CN117503890B - 一种灵芝砂仁复合物gfac-7及其在制备预防和/或治疗胃溃疡药物中的应用 - Google Patents
一种灵芝砂仁复合物gfac-7及其在制备预防和/或治疗胃溃疡药物中的应用 Download PDFInfo
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Abstract
本发明提供了一种灵芝砂仁复合物GFAC‑7及其在制备预防和/或治疗受试者胃溃疡产品中的应用,属于胃溃疡的预防和治疗技术领域。本发明首次发现灵芝砂仁复合物GFAC‑7在预防或治疗胃溃疡方面以及抑制幽门螺杆菌方面均取得较好效果,治疗后明显改善小鼠胃脏器指数、溃疡面积、溃疡指数和溃疡抑制率,能够改善胃溃疡小鼠胃损伤后期的炎性浸润,减少炎症损伤,能够增加小鼠抗氧化的能力,降低氧化损伤,促进胃黏膜的完整和胃内环境的稳态。灵芝砂仁复合物GFAC‑7通过减轻炎症损伤、提高胃抗氧化能力以及维持胃内环境稳态对胃溃疡有预防和治疗作用,将GFAC‑7开发成为具有预防保护胃溃疡产品具有重要意义。
Description
技术领域
本发明属于胃溃疡的预防和治疗技术领域,具体涉及一种灵芝砂仁复合物GFAC-7及其在制备预防和/或治疗胃溃疡药物中的应用。
背景技术
胃溃疡是一种常见病、多发病,不同的饮食、作息、生活习惯、情绪和遗传因素等都会直接或者间接影响胃溃疡的发展进程,但大量地酗酒仍是病情反复的主要因素之一。过量饮酒所诱导的胃溃疡主要由于氧化应激和炎症反应所引起,主要表现包括胃黏膜表面的广泛糜烂和出血,并且伴随有大量的促炎因子和氧自由基的产生,以及免疫细胞在溃疡区域聚集并伴随着淋巴细胞的分化。炎症细胞的积累和ROS的释放参与了溃疡的炎症反应和氧化损伤,这种积累导致广泛的出血性溃疡和组织坏死,从而加剧胃粘膜损伤的程度。溃疡的并发症,如出血和穿孔,严重时甚至会危及生命。内窥镜和药物治疗的进步并没有大大降低与此类出血相关的死亡率,因为合并症现在是这些患者死亡的主要原因。在有多种合并症的患者中越来越多地使用抗血栓药物,这给溃疡管理带来了新的挑战。因此迫切需要前瞻性研究来确定胃溃疡护理和治疗的研究方向。
灵芝作为传统中药材,具有良好的免疫调节功能,灵芝中主要含有灵芝三萜、灵芝多糖、甾体、蛋白质和核苷等多类化合物。其中三萜类化合物具有抗高血压、降胆固醇、保肝和抗组胺作用,以及抗肿瘤和抗血管生成活性。已经证明,灵芝当中的三萜类化合物,特别是灵芝酸(GAs),是重要的生物活性成分,负责多种生物学效应,包括抗炎、抗肿瘤、抗HIV和降血脂的活性。据报道,灵芝多糖的化学特性,具有抗氧化、抗肿瘤和抗菌活性。这里我们可以推测,多糖的抗氧化特性,特别是自由基清除活性,似乎与抗氧化酶(SOD、CAT和GSH)活性的增加更相关,而抗肿瘤潜力似乎与宿主的免疫功能特别相关。砂仁是一味化湿药物,为姜科植物阳春砂、绿壳砂或者海南砂的干燥成熟果实。药理学研究表明,砂仁具有降血糖、抗炎镇痛、抗菌以及抗氧化等多种药理活性。L-谷氨酰胺,是蛋白质合成中的编码氨基酸,哺乳动物非必需氨基酸,在体内可以由葡萄糖转变而来。
灵芝砂仁复合物是由以灵芝、砂仁、L-谷氨酰胺为主要原料组成的复合物(Ganoderma fructus amomi complex,以下简称GFAC-7)。本研究选用易于处理并且适合药物测试的C57BL/6小鼠品系作为胃溃疡造模实验动物,探究GFAC-7对乙醇诱导小鼠胃溃疡的保护作用,为GFAC-7产品的开发提供实验数据和科学依据。
发明内容
有鉴于此,本发明的目的之一在于提供一种灵芝砂仁复合物(Ganoderma fructusamomi complex,以下简称GFAC-7),所述GFAC-7包含:灵芝粉;砂仁粉;L-谷氨酰胺;西兰花种子水提物;小茴香;肉豆蔻;岩藻多糖;糖醇。
优选地,所述GFAC-7包含:以重量百分比计,灵芝粉2-4%;砂仁粉8-12%;L-谷氨酰胺45-55%;西兰花种子水提物1-3%;小茴香0.1-0.5%;肉豆蔻0.4-0.8%;岩藻多糖0.4-0.8%;糖醇30-35%。
优选地,所述GFAC-7包含:以重量百分比计,灵芝粉3.33%;砂仁粉10%;L-谷氨酰胺50%;西兰花种子水提物1.67%;小茴香0.33%;肉豆蔻0.67%;岩藻多糖0.67%;糖醇33.33%。
优选地,所述糖醇为赤藓糖醇、麦芽糖醇、异麦芽糖醇、木糖醇、D-甘露糖醇中的一种或多种。
优选地,所述糖醇为赤藓糖醇。
经过长时间的探索和研究,申请人意外的发现,单独采用灵芝砂仁复合物中的一种或多种组分均无法很好地预防和/或治疗胃溃疡,而本发明特定含量的灵芝砂仁复合物GFAC-7却表现出较好的疗效。
因此,本发明的另一个目的在于提供包含所述的灵芝砂仁复合物GFAC-7的制剂。
