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Article(id=1239268420764627686, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239268417962832543, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.07.10, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1687708800000, receivedDateStr=2023-06-26, revisedDate=null, revisedDateStr=null, acceptedDate=1714924800000, acceptedDateStr=2024-05-06, onlineDate=1773394216003, onlineDateStr=2026-03-13, pubDate=1721836800000, pubDateStr=2024-07-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773394216003, onlineIssueDateStr=2026-03-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773394216003, creator=13701087609, updateTime=1773394216003, updator=13701087609, issue=Issue{id=1239268417962832543, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='7', pageStart='481', pageEnd='560', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773394215336, creator=13701087609, updateTime=1773394445099, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1239269381725810851, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239268417962832543, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1239269381725810852, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239268417962832543, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=535, endPage=540, ext={EN=ArticleExt(id=1239268421037257459, articleId=1239268420764627686, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Berberine ameliorates intestinal injury in sepsis by regulating Nrf2/HO-1 pathway, columnId=1207314218647392369, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Original Article, runingTitle=null, highlight=null, articleAbstract=
AIM

To explore the effects of berberine on intestinal injury in sepsis rats and its mechanism.

METHODS

Forty male healthy SD rats were randomly divided into sham group, model group, berberine low, medium, and high dose (25, 50, 100 mg·kg-1) groups, with 8 rats in each group, and the corresponding dose was given by gavage for 7 d. Sepsis model was prepared by cecum ligation and perforation (CLP). After 24 h of modeling, the rats were anesthetized and the ileum specimens were collected. The pathological changes of the ileum were observed and scored under light microscope. The contents of serum heme oxygenase-1 (HO-1), diamine oxidase (DAO), intestinal fatty acid binding protein (iFABP), tumor necrosis factor-α (TNF-α), interleukin (IL) -6 and IL-1β were detected by ELISA. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in ileum were detected by colorimetric analysis. The protein levels of HO-1, nuclear factor E2-related factor 2 (Nrf2) and IL-1β in ileum were detected by Western blot.

RESULTS

Compared with the sham group, ileum histopathological score was significantly increased in the model group (P<0.01), and contents of HO-1, IL-1β, IL-6, TNF-α, DAO, iFABP in serum, and MDA in intestinal tissue were increased, while SOD activity was decreased, and the expressions of Nrf2, HO-1 and IL-1β protein in the model group were significantly increased (P<0.01). Compared with the model group, the ileum histopathologic score of the berberine high dose group was significantly decreased (P<0.01), the contents of IL-1β, IL-6, TNF-α, DAO, iFABP in serum and MDA in intestinal tissue were also decreased (P<0.05), while the HO-1 content in serum and SOD activity in intestinal tissue were increased (P<0.01), and the protein expressions of Nrf2 and HO-1 in the berberine high dose group were significantly increased, but the IL-1β protein expression was decreased (P<0.05).

CONCLUSION

Berberine can effectively improve intestinal damage caused by sepsis, and its mechanism may be related to the up-regulation of Nrf2/HO-1 expression.

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目的

探讨小檗碱改善脓毒症大鼠肠道损伤的作用及其机制。

方法

将40只雄性健康SD大鼠随机分为假手术组，模型组，小檗碱低、中、高剂量（25、50、100 mg·kg-1）组，每组8只，灌胃给予对应剂量7 d后采用盲肠结扎穿孔（CLP）法造脓毒症大鼠模型。造模后24 h麻醉取血并留取回肠标本，观察大鼠回肠组织光镜下的病理变化并进行病理评分比较。利用ELISA法检测各组大鼠血清血红素加氧酶-1（HO-1）、二胺氧化酶（DAO）、肠脂肪酸结合蛋白（iFABP）、肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-6、IL-1β的含量，比色分析法检测大鼠回肠组织中丙二醛（MDA）含量及超氧化物歧化酶（SOD）活性，Western blot法检测回肠组织HO-1、核因子E2相关因子2（Nrf2）及IL-1β蛋白水平。

