鼠的海马组织中炎症因子TNF-α的mRNA表达水平；
图2为实施例1中不同处理组小鼠的海马组织中炎症因子IL-1β的mRNA表达水平；
图3为实施例1中不同处理组小鼠的海马组织中炎症因子IL-6的mRNA表达水平；
图4为实施例2中不同处理组小鼠的回肠和结肠组织的透射电镜图；
图5为实施例2中不同处理组小鼠的血清内毒素水平；
图6为实施例2中不同处理组小鼠的结肠ZO-1蛋白的表达水平；
图7为实施例2中不同处理组小鼠的结肠紧密连接蛋白occludin的表达水平；
图8为实施例3中不同处理组小鼠粪便中病原菌Helicobacter和Mucispirillum的相对丰度；
图9为实施例3中不同处理组小鼠粪便中短链脂肪酸含量。
具体实施方式
下面结合附图和具体实施例对本发明的技术方案作详细说明。
本发明中的桑皮苷A和白藜芦醇可在实验室提取或商购高纯品。下述实施例中所用的桑皮苷A和白藜芦醇均购于成都普思生物科技股份有限公司，但不限于此。
实施例1 桑皮苷A对高果糖饮食小鼠海马区神经炎症的影响
实验方法：C57BL/6N小鼠随机分为正常组(n＝15)和模型组(n＝60)，正常组给予普通饲料，模型组给予含果糖饲料，其它饲养条件两组均相同。4周后，模型组小鼠随机分成4组，分别为果糖模型组(n＝15)、20mg/kg桑皮苷A给药组(n＝15)、40mg/kg桑皮苷A给药组(n＝15)和20mg/kg白藜芦醇给药组(n＝15)。模型组继续用果糖饲料喂养，桑皮苷A给药组和白藜芦醇给药组在用果糖饲料喂养的同时，将桑皮苷A或白藜芦醇用生理盐水制成悬浮液后灌胃给药，每天灌胃1次。给药8周后，将处理小鼠快速在冰台上取出海马组织，提取RNA并采用实时荧光定量PCR方法检测炎症因子IL-1β、IL-6、TNF-α表达水平。
实验结果：
不同处理组小鼠的海马组织中炎症因子TNF-α、IL-1β、IL-6的mRNA表达水平结果分别见图1、图2和图3。在图1-3中，C表示正常组，F表示果糖模型组，M1表示20mg/kg桑皮苷A给药组，M2表示40mg/kg桑皮苷A给药组，R表示20mg/kg白藜芦醇给药组。由图1-3可以看出，与果糖模型组小鼠比较，桑皮苷A和白藜芦醇给药后，小鼠海马区TNF-α、IL-1β、IL-6的mRNA水平显著降低，这表明桑皮苷A和白藜芦醇可以抑制高果糖饮食小鼠海马区神经炎症。
实施例2 桑皮苷A对高果糖饮食小鼠肠道屏障损伤的影响
见上实验方法：C57BL/6N小鼠随机分为正常组(n＝15)和模型组(n＝60)，正常组给予普通饲料，模型组给予含果糖饲料，其它饲养条件两组均相同。4周后，模型组小鼠随机分成4组，分别为果糖模型组(n＝15)、20mg/kg桑皮苷A给药组(n＝15)、40mg/kg桑皮苷A给药组(n＝15)和20mg/kg白藜芦醇给药组(n＝15)。模型组继续用果糖饲料喂养，桑皮苷A给药组和白藜芦醇给药组在用果糖饲料喂养的同时，将桑皮苷A或白藜芦醇用生理盐水制成悬浮液后灌胃给药，每天灌胃1次。给药8周后，将小鼠麻醉取血，采用鲎试剂盒检测血清内毒素(LPS)水平；将处理小鼠快速在冰台上分别取小鼠回肠和结肠组织，采用透射电镜方法观察肠上皮细胞的超微结构变化，采用Western blot方法检测各组结肠紧密连接蛋白occludin和ZO-1蛋白的表达水平。
实验结果：
不同处理组小鼠的回肠和结肠组织的透射电镜图结果见图4，其中，C表示正常组，F表示果糖模型组，M2表示40mg/kg桑皮苷A给药组，R表示20mg/kg白藜芦醇给药组。由图4可见，与果糖模型组小鼠比较，桑皮苷A和白藜芦醇给药后，小鼠回肠和结肠的粘膜层和肌层厚度增 加，隐窝数量增加，固有层水肿程度减轻，上皮细胞线粒体结构和紧密连接结构正常，相邻上皮细胞间隙距离较小。
不同处理组小鼠的血清内毒素水平结果见图5，结肠ZO-1蛋白的表达水平结果见图6，紧密连接蛋白occludin的表达水平结果见图7。图5-7中，C表示正常组，F表示果糖模型组，M1表示20mg/kg桑皮苷A给药组，M2表示40mg/kg桑皮苷A给药组，R表示20mg/kg白藜芦醇给药组。由图5-7可见，与果糖模型组小鼠比较，桑皮苷A和白藜芦醇给药后，结肠ZO-1和紧密连接蛋白occludin的表达水平显著增加，而血清内毒素水平显著降低。
实施例3 桑皮苷A对高果糖饮食小鼠肠道菌群紊乱的影响
见上实验方法：C57BL/6N小鼠随机分为正常组(n＝15)和模型组(n＝60)，正常组给予普通饲料，模型组给予含果糖饲料，其它饲养条件两组均相同。4周后，模型组小鼠随机分成4组，分别为果糖模型组(n＝15)、20mg/kg桑皮苷A给药组(n＝15)、40mg/kg桑皮苷A给药组(n＝15)和20mg/kg白藜芦醇给药组(n＝15)。模型组继续用果糖饲料喂养，桑皮苷A给药组和白藜芦醇给药组在用果糖饲料喂养的同时，将桑皮苷A或白藜芦醇用生理盐水制成悬浮液后灌胃给药，每天灌胃1次。给药8周后，取各组小鼠新鲜粪便进行粪便菌群16S rRNA测序分析，采用气相色谱方法检测短链脂肪酸含量。
实验结果：
不同处理组小鼠粪便中病原菌Helicobacter和Mucispirillum的相对丰度结果见图8，短链脂肪酸含量结果见图9，其中，C表示正常组，F表示果糖模型组，M2表示40mg/kg桑皮苷A给药组，R表示20mg/kg白藜芦醇给药组。在图8中，图8A为病原菌Helicobacter的相对丰度，图8B为病原菌Mucispirillum的相对丰度；在图9中，9-1为乙酸含量，图9-2为丙酸含量，图9-3为丁酸含量。由图8-9可见，桑皮苷A和白藜芦醇给药后，小鼠肠道菌群β多样性发生明显改变，病原菌Helicobacter和Mucispirillum的相对丰度显著降低，粪便短链脂肪酸含量显著增加。

Claims (4)

  1. 桑皮苷A及其衍生物在制备保护肠道屏障的药物中的应用,其特征在于，所述药物中，桑皮苷A或其衍生物为活性成分，所述衍生物为白藜芦醇。
  2. 如权利要求1所述的应用，其特征在于，所述保护肠道屏障包括抑制由肠道屏障损伤引起的中枢神经炎症和调节肠道菌群紊乱。
  3. 如权利要求1所述的应用，其特征在于，所述的药物包括桑皮苷A或其衍生物，以及在药学上可接受的载体。
  4. 如权利要求1或2或3所述的应用，其特征在于，所述药物的剂型为固体制剂或液体制剂。
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