具体地,所述的制剂的剂型包括但不限于粉剂、片剂、丸剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、油剂。进一步具体地,所述的制剂的剂型为粉剂。具体地,所述的组方中包括医学上可接受的载体。进一步具体地,所述的载体包括但不限于赋性剂、缓冲剂、乳化剂、稳定剂、稀释剂、粘合剂、防腐剂。
本发明的另一个目的在于提供所述的灵芝砂仁复合物GFAC-7或上述复合物在制备预防和/或治疗受试者胃溃疡药物中的应用。
所述受试者可以为任何哺乳动物,优选地,受试者为大鼠、小鼠、兔子、猴或人。
本发明预防和/或治疗通过减轻炎症损伤、提高胃抗氧化能力以及维持胃内环境稳态中的一种或多种实现。
本发明预防和/或治疗所用剂量可以根据受试对象进行调整。GFAC-7推荐用量为0.05-6g/d,具体可以选择0.05 g/d、0.1 g/d、0.5 g/d、1 g/d、2 g/d、3 g/d、4 g/d、5 g/d、6 g/d。
本发明首次提供一种灵芝砂仁复合物GFAC-7,发现其在预防或治疗胃溃疡取得较好疗效。治疗后小鼠胃脏器指数、溃疡面积、溃疡指数和溃疡抑制率都得到明显改善。胃组织的病理组织学检查结果显示GFAC-7可以保护胃组织。胃溃疡小鼠炎症研究中,GFAC-7组能改善胃溃疡小鼠胃损伤后期的炎性浸润,减少炎症损伤。在胃溃疡小鼠氧化损伤研究中,GFAC-7能够增加小鼠抗氧化的能力,降低氧化损伤。GFAC-7通过改善PGE2和NO,促进胃黏膜的完整和胃内环境的稳态。可以判定GFAC-7样品通过减轻炎症损伤、提高胃抗氧化能力以及维持胃内环境稳态对胃溃疡有预防和治疗作用,将GFAC-7开发成为具有预防和/或治疗胃溃疡的产品具有重要意义。
附图说明
图1 给药后小鼠胃溃疡组织观察。
图2 给药后小鼠胃脏器指数。
图3 给药后小鼠胃溃疡指数。
图4 GFAC-7样品对小鼠胃组织病理学的影响。
图5 GFAC-7对小鼠血清炎症因子的影响。
图6 GFAC-7对胃组织中GSH含量的影响。
图7 GFAC-7对胃组织中SOD含量的影响。
图8 GFAC-7对胃组织中CAT含量的影响。
图9 GFAC-7对胃组织中MDA含量的影响。
图10 GFAC-7对胃组织中NO和PGE2含量的影响。
具体实施方式
下面结合实施例,更具体地说明本发明的内容。应该理解,本发明的实施并不局限于下面的实施例,对本发明所做的任何形式上的变通和/或改变都落入本发明保护范围。实施例中未注明具体条件的实施方法,通常按照常规条件中所述的条件或按照制造厂商所建议的条件。实施例使用的原料、试剂以及试剂盒等均通过商业途径购买获得。
本发明实施例所用GFAC-7样品由健码制药(广东)有限公司提供。使用的主要仪器和试剂如下:JJ500型电子天平(常熟市双杰测试仪器厂)、BT224S型万分之一电子天平(北京赛多利斯科学仪器有限公司)、HVE-50全自动高压灭菌锅(日本平山制作所)、AF103AS雪花制冰机(上海斯科茨曼制冰系统有限公司)、DHG-9030A型电热恒温鼓风干燥箱(上海一恒科学仪器有限公司)、Master-Q15型超纯水机(山东博科生物产业有限公司)、Scieuitife-702型超低温冰箱(美国Thermo科技公司)、Centrifuge5418小型高速冷冻离心机(德国Eppendotf公司)、SpectraMax i3x酶标仪(美谷分子仪器有限公司)、JXFSTPRP-24全自动样品快速研磨机(上海净信实业发展有限公司)、正置显微镜(Olympus)、PerkinElmer倒置显微镜(珀金埃尔默企业管理有限公司)、ZT-12M型生物组织脱水机(湖北省孝感市亚光医用电子技术有限公司)、YB-6LF生物组织石蜡包埋机(湖北省孝感市亚光医用电子技术有限公司)、3126F型石蜡切片机(湖北省孝感市亚光医用电子技术有限公司)、YT-7FB型生物组织摊烤片机(湖北省孝感市亚光医用电子技术有限公司)、GSH、SOD、CAT和MDA试剂盒(南京建成生物工程研究所)、TNF-α、IL-6、IL-12和IFN-γELISA试剂盒(江苏菲亚生物科技有限公司)、苏木素和伊红染液(北京雷根生物技术有限公司)。使用的组分原料为:灵芝粉(陕西华泽生物科技有限公司);砂仁粉(汉中天然谷生物科技股份有限公司);L-谷氨酰胺(河北华阳生物科技有限公司);西兰花种子水提物(深圳福山生物科技有限公司);小茴香(江苏永瑞生物有限公司);肉豆蔻陕西华泽生物科技有限公司;岩藻多糖(青岛明月海藻集团有限公司);糖醇(保龄宝生物股份有限公司)。
剂量选择:GFAC-7人体推荐用量为3 g/d,本实验设GFAC-7低、中、高3个给药剂量组,分别为225mg/kg BW、450mg/kg BW和900mg/kg BW,根据动物实验换算,相当于人体推荐用量的0.5、1、2倍。