结果

与假手术组相比，模型组回肠组织病理学评分显著升高（P<0.01），血清HO-1、IL-1β、IL-6、TNF-α、DAO、iFABP及肠组织MDA含量升高，而肠组织SOD活性降低，Nrf2、HO-1及IL-1β蛋白表达明显升高（P<0.01）。与模型组相比，小檗碱高剂量组回肠组织病理学评分明显降低（P<0.01），血清IL-1β、IL-6、TNF-α、DAO、iFABP及肠组织MDA含量也降低（P<0.05），而血清HO-1含量及肠组织SOD活性升高（P<0.01），Nrf2、HO-1表达上调，IL-1β表达降低（P<0.05）。

结论

小檗碱能有效改善脓毒症导致的肠损伤，其机制可能与小檗碱上调Nrf2/HO-1表达相关。

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周蕾，E-mail：
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仇先明，男，主治医师，硕士，主要从事中西医结合急危重症救治的研究，E-mail：

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仇先明，男，主治医师，硕士，主要从事中西医结合急危重症救治的研究，E-mail：

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仇先明，男，主治医师，硕士，主要从事中西医结合急危重症救治的研究，E-mail：

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articleId=1239268420764627686, language=CN, label=图1, caption=各组大鼠肠组织病理改变（HE染色，×100，n=8）

A：假手术组，B：模型组，C：小檗碱低剂量组，D：小檗碱中剂量组，E：小檗碱高剂量组

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A：假手术组，B：模型组，C：小檗碱低剂量组，D：小檗碱中剂量组，E：小檗碱高剂量组

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组别DAOiFABPMDASOD
假手术9.73±2.06233.19±119.770.50±0.1431.80±8.14
模型14.87±6.54c306.42±54.57c2.14±0.89c14.36±3.28c
小檗碱低剂量10.97±4.69d313.42±113.46d1.17±0.60d22.56±4.17d
小檗碱中剂量11.39±1.78dg239.09±85.15eg0.78±0.15eg21.75±8.01dg
小檗碱高剂量9.45±2.95egj220.68±67.19egj0.68±0.33fij27.64±6.53fgj
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各组DAO、iFABP、MDA、SOD比较

, figureFileSmall=null, figureFileBig=null, tableContent=
组别DAOiFABPMDASOD
假手术9.73±2.06233.19±119.770.50±0.1431.80±8.14
模型14.87±6.54c306.42±54.57c2.14±0.89c14.36±3.28c
小檗碱低剂量10.97±4.69d313.42±113.46d1.17±0.60d22.56±4.17d
小檗碱中剂量11.39±1.78dg239.09±85.15eg0.78±0.15eg21.75±8.01dg
小檗碱高剂量9.45±2.95egj220.68±67.19egj0.68±0.33fij27.64±6.53fgj
), ArticleFig(id=1239268428909965321, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239268420764627686, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别HO-1IL-1βIL-6TNF-α
假手术0.72±0.184.83±0.8310.31±5.5040.01±4.38
模型4.58±0.49c232.50±157.60c250.50±113.10c52.39±3.53c
小檗碱低剂量5.18±1.83d120.60±107.70e248.30±161.70d50.03±3.94d
小檗碱中剂量11.75±1.84fi25.57±11.97fi130.00±173.90fi47.38±3.21eg
小檗碱高剂量12.83±2.43fij24.11±15.70fik37.14±36.24fik45.64±7.28ehj
), ArticleFig(id=1239268428993851401, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239268420764627686, language=CN, label=表2, caption=

