WO2019218986A1 - 鸢尾黄素在治疗鸡坏死性肠炎中的医用用途 - Google Patents

鸢尾黄素在治疗鸡坏死性肠炎中的医用用途 Download PDF

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WO2019218986A1
WO2019218986A1 PCT/CN2019/086738 CN2019086738W WO2019218986A1 WO 2019218986 A1 WO2019218986 A1 WO 2019218986A1 CN 2019086738 W CN2019086738 W CN 2019086738W WO 2019218986 A1 WO2019218986 A1 WO 2019218986A1
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necrotic enteritis
chicken
treatment
clostridium perfringens
medical use
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侯云峰
邓旭明
张传津
刘水
王建锋
朱俊平
聂婧
张建
王婷婷
周永林
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山东广元药业科技有限公司
山东金铸基药业有限公司
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Priority to US16/963,208 priority Critical patent/US11491135B2/en
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  • the invention discloses the medical use of the flavonoid in the treatment of chicken necrotic enteritis, and relates to the application of the flavonoid in the preparation of the medicine for treating chicken necrotic enteritis, and belongs to the technical field of medicine.
  • Clostridium perfringens is an anaerobic Gram-positive Bacillus, widely found in natural soils, water bodies, food, human and animal waste, livestock feed and animal intestines. It is the normal intestinal flora of humans and animals. , is a conditional pathogen. At present, according to the secreted exotoxin, it is divided into A-E a total of 5 serotypes, poultry mainly infected with type A and C type Clostridium perfringens, especially type A. After infection with poultry, Clostridium perfringens mainly causes necrotic enteritis.
  • the symptoms are characterized by chicken spirit euphemism, loose feathers, reduced appetite or abolishment, and blood discharge, and the production performance is seriously degraded.
  • the lesions are mainly concentrated in the small intestine, which is characterized by thinning of the intestinal wall, and there is focal or sliced intestinal mucosal necrosis. According to relevant research statistics, the economic losses caused by necrotic enteritis in the global poultry industry are as high as several billion dollars, which seriously jeopardizes the development of poultry breeding industry.
  • TFP type IV pili
  • TFP is a kind of moving organ that exists on the bacterial cell membrane.
  • TFP enables Clostridium perfringens to have the ability to move on the surface of semi-solid media such as its natural habitat and soft and hard agar. This special mode of movement is called Gliding motility.
  • bacterial functions including Clostridium perfringens adhesion and colonization in the intestine, sliding movement, and biofilm formation are all related to TFP. By inhibiting the function of Clostridium perfringens TFP, it can interfere with the adhesion and colonization of bacteria in the intestine, thereby achieving the purpose of infection against Clostridium perfringens.
  • Iris flavonoid is a naturally occurring isoflavone compound found mainly in the roots and stems of the Iris and Shooting plants of the family Iris.
  • Current research indicates that Iris flavin has biological activities such as anti-inflammatory, anti-cancer, liver-protecting, anti-oxidative and estrogen-like effects.
  • a large number of literatures have reported the pharmacological activities of Iris flavin, but as of now, there is no research on the treatment of chicken necrotic enteritis caused by Clostridium perfringens.
  • the invention provides the medical use of the flavonoid in the treatment of chicken necrotic enteritis, and has good therapeutic effect on chicken necrotic enteritis caused by Clostridium perfringens.
  • the molecular structure of the flavonoids of the present invention is as follows:
  • the molecular formula is: C 16 H 12 O 6 ; molecular weight: 300.263.
  • the invention has the protective effect on the chicken necrotic enteritis caused by Clostridium perfringens infection by the sliding motion inhibition test, the biofilm formation inhibition test and the chicken necrotic enteritis model test of the Clostridium perfringens:
  • Clostridium perfringens standard strain ATCC13124 was anaerobic cultured in liquid BHI medium at 37 ° C for 12 h, after which 300 ⁇ l of the culture was further cultured in liquid BHI and anaerobic cultured at 37 ° C for 5 h. 1 ml of the culture was taken, and the supernatant was discarded by centrifugation at 10,000 g, and the bacterial body weight was suspended in 500 ⁇ l of BHI liquid medium, and the mixture was concentrated twice.