实验动物:C57BL/6J雄性小鼠48只,20~25g,SPF级,由广东省医学实验动物中心提供,动物生产许可证号:SCXK(2022-0002)。
饲养环境:实验期动物房环境温度24.0±2.0°C,相对湿度54-65%,换气次数>15次/小时,12小时照明/12小时黑暗,明暗交替,实验动物使用许可证号:SYXK(粤)2022-0125。
本发明部分中英文缩写含义如下表所示:
中英文缩写对照词表
英文简写 | 英文全称 | 中文全称 |
GFAC-7 | Ganoderma fructus amomi complex | 灵芝砂仁复合物 |
MDA | Malondialdehyde | 丙二醛 |
GSH | Glutathione | 谷胱甘肽 |
NO | Nitric Oxide | 一氧化氮 |
CAT | Catalase | 过氧化氢酶 |
SOD | Superoxide Dismutase | 超氧化物歧化酶 |
TNF-α | Tumor necrosis factor-α | 肿瘤坏死因子-α |
IL-6 | Interleukin-6 | 白介素-6 |
IL-12 | Interleukin-12 | 白介素-12 |
IL-1β | Interleukin-1β | 白介素-1β |
IFN-γ | Interferon-γ | 干扰素-γ |
PGE2 | Prostaglandin E2 | 前列腺素E2 |
SPF | Specific pathogen free | 无特定病原 |
H&E | Hematoxylin and eosin | 苏木素和伊红 |
GAs | Ganoderma lucidum acid | 灵芝酸 |
HIV | Human immunodeficiency virus | 类免疫缺陷病毒 |
PBS | Phosphate buffered saline | 磷酸缓冲盐溶液 |
ELISA | Enzyme-linked Immunosorbent Assay | 酶联免疫吸附试验 |
实施例1 胃溃疡小鼠模型的建立以及GFAC-7治疗效果验证
1.1 样品溶液的配制
本发明实施例中所用灵芝砂仁复合物GFAC-7样品含量包含:灵芝粉3.33g;砂仁粉10 g;L-谷氨酰胺50 g;西兰花种子水提物1.67 g;小茴香0.33 g;肉豆蔻0.67 g;岩藻多糖0.67 g;糖醇33.33 g。
低剂量:GFAC-7样品450mg,加蒸馏水至20 ml混匀,得22.5 mg/ml 低剂量样品液;中剂量:GFAC-7样品900 mg,,加蒸馏水至20 ml混匀,得45 mg/ml中剂量样品液;高剂量:GFAC-7样品1800 mg,加蒸馏水至20 ml混匀,得90 mg/ml高剂量样品液。
1.2 给药与造模
选用20~25 g的SPF级7周龄C57雄性小鼠48只,在SPF级环境下适应性喂养7 d,动物自由饮食和饮水,喂养普通饲料。随后将小鼠随机分为6组,分别为空白组、模型组、阳性药组、GFAC-7低剂量组、GFAC-7中剂量组和GFAC-7高剂量组,每组8只,均使用普通饲料喂养,并对各组小鼠编号、称重。
对GFAC-7高、中、低剂量组每天灌胃相应剂量的GFAC-7样品溶液,空白对照组和模型对照组灌胃等体积的蒸馏水,阳性药治疗组小鼠每日以50mg/kg雷尼替丁灌胃0.3mL,连续灌胃14天。每天对小鼠的体重进行记录,并根据小鼠体重变化调整灌胃量。第15天实验结束后,将所有小鼠禁食(不禁水)24h 后称重,记录体重,然后将模型组、阳性药组、GFAC-7组小鼠分别以0.01mL /g无水乙醇诱导胃溃疡,30min后小鼠使用戊巴比妥钠麻醉后眼眶静脉丛取血,脱颈处死,收集全血并用高速离心机将全血离心(4000r/min,4℃,10min)得到血清置于-80℃待用。并迅速取出小鼠全胃并称重,沿胃大弯将胃剖开,用生理盐水洗净后平铺于白纸上用相机拍照,将1/2大小的胃组织一侧放置4%多聚甲醛固定液中固定,用于组织病理学检查,剩余部分胃组织用液氮速冻后置于-80℃冻存,用于后期各项生化指标的检测。
1.3 统计学处理
采用GraphPad Prism 9.0软件对试验数据进行分析,应用One-Way ANOVA和非参数统计方法(秩和检验)方法进行组间显著性差异比较分析,P值小于0.05表明有统计学差异,试验结果以mean±SD表示。
2 检测指标
2.1 体重与摄食量
每日定时称量各组小鼠体重并且记录。每日定时称量各组小鼠饲料剩余量,用前一日给予量减去剩余量,即为每组小鼠的日摄食量。
2.2 小鼠胃损伤评估