各组大鼠血清HO-1和炎症因子比较

, figureFileSmall=null, figureFileBig=null, tableContent=
组别HO-1IL-1βIL-6TNF-α
假手术0.72±0.184.83±0.8310.31±5.5040.01±4.38
模型4.58±0.49c232.50±157.60c250.50±113.10c52.39±3.53c
小檗碱低剂量5.18±1.83d120.60±107.70e248.30±161.70d50.03±3.94d
小檗碱中剂量11.75±1.84fi25.57±11.97fi130.00±173.90fi47.38±3.21eg
小檗碱高剂量12.83±2.43fij24.11±15.70fik37.14±36.24fik45.64±7.28ehj
), ArticleFig(id=1239268429094514701, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239268420764627686, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别HO-1Nrf2IL-1β
假手术0.21±0.050.47±0.060.76±0.15
模型0.34±0.04c0.81±0.19c1.20±0.15c
小檗碱低剂量0.47±0.07e0.92±0.19e1.02±0.11d
小檗碱中剂量0.70±0.11eh1.28±0.20eh0.91±0.12dg
小檗碱高剂量1.58±0.38eil1.32±0.11eik0.85±0.02ehj
), ArticleFig(id=1239268429174206478, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239268420764627686, language=CN, label=表3, caption=

各组肠组织HO-1、Nrf2、IL-1β蛋白比较

, figureFileSmall=null, figureFileBig=null, tableContent=
组别HO-1Nrf2IL-1β
假手术0.21±0.050.47±0.060.76±0.15
模型0.34±0.04c0.81±0.19c1.20±0.15c
小檗碱低剂量0.47±0.07e0.92±0.19e1.02±0.11d
小檗碱中剂量0.70±0.11eh1.28±0.20eh0.91±0.12dg
小檗碱高剂量1.58±0.38eil1.32±0.11eik0.85±0.02ehj
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小檗碱调节Nrf2/HO-1信号通路改善脓毒症肠道损伤
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仇先明 1 , 代文 2 , 王全珍 1 , 张飞虎 3 , 孔立 3 , 姜志明 1 , 周蕾 1, 4
中国新药与临床杂志 | 论著 2024,43(7): 535-540
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中国新药与临床杂志 | 论著 2024, 43(7): 535-540
小檗碱调节Nrf2/HO-1信号通路改善脓毒症肠道损伤
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仇先明1 , 代文2, 王全珍1, 张飞虎3, 孔立3, 姜志明1, 周蕾1, 4
作者信息
  • 1.山东第一医科大学第一附属医院/山东省千佛山医院 重症医学科，山东 济南　250014
  • 2.滨州医学院附属烟台分院 急诊医学科，山东 烟台　264100
  • 3.山东中医药大学附属医院 急诊中心，山东 济南　250014
  • 4.山东中医药大学第一临床医学院，山东 济南　250399

    • 仇先明，男，主治医师，硕士，主要从事中西医结合急危重症救治的研究，E-mail：

通讯作者:

周蕾，E-mail：
Berberine ameliorates intestinal injury in sepsis by regulating Nrf2/HO-1 pathway
Xian-ming QIU1 , Wen DAI2, Quan-zhen WANG1, Fei-hu ZHANG3, Li KONG3, Zhi-ming JIANG1, Lei ZHOU1, 4
Affiliations
  • 1.Department of Respiratory Intensive Care Unit, First Affiliated Hospital of Shandong First Medical University, Ji-nan SHANDONG 250014, China
  • 2.Department of Emergency, Yantai Affiliated Hospital of Binzhou Medical University, Yantai SHANDONG 264100, China
  • 3.Department of Emergency Center, Shandong University of Traditional Chinese Medicine Affiliated Hospital, Ji-nan SHANDONG 250014, China
  • 4.First Clinical Medical College of Shandong University of Traditional Chinese Medicine, Ji-nan SHANDONG 250399, China
出版时间: 2024-07-25 doi: 10.14109/j.cnki.xyylc.2024.07.10
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摘要
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目的