  • a positive control group supplemented with 0.4 ⁇ l of filter-sterilized DMSO (without addition of flavonoids) and a negative control group of 400 ⁇ l of liquid TSB medium were set up, and 24-well plates were placed in an anaerobic culture at 30 ° C for 5 days. After the supernatant was removed, the PBS was washed twice, and dried at room temperature for 30 min. Filter-sterilized 1% crystal violet 400 ⁇ l was added, incubated at room temperature for 30 min, crystal violet was discarded, and washed twice with sterile PBS.
  • 17-day-old male Arbor Acre broiler chickens were orally administered with 0.5 ml (1 ⁇ 10 9 CFUs) of cultured Clostridium perfringens ATCC13124 resuspended in sterile PBS, the next day (18 days) The age was again given the same amount of bacteria to try to colonize, and a model of chick necrotic enteritis was established. In the healthy group, 0.5 ml of sterile PBS was orally administered as a control.
  • the chicks were orally administered with 25 mg/kg of Iris flavin (dissolved in sterile PBS) 4 h before the oral infection (17 days old), and administered once every 12 h.
  • a positive control group in which no treatment was administered and a healthy control group in which no infection was administered were also established.
  • the positive control group and the healthy control group were also weighed and administered orally with the corresponding volume of sterile PBS.
  • the above three groups of 10 chickens in each group were treated with a total of 5 days (treatment to 21 days old). All the chickens were sacrificed by 21-day-old cervical dislocation. The necropsy was taken, and the duodenum was taken to the jejunum.
  • the intestinal pathological changes were observed with the naked eye, and the intestinal damage score was scored according to the degree of intestinal damage (see Figure 3). Intestinal injury score using 0-6 points: 0 points (no obvious damage), 1 point (thin wall thinning, brittle), 2 points (1-5 necrotic lesions appear), 3 points (appears 6-15 A necrotic foci), 4 points (16 or more necrotic lesions appear), 5 points (2-3 mm long flaky necrosis), and 6 points (large diffuse necrosis).
  • the above small intestine was collected, HE stained to make pathological sections, and histopathological changes were observed under the microscope (see Fig. 4).
  • the results of intestinal lesions showed that the pathological changes of the intestinal tract of necrotic enteritis were significantly reduced after treatment with Irisin. Histopathological observation showed that the small intestine villi of the healthy group had intact structure and no hemorrhage and inflammatory exudation; the small intestine villi of the control group were dissolved and the structure was incomplete, accompanied by massive hemorrhage; after treatment with appendix flavin, the above pathology Histological damage was significantly relieved.
  • the results of daily weight gain showed that the daily gain of broiler in the treatment group was similar to that in the healthy group, which was significantly higher than that in the infected group.
  • the positive effect of the present invention is to provide a new medical use of Iris flavin for the treatment of chicken necrotic enteritis, which can significantly reduce the pathological changes of the intestinal tract of the necrotic enteritis chicken, and the Clostridium perfringens
  • the chicken necrotic enteritis has a good therapeutic effect.
  • Figure 1 is a picture showing the sliding motion of Clostridium perfringens on BH A in the case of Iris flavin
  • Figure 2 is a diagram showing the formation of the biofilm of Clostridium perfringens effectively by Iris flavin
  • Figure 3 is a graph showing the intestinal damage score according to the degree of intestinal damage
  • Figure 4 is a photograph of histopathological changes observed under the microscope
  • Figure 5 is a graph showing the effect of Irisin on the daily weight gain of broiler chickens with necrotic enteritis.
  • Treatment of chicken necrotic enteritis as described by flavonoids refers to necrotic enteritis caused by bacteria.
  • the treatment of chicken necrotic enteritis described by Iris flavonoid refers to necrotic enteritis caused by Clostridium perfringens.