取出小鼠全胃并且称重,沿胃大弯将胃剖开,用PBS洗净后平铺于白纸上用相机拍照,出血部分利用ImageJ软件计算出血面积,最后计算胃溃疡率(%)=(胃损伤面积/胃组织面积)×100和胃溃疡抑制率(%)=(Model组胃损伤面积-实验组胃损伤面积)/ Model组胃损伤面积×100。
2.3 血清中IL-1β、IL-6、IL-12和TNF-α含量
将血液收集,4℃高速离心机中,4000r/min,离心10 min。取上清液,用ELISA试剂盒测定小鼠血清IL-1β、IL-6、IL-12和TNF-α水平。
2.4 胃组织匀浆中GSH、SOD、CAT和MDA含量
使用千分之一分析天平称取胃脏组织约0.1 g,按照重量(g):体积(mL)=1:9的比例加入9倍的体积的生理盐水,在全自动样品快速研磨机中匀浆,3500 r/min,离心10分钟,制备10%的组织匀浆。离心后取上清液,用试剂盒测定小鼠胃中GSH、SOD、CAT和MDA含量。
2.5 胃组织匀浆中NO和PGE2含量
使用千分之一分析天平称取胃脏组织约0.1 g,按照重量(g):体积(mL)=1:9的比例加入9倍的体积的生理盐水,在全自动样品快速研磨机中匀浆,3500 r/min,离心10分钟,制备10%的组织匀浆。离心后取上清液,用试剂盒以及ELISA试剂盒测定小鼠胃中NO和PGE2含量。
2.6 胃组织病理组织学检查
解剖小鼠,沿胃大弯将胃剖开,用生理盐水洗净后,取1/2大小的胃组织放入包埋盒,经固定、脱水和包埋后,将包埋好的组织放入-20°C进行预冷,再使用切片机进行切片。将切好的片使用苏木素-伊红染色,最后使用电子显微镜观察。
2.7 组合物对幽门螺杆菌的清除作用测定
组合物对幽门螺杆菌的清除作用采用细胞使用进行验证。幽门螺杆菌(Hp)抗药型菌株解冻后进行固体培养基涂板,微氧环境中36.8℃培养3.5d;重新接种,二次培养,微氧环境中36.8℃培养3.5d;传代第7代。收集菌株研磨至冻存液中,-80℃冷冻保存,备用。
配置培养基:将空白对照、阳性药组(Ranitidine,终浓度为10μg/mL)、GFAC-7组(终浓度为10μg/mL)分别用纯水配成溶液,分别加入1mL上述溶液于空白固体培养基中。将菌株冻存液解冻,菌液浓度稀释至5×108cfu/mL,点状接种于各个组,36.8℃微氧环境,培养72h。每组三次重复。
2.8 结果判定
方法一:模型组与空白组比较,模型组小鼠胃黏膜层的胃损伤面积和胃溃疡率升高且具有统计学意义(P<0.05),以及血清炎症指标(TNF-α、IL-6、IL-12和IFN-γ)且具有统计学意义(P<0.05)表示模型成立。在模型成立的前提下,小鼠胃黏膜层的胃损伤面积和胃溃疡率,或者血清炎症指标(TNF-α、IL-6、IL-12和IFN-γ)中的两项指标显著降低和病理组织学检查结果得到显著改善,即可判定受试样品对乙醇诱导胃溃疡有治疗作用。
方法二:如若满足胃组织中GSH、SOD和CAT检测指标全部或任意两项指标显著升高以及MDA检测指标显著降低和组织病理学检查改善,即可判定受试样品对乙醇诱导胃溃疡有治疗作用。
3 结果
3.1 GFAC-7样品对无水乙醇诱导的小鼠胃部病变的影响
观察小鼠胃黏膜组织出现的溃烂情况形态,由图1可知,Control组小鼠胃黏膜表面外观良好,无明显黏膜糜烂;Model组小鼠胃黏膜层糜烂出血,完整性破坏,黏膜下层充血,说明造模成功。阳性药雷尼替丁组与Model组相比,能明显改善胃黏膜的损伤,减少胃溃疡面积。与Model组相比,GFAC-7治疗组可以使胃部出血现象相对减少,一定程度上减少溃疡病变,其中GFAC-7 H治疗组效果比较明显,但仍然存在一定的出血和溃烂。
3.2 GFAC-7样品对小鼠胃重和胃脏器指数的影响
通过对无水乙醇诱导胃溃疡小鼠胃重量进行统计分析,由表1和图2可知,在通过无水乙醇灌胃后,与Control组小鼠对比,Model组小鼠胃部出现明显的肿胀,胃黏膜层增厚,胃部重量显著增加,说明乙醇在胃部长时间滞留,并且会对胃造成明显的负担。GFAC-7中剂量组和高剂量组在胃脏器指数上与Model组小鼠存在显著性差异,说明GFAC-7样品在本试验条件下能明显降低乙醇造成的小鼠胃重的增加,缓解胃部肿胀。
表1GFAC-7样品给药小鼠胃重量比较(mean±SD,n=8)
Groups | Δ胃(g/g) | 脏器指数 (%) |
Control | 0.1278±0.01054 | 0.5398±0.03428**** |
Model | 0.2306±0.01880 | 0.9562±0.07677 |
Ranitidine | 0.1718±0.01573 | 0.7042±0.05566**** |
GFAC-7 L | 0.2142±0.01323 | 0.8740±0.03660 |
GFAC-7 M | 0.1944±0.03778 | 0.8308±0.1597* |
GFAC-7 H | 0.1906±0.01730 | 0.7933±0.05524** |
注:Control:空白组,Model:模型对照组,Ranitidine:雷尼替丁组;与Model相比,*p<0.05,**p<0.01,*** p<0.001,**** p<0.0001
3.3 GFAC-7样品对无水乙醇诱导胃溃疡小鼠溃疡指数的影响
从表2和图3可以看出,与Control组小鼠比较,Model组的胃损伤面积最大和溃疡指数最高,阳性药处理组小鼠胃损伤面积和溃疡指数显著低于Model组,并且溃疡抑制率达到59.62%。GFAC-7处理组小鼠胃溃疡指数呈现剂量依赖性下降,并且GFAC-7 H组溃疡指数与Model组有显著性差异。在胃溃疡抑制率方面,GFAC-7处理组小鼠的溃疡抑制率随着剂量的增加而增大。这些结果说明,GFAC-7可以减少胃溃疡小鼠溃疡面积和降低胃溃疡指数,减少乙醇造成的胃损伤。
表2 GFAC-7样品给药小鼠胃溃疡面积和溃疡抑制率比较(mean±SD,n=8)
Groups | 胃组织面积(cm 2) | 胃损伤面积(cm 2) | 胃溃疡指数(%) | 胃溃疡抑制率(%) |
Control | 1.447±0.1102 | 0.000±0.000**** | 0.000±0.000**** | 100.00±0.00 |
Model | 1.380±0.1285 | 0.1775±0.05599 | 13.24±3.859 | 0.000±0.00 |
Ranitidine | 1.529±0.2915 | 0.07167±0.02581*** | 4.775±1.921**** | 59.62±14.54 |
GFAC-7 L | 1.490±0.1364 | 0.1480±0.03758 | 10.18±2.153 | 20.38±21.05 |
GFAC-7 M | 1.562±0.1613 | 0.1328±0.03613 | 8.663±2.707 | 25.45±18.22 |
GFAC-7 H | 1.592±0.1456 | 0.09867±0.05159 * | 6.039±2.808*** | 44.41±29.06 |
注:与Model相比,*p<0.05,**p<0.01,*** p<0.001,**** p<0.0001
3.4 GFAC-7样品对无水乙醇诱导胃溃疡小鼠胃组织病理学的影响
小鼠胃部组织结构H&E染色切片如图4所示,Control组小鼠胃壁结构清楚,上皮深层结构完整,胃部组织腺体结构排列整齐和连续,胃粘膜层上表皮结构完整,胃黏膜均匀平整,无明显缺损,并且未见到水肿、炎症细胞浸润和出血点。Model组小鼠胃组织整体失去完整结构,腺体发生深层病变,顶端腺体细胞结构大量片状脱落,内部腺体结构排列紊乱,胃粘膜层结构损伤,并且出现部分凝固性坏死,伴随着炎症细胞的浸润和分散的出血点。与Model组比较,阳性药Ranitidine治疗组明显改善了胃部组织腺体的排列结构,与Control组小鼠的胃组织结构比较接近,并且胃粘膜层比较完整,腺体外部结构存在少量的出血点。与Model组相比,GFAC-7 L处理组小鼠胃组织的腺体细胞排列的改善比较有限,粘膜层离散状态明显,且部分水肿和出血点的存在,但顶端腺体脱落有所改善,并且存在比较完整的细胞结构。GFAC-7 M组可见明显的改善腺体排列结构的整齐和连续,明显减少了腺体细胞结构的脱落,粘膜层结构完整,仅存在少量的出血点和炎症浸润。GFAC-7 H组处理组小鼠的胃黏膜较为均匀平整,腺体细胞结构完整,无明显缺损,与Control组小鼠的胃组织结构比较接近,但粘膜层仍然可见存在少量的水肿。H&E染色结果显示,高剂量的GFAC-7处理组效果优于低剂量和中剂量的GFAC-7处理组。
3.5 GFAC-7样品对无水乙醇诱导胃溃疡小鼠血清中炎症因子IL-1β、IL-6、IL-12和TNF-α水平的影响
乙醇诱发胃溃疡会引起与嗜中性粒细胞浸润增加相关的炎症反应,炎症反应产生的炎症因子数量与急性胃溃疡的严重程度有关,并且有可能进一步增加细胞和器官的损伤。使用酶联免疫吸附法(ELISA)检测小鼠血清IL-1β、IL-6、IL-12和TNF-α水平。结果如图5和表3所示,在本实验中,Control组小鼠无炎症反应,血清IL-1β、IL-6、IL-12和TNF-α水平最低,并且Control组和Model组之间存在显著性差异,在Model组中,血清炎症水平最高,说明过量乙醇的摄入导致小鼠发生应激炎症反应,炎症因子水平升高。与Model组相比,GFAC-7 L和GFAC-7 H给药组可以明显降低IL-1β水平,GFAC-7 M和GFAC-7 H组显著降低了IL-6的水平,所有剂量的GFAC-7处理组小鼠的IL-12含量都得到改善,以及GFAC-7 H组小鼠血清TNF-α的含量显著低于Model组。GFAC-7可能通过降低无水乙醇诱导胃溃疡小鼠胃损伤后期的炎性浸润,从而保护小鼠胃免受二次损伤,预防乙醇诱导的胃溃疡。