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Abstract

提供了一种鸢尾黄素在制备治疗鸡坏死性肠炎药物中的用途，鸢尾黄素用于治疗鸡坏死性肠炎，可显著降低坏死性肠炎鸡只肠道的病理变化程度，对产气荚膜梭菌所致的鸡坏死性性肠炎具有良好的治疗效果。

Description

鸢尾黄素在治疗鸡坏死性肠炎中的医用用途
本申请要求于2018年5月17日提交中国专利局、申请号为201810470739.7、发明名称为“鸢尾黄素在治疗鸡坏死性肠炎中的医用用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明公开了鸢尾黄素在治疗鸡坏死性肠炎中的医用用途，涉及鸢尾黄素在制备治疗鸡坏死性肠炎药物中的应用，属于医药技术领域。
背景技术
产气荚膜梭菌是一种厌氧性革兰氏阳性芽孢杆菌，广泛存在于自然界的土壤、水体、食物、人畜粪便、家畜饲料及动物肠道中，是人和动物的正常肠道菌群，属条件致病菌。目前根据其分泌的外毒素不同，将其分为A-E共个5血清型，家禽主要感染A型及C型产气荚膜梭菌，尤以A型为主。产气荚膜梭菌感染家禽后，主要引起坏死性肠炎，其症状表现为鸡只精神委靡、羽毛松乱、食欲减少或废绝，排血便，生产性能严重下降。病变主要集中在小肠部位，表现为肠壁变薄，有局灶性或成片的肠粘膜坏死脱落。据有关研究统计，全球家禽行业因坏死性肠炎造成的经济损失高达数十亿美元，严重危害了家禽养殖业的发展。
产气荚膜梭菌在肠道内的粘附定植主要是通过其四型菌毛(Type IV pili，TFP)介导的。TFP是一种存在于细菌细胞膜上的一种运动器官，TFP使得产气荚膜梭菌具有在其自然生境和软硬琼脂等半固体的介质表面运动的能力，这种特殊的运动方式被称作滑动运动(Gliding motility)。据研究表明，包括产气荚膜梭菌在肠道的粘附定植、滑动运动、生物被膜的形成等细菌功能都与TFP具有一定的联系。通过抑制产气荚膜梭菌TFP的功能，能够干扰细菌在肠道内的粘附定植，从而达到抗产气荚膜梭菌感染的目的。
通过在饲料中添加抗生素是预防并治疗家禽感染坏死性肠炎的主要手段，然而，由于抗生素大量使用所致的细菌耐药性问题及抗生素残留问 题对公众健康造成了严重威胁，因此，开发安全有效的抗生素替代物正日益成为研究的热点。天然化合物具有毒性较低、来源丰富、安全范围广等优点，是筛选抗生素替代物的重要资源。
鸢尾黄素是一种天然存在的异黄酮类化合物，主要存在于鸢尾科鸢尾属和射干属植物的根、茎中。目前的研究表明，鸢尾黄素具抗炎、抗癌、保肝、抗氧化及雌激素样作用等生物学活性。近年来，大量的文献对鸢尾黄素的药理活性进行了报道，但是，截至目前国内外尚无鸢尾黄素用于治疗产气荚膜梭菌所致鸡坏死性肠炎的相关研究。
发明内容
本发明提供了鸢尾黄素在治疗鸡坏死性肠炎中的医用用途，对产气荚膜梭菌所致的鸡坏死性肠炎具有良好的治疗效果。
本发明所述的鸢尾黄素的分子结构如下所示:
Figure PCTCN2019086738-appb-000001
分子式为:C 16H 12O 6；分子量:300.263。
本发明通过产气荚膜梭菌滑动运动抑制试验、生物被膜形成抑制试验以及雏鸡坏死性肠炎模型试验证鸢尾黄素对产气荚膜梭菌感染所致的鸡坏死性肠炎具有保护作用：
一、滑动运动抑制试验
产气荚膜梭菌标准株ATCC13124于液体BHI培养基37℃厌氧培养12h，之后取300μl该培养物继续培养于液体BHI中，37℃厌氧培养5h。取1ml培养物，10000g离心弃上清，菌体重悬于500μl BHI液体培养基中，使之二倍浓缩。之后取5μl浓缩的菌液分别滴加于预先制备并于37℃烘箱干燥1h的含8μg/ml、32μg/ml鸢尾黄素的0.7％BHIA的平板上，37℃厌氧培养48h，采集图像(参见图1)。结果表明，8μg/ml及32μg/ml鸢尾 黄素均能显著抑制产气荚膜梭菌在BHIA上的滑动运动，且32μg/ml鸢尾黄素作用效果更为明显。
二、生物被膜形成抑制试验