表3给药后小鼠血清炎症IL-1β、IL-6、IL-12和TNF-α四项水平的影响(mean± SD,n=6)
Groups | IL-1β (ng/L) | IL-6 (pg/ml) | IL-12(ng/L) | TNF-α(ng/L) |
Control | 80.56± 4.983*** | 127.1± 9.603**** | 8.937± 0.1258**** | 760.5± 48.59**** |
Model | 96.24± 3.955 | 168.0± 3.817 | 10.29± 0.2720 | 910.6± 25.94 |
Ranitidine | 83.61± 6.333** | 136.1±7.860**** | 8.589± 0.4617**** | 810.5± 50.83** |
GFAC-7 L | 86.15± 5.047* | 162.4± 7.547 | 9.372± 0.2216** | 869.6± 32.61 |
GFAC-7 M | 89.25± 4.965 | 151.4± 7.884** | 9.507± 0.6044* | 841.1± 39.06 |
GFAC-7 H | 83.48± 5.241** | 141.5± 6.619**** | 8.792± 0.4448**** | 803.9± 48.20** |
注:与Model相比,*p<0.05,**p<0.01,*** p<0.001,**** p<0.0001
3.6 GFAC-7样品对无水乙醇诱导胃溃疡小鼠胃组织中GSH水平的影响
当胃黏膜内部环境因刺激而处于氧化应激的压力下,会使得胃组织谷胱甘肽的水平降低,导致胃粘膜进一步损伤。由表4和图6得知,与Model组相比,Control组小鼠胃组织GSH的含量明显高于Model组,说明乙醇的摄入明显降低了小鼠胃组织抗氧化能力,导致GSH含量显著下降。与Model组相比较,阳性药Ranitidine可以改善GSH水平,恢复GSH的胃组织水平。相对于Model组,GFAC-7 L和GFAC-7 M给药组小鼠的胃组织GSH含量显著高于Model组,说明GFAC-7可以改善小鼠GSH水平,增加胃组织抗氧化能力。
表4给药后小鼠胃组织中GSH含量(mean±SD, n=6)
Groups | GSH(μmol/gprot) |
Control | 24.79±5.251**** |
Model | 6.517±4.654 |
Ranitidine | 16.81±4.273* |
GFAC-7 L | 19.67±4.966** |
GFAC-7 M | 17.62±6.090* |
GFAC-7 H | 14.66±8.205 |
注:与Model相比,*p<0.05,**p<0.01,***p<0.001,**** p<0.0001
3.7 GFAC-7样品对无水乙醇诱导胃溃疡小鼠胃组织中SOD水平的影响
鉴于氧自由基参与胃粘膜病变的发生和发展,SOD对于预防和治疗胃粘膜损伤和溃疡至关重要。检测结果如表5和图7所示,相对于Control组,Model组小鼠胃组织SOD含量显著下降,SOD活性的降低可能归因于O2-的过量产生,它需要消耗大量的酶来清除它。阳性药Ranitidine治疗组小鼠SOD水平恢复明显,基本恢复与Control组接近。相对于Model组,GFAC-7处理组中剂量和高剂量的小鼠SOD水平显著升高,表明GFAC-7的处理,提高了胃抗氧化能力,以抵抗氧自由基造成的损伤。
表5给药后小鼠胃组织中SOD含量(mean±SD, n=6)
Groups | SOD(U/mgprot) |
Control | 15.63±2.916 ** |
Model | 6.552±4.037 |
Ranitidine | 15.08±4.290 |
GFAC-7 L | 11.12±2.690 |
GFAC-7 M | 13.31±2.721 |
GFAC-7 H | 14.44±2.826* |
注:与Model相比,*p<0.05,**p<0.01,***p<0.001
3.8 GFAC-7样品对无水乙醇诱导胃溃疡小鼠胃组织中CAT水平的影响
CAT是机体氧化应激水平相关物质,是抵抗氧化损伤的重要防线,CAT作为内源性抗氧化酶,它的升高能够降低胃溃疡小鼠的胃脂质过氧化水平。从表6和图8可以看出,与Model组相比,Control组小鼠胃组织CAT含量显著高于Model组小鼠,这表明,在小鼠胃组织暴露于酒精的情况下,Model组小鼠胃组织CAT显著降低,抵御氧化损伤的能力下降。与Model组相比较,高剂量的GFAC-7处理组增加了小鼠胃组织CAT的含量,并且存在显著性差异。说明,GFAC-7给药能够增加小鼠CAT的表达,增加胃组织抗氧化能力,从而减轻过量乙醇诱导的急性胃溃疡。
表6给药后小鼠胃组织中CAT含量(mean±SD, n=6)
Groups | CAT(U/mgprot) |
Control | 7.005±1.205 ** |
Model | 3.838±1.803 |
Ranitidine | 6.373±1.069 |
GFAC-7 L | 4.429±0.8483 |
GFAC-7 M | 4.094±1.701 |
GFAC-7 H | 6.438±1.486* |
注:与Model相比,*p<0.05,**p<0.01,***p<0.001
3.9 GFAC-7样品对无水乙醇诱导胃溃疡小鼠胃组织中MDA水平的影响
丙二醛(MDA)是脂质过氧化产物,MDA的水平能够反应组织的氧化损伤程度,是评估氧化应激严重程度的脂质过氧化生物标志物,从而可以用来评估GFAC-7对抗氧化损伤的作用。从表7和图9可以看出,与Control组相比较,Model组小鼠胃组织在乙醇的刺激下MDA水平有明显的提高,阳性药Ranitidine能明显减少上述胃组织氧化损伤标志物的表达。GFAC-7 H给药组的小鼠可以显著降低胃组织MDA含量。结果表明,GFAC-7 给药干预后能够减轻对胃组织的损伤,减少脂质过氧化物的产生。
表7给药后小鼠胃组织中MDA含量(mean±SD, n=6)
Groups | MDA(nmol/mgprot) |
Control | 0.1998±0.04065 ** |
Model | 0.3945±0.1469 |
Ranitidine | 0.1974±0.04944 |
GFAC-7 L | 0.3302±0.1817 |
GFAC-7 M | 0.2093±0.09292 |
GFAC-7 H | 0.1870±0.04035* |
注:与Model相比,*p<0.05,**p<0.01,***p<0.001
3.10 GFAC-7样品对无水乙醇诱导胃溃疡小鼠胃组织中NO和PGE2水平的影响
PGE2和NO在胃粘膜中具有扩张血管、稳定微血管结构、改善微循环的作用,NO被认为与碳酸氢盐分泌和胃粘液形成,维持胃内环境稳态有关,PGE2控制胃酸分泌、细胞毒性化学物质释放、肥大细胞膜稳定性和组织再生,因此在溃疡的预防和愈合中起关键作用。因此,胃组织中PGE2和NO的表达是评价胃黏膜微循环屏障的关键指标。结果如表8和图10所示,酒精暴露的情况下,Model组小鼠胃组织NO水平显著降低,在GFAC-7给药处理后,即使没有显著性差异,但小鼠胃组织NO的水平呈现上升趋势;Model组小鼠胃组织中PGE2含量相比于Control组降低,GFAC-7M可以比较好的提高PGE2水平,虽然没有显著性差异。提示GFAC-7可能通过维持胃内粘液分泌和胃血流,控制胃酸分泌和组织再生从而达到溃疡预防和愈合的作用。
表8 给药后小鼠胃组织中NO和PGE2含量(mean±SD, n=6)
Groups | NO(μmol/gprot) | PGE2 (ng/L) |
Control | 0.2418±0.1383** | 79.14±14.59 |
Model | 0.07646±0.03108 | 64.58±12.79 |
Ranitidine | 0.09912±0.02502 | 64.65±27.70 |
GFAC-7 L | 0.1815±0.03452 | 69.36±18.11 |
GFAC-7 M | 0.1874±0.05153 | 77.48±23.71 |
GFAC-7 H | 0.1777±0.05111 | 65.74±17.94 |
注:与Model相比,*p<0.05,**p<0.01,***p<0.001
3.11 GFAC-7组合物对抗药型幽门螺杆菌的抑制作用
结果如表9所示,与对照组和阳性药组相比,GFAC-7组合物幽门螺杆菌接种生存率显著下降。表明GFAC-7组合物可以显著抑制幽门螺杆菌的生长。
表9 组合物对幽门螺杆菌的抑制作用
对照组 | 阳性药组 | GFAC-7组 | |
三次实验平均菌落数 | 138 | 96 | 64 |
下降率(相对于对照组) | -- | 30.4% | 53.6% |
4 总结