产气荚膜梭菌于液体BHI中37℃厌氧培养12h，离心弃上清，用灭菌PBS洗涤一次，之后用TSB液体培养基重悬并调整至OD 600nm＝0.1，取400μl调整后的细菌培养物，加至24孔板中，之后与细菌培养物内分别加入不同浓度的鸢尾黄素，使得24孔板内鸢尾黄素的终浓度分别为4μg/ml、8μg/ml、16μg/ml及32μg/ml，另设立加入0.4μ1过滤灭菌的DMSO(不加入鸢尾黄素)的阳性对照组以及400μ1液体TSB培养基的阴性对照组，24孔板置于30℃厌氧培养5d。之后吸弃上清，灭菌PBS洗两次，室温干燥30min，加入过滤灭菌的1％结晶紫400μ1，室温孵育30min，弃结晶紫，再次用灭菌PBS洗两次。向每孔中加入33％乙酸溶解结晶紫，吹打混匀后取300μl分别加入96孔板的3个独立孔中，每孔100μ1，于酶标仪570nm测定吸光值，根据结晶紫吸光值计算生物被膜形成率。结果表明，鸢尾黄素能够有效抑制产气荚膜梭菌生物被膜的形成(参见图2)。
三、雏鸡坏死性肠炎模型试验的治疗学研究
1、雏鸡坏死性肠炎模型
取17日龄的雄性爱拔益加(Arbor Acre)肉仔鸡经口给予0.5ml(1×10 9CFUs)重悬于灭菌PBS的产气荚膜梭菌ATCC13124培养物，次日(18日龄)再次给予相同菌量的菌液以攻菌，建立雏鸡坏死性肠炎模型，健康组鸡只经口给予0.5ml灭菌PBS作为对照。
2、肠道病变评分试验
雏鸡经口攻菌感染前4h(17日龄)按鸡只体重经口给予25mg/kg的鸢尾黄素(溶解于灭菌PBS)，每12h给药一次。另设立不给药治疗的阳性对照组及不攻菌感染的健康对照组，阳性对照组与健康对照组鸡只同样称重并按体重经口给予相应体积的灭菌PBS。上述三组每组10只鸡，治疗组共给药治疗5天(治疗至21日龄)。21日龄颈椎脱臼处死全部鸡只，剖检，取十二指肠至空肠，肉眼观察肠道病理变化，根据肠道损伤程度进行 肠道损伤评分(参见图3)。肠道损伤评分采用0-6分制:0分(没有明显损伤)、l分(肠壁变薄、变脆)、2分(出现1-5个坏死灶)、3分(出现6-15个坏死灶)、4分(出现16个或16个以上坏死灶)、5分(出现2-3cm长的片状坏死)、6分(出现大片的弥漫性坏死)。另将上述小肠采集病料，HE染色制作病理切片，镜下观察病理组织学变化(参见图4)。
攻菌期间每日对全部肉鸡称重，计算平均体重及日增重，以考察鸢尾黄素治疗后对患坏死性肠炎肉鸡日增重的影响(参见图5)。
肠道病变评分结果表明，经鸢尾黄素治疗后，显著降低了坏死性肠炎鸡只肠道的病理变化程度。病理组织学观察结果表明，健康组肉鸡小肠肠绒毛结构完整，无出血及炎性渗出；对照组肉鸡小肠绒毛坏死溶解，结构不完整，伴有大量出血；经鸢尾黄素治疗后，上述病理组织学损伤明显缓解。日增重结果表明，治疗组肉鸡日增重与健康组肉鸡相近，显著高于感染组肉鸡。
综合以上结果，说明鸢尾黄素对产气荚膜梭菌所致的鸡坏死性肠炎具有良好的保护作用。
本发明的积极效果在于:提供了鸢尾黄素的一种新医用用途，用于治疗鸡坏死性肠炎，可显著降低坏死性肠炎鸡只肠道的病理变化程度，对产气荚膜梭菌所致的鸡坏死性肠炎具有良好的治疗效果。
附图说明
图1为鸢尾黄素均能显著抑制产气荚膜梭菌在BH工A上的滑动运动图片；
图2为鸢尾黄素能够有效抑制产气荚膜梭菌生物被膜的形成图；
图3为根据肠道损伤程度进行肠道损伤评分图；
图4为镜下观察病理组织学变化照片；
图5为鸢尾黄素治疗后对患坏死性肠炎肉鸡日增重的影响图。
具体实施方式
实施例1
鸢尾黄素在制备治疗鸡坏死性肠炎药物中的应用，以鸢尾黄素为活性制成药学上可接受任何剂型。
实施例2
鸢尾黄素所述的治疗鸡坏死性肠炎指由细菌引起的坏死性肠炎。
实施例3
鸢尾黄素所述的治疗鸡坏死性肠炎是指由产气荚膜梭菌引起的坏死性肠炎。

Claims (4)

  1. 鸢尾黄素在制备治疗鸡坏死性肠炎药物中的医用用途。
  2. 权利要求1所述鸢尾黄素在制备治疗鸡坏死性肠炎药物中的医用用途中涉及的鸡坏死性肠炎指由细菌引起的坏死性肠炎。
  3. 权利要求1所述鸢尾黄素在制备治疗鸡坏死性肠炎药物中的医用用途中涉及的鸡坏死性肠炎指由产气荚膜梭菌引起的坏死性肠炎。
  4. 以鸢尾黄素为活性成分制成药学上可接受任何剂型。
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