本实验通过分别经口灌胃给予小鼠GFAC-7样品低、中、高剂量连续14天,剂量分别为225mg/kg BW、450mg/kg BW、900mg/kg BW,相当于人体推荐用量的0.5、1、2倍。与Model组相比,GFAC-7给药后,中剂量和高剂量降低小鼠胃脏器指数,溃疡面积减小,胃溃疡指数呈现剂量依赖性下降,其中GFAC-7 H组溃疡指数明显低于Model组。在胃溃疡抑制率方面,GFAC-7处理组小鼠的溃疡抑制率随着剂量的增加而增大。
通过显微镜观察小鼠胃组织切片,发现GFAC-7样品各剂量组的胃组织腺体排列整齐,减少了顶端腺体细胞结构片状脱落,胃黏膜较为均匀平整,出血点和炎症浸润减少,其中高剂量组的效果最显著。
急性乙醇的摄入能够引发炎症,GFAC-7 L和GFAC-7 H给药组可以明显降低IL-1β水平,GFAC-7 M和GFAC-7 H组显著降低了IL-6的水平,所有剂量的GFAC-7处理组小鼠的IL-12含量都得到改善,以及GFAC-7 H组小鼠血清TNF-α的含量显著降低。说明GFAC-7能改善胃溃疡小鼠胃损伤后期的炎性浸润,减轻炎症损伤。
氧化损伤是胃溃疡的重要机制,GFAC-7 L和GFAC-7 M给药组小鼠GSH含量明显升高,GFAC-7 M和GFAC-7 H的小鼠SOD水平显著升高,并且GFAC-7 H处理组能明显增加了小鼠胃组织CAT的含量,GFAC-7 H给药组的小鼠可以显著降低胃组织MDA含量,这表明GFAC-7能够增加小鼠抗氧化的能力,减少脂质过氧化物的产生,抵抗氧自由基造成的损伤。
PGE2和NO是胃粘膜和维持胃内环境稳态关键,在GFAC-7给药处理后,即使没有显著性差异,但小鼠胃组织NO的水平有所升高,GFAC-7M可以比较好的提高PGE2水平,GFAC-7可能通过维持胃内粘液分泌和胃血流,控制胃酸分泌和组织再生从而达到溃疡预防和愈合的作用。
幽门螺杆菌生长实验表明, GFAC-7组合物可以显著抑制幽门螺杆菌的生长。
总而言之,给予GFAC-7后,我们分析了小鼠胃脏器指数、溃疡面积、溃疡指数和溃疡抑制率都得到明显改善。胃组织的病理组织学检查结果显示GFAC-7可以保护胃组织。胃溃疡小鼠炎症研究中,GFAC-7组能改善胃溃疡小鼠胃损伤后期的炎性浸润,减少炎症损伤。在胃溃疡小鼠氧化损伤研究中,GFAC-7能够增加小鼠抗氧化的能力,降低氧化损伤。GFAC-7通过改善PGE2和NO,促进胃黏膜的完整和胃内环境的稳态。可以判定GFAC-7样品通过减轻炎症损伤、提高胃抗氧化能力以及维持胃内环境稳态,对胃溃疡有预防和治疗作用。同时,GFAC-7对幽门螺杆菌的生长也有显著的抑制作用,将GFAC-7开发成为具有预防保护胃溃疡产品具有重要意义。
申请人声明通过上述实施实例来说明本发明的产品、用途及其使用方式,但本发明并不局限于上述详细用途或使用方式,即不意味着本发明必须依赖上述详细用途和使用方式才能实验。所属技术领域的人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加,具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (9)
1.一种预防和/或治疗胃溃疡的灵芝砂仁复合物,其特征在于,所述复合物以重量百分比计,由灵芝粉2-4%,砂仁粉8-12%,L-谷氨酰胺45-55%,西兰花种子水提物1-3%,小茴香0.1-0.5%,肉豆蔻0.4-0.8%,岩藻多糖0.4-0.8%,糖醇30-35%组成。
2.如权利要求1所述的灵芝砂仁复合物,其特征在于,所述复合物以重量百分比计,由灵芝粉3.33%,砂仁粉10%,L-谷氨酰胺50%,西兰花种子水提物1.67%,小茴香0.33%,肉豆蔻0.67%,岩藻多糖0.67%,糖醇33.33%组成。
3.如权利要求1-2任一项所述的灵芝砂仁复合物,其特征在于,所述糖醇为赤藓糖醇、麦芽糖醇、异麦芽糖醇、木糖醇、D-甘露糖醇中的一种或多种。
4.包含权利要求1-3任一项所述的灵芝砂仁复合物的制剂,所述制剂的剂型为粉剂、片剂、丸剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂或油剂。
5.权利要求1-3任一项所述的灵芝砂仁复合物或权利要求4所述的制剂在制备预防和/或治疗受试者胃溃疡药物中的应用。
6.如权利要求5所述的应用,其特征在于,所述受试者为哺乳动物。
7.如权利要求5所述的应用,其特征在于,所述受试者选自大鼠、小鼠、兔子、猴或人。
8.如权利要求5所述的应用,其特征在于,所述预防和/或治疗通过减轻炎症损伤、提高胃抗氧化能力以及维持胃内环境稳态中的一种或多种实现。
9.如权利要求5-8任一项所述的应用,其特征在于,所述复合物预防和/或治疗的使用量为0.05-6 g/d。
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