探讨小檗碱改善脓毒症大鼠肠道损伤的作用及其机制。

方法

将40只雄性健康SD大鼠随机分为假手术组，模型组，小檗碱低、中、高剂量（25、50、100 mg·kg-1）组，每组8只，灌胃给予对应剂量7 d后采用盲肠结扎穿孔（CLP）法造脓毒症大鼠模型。造模后24 h麻醉取血并留取回肠标本，观察大鼠回肠组织光镜下的病理变化并进行病理评分比较。利用ELISA法检测各组大鼠血清血红素加氧酶-1（HO-1）、二胺氧化酶（DAO）、肠脂肪酸结合蛋白（iFABP）、肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-6、IL-1β的含量，比色分析法检测大鼠回肠组织中丙二醛（MDA）含量及超氧化物歧化酶（SOD）活性，Western blot法检测回肠组织HO-1、核因子E2相关因子2（Nrf2）及IL-1β蛋白水平。

结果

与假手术组相比，模型组回肠组织病理学评分显著升高（P<0.01），血清HO-1、IL-1β、IL-6、TNF-α、DAO、iFABP及肠组织MDA含量升高，而肠组织SOD活性降低，Nrf2、HO-1及IL-1β蛋白表达明显升高（P<0.01）。与模型组相比，小檗碱高剂量组回肠组织病理学评分明显降低（P<0.01），血清IL-1β、IL-6、TNF-α、DAO、iFABP及肠组织MDA含量也降低（P<0.05），而血清HO-1含量及肠组织SOD活性升高（P<0.01），Nrf2、HO-1表达上调，IL-1β表达降低（P<0.05）。

结论

小檗碱能有效改善脓毒症导致的肠损伤，其机制可能与小檗碱上调Nrf2/HO-1表达相关。

脓毒症  /  肠屏障  /  核因子E2相关因子2  /  血红素加氧酶-1  /  小檗碱  /  炎症
AIM

To explore the effects of berberine on intestinal injury in sepsis rats and its mechanism.

METHODS

Forty male healthy SD rats were randomly divided into sham group, model group, berberine low, medium, and high dose (25, 50, 100 mg·kg-1) groups, with 8 rats in each group, and the corresponding dose was given by gavage for 7 d. Sepsis model was prepared by cecum ligation and perforation (CLP). After 24 h of modeling, the rats were anesthetized and the ileum specimens were collected. The pathological changes of the ileum were observed and scored under light microscope. The contents of serum heme oxygenase-1 (HO-1), diamine oxidase (DAO), intestinal fatty acid binding protein (iFABP), tumor necrosis factor-α (TNF-α), interleukin (IL) -6 and IL-1β were detected by ELISA. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in ileum were detected by colorimetric analysis. The protein levels of HO-1, nuclear factor E2-related factor 2 (Nrf2) and IL-1β in ileum were detected by Western blot.

RESULTS

Compared with the sham group, ileum histopathological score was significantly increased in the model group (P<0.01), and contents of HO-1, IL-1β, IL-6, TNF-α, DAO, iFABP in serum, and MDA in intestinal tissue were increased, while SOD activity was decreased, and the expressions of Nrf2, HO-1 and IL-1β protein in the model group were significantly increased (P<0.01). Compared with the model group, the ileum histopathologic score of the berberine high dose group was significantly decreased (P<0.01), the contents of IL-1β, IL-6, TNF-α, DAO, iFABP in serum and MDA in intestinal tissue were also decreased (P<0.05), while the HO-1 content in serum and SOD activity in intestinal tissue were increased (P<0.01), and the protein expressions of Nrf2 and HO-1 in the berberine high dose group were significantly increased, but the IL-1β protein expression was decreased (P<0.05).

CONCLUSION

Berberine can effectively improve intestinal damage caused by sepsis, and its mechanism may be related to the up-regulation of Nrf2/HO-1 expression.

sepsis  /  intestinal barrier  /  nuclear factor E2-related factor 2  /  heme oxygenase-1  /  berberine  /  inflammatory
仇先明, 代文, 王全珍, 张飞虎, 孔立, 姜志明, 周蕾. 小檗碱调节Nrf2/HO-1信号通路改善脓毒症肠道损伤. 中国新药与临床杂志, 2024 , 43 (7) : 535 -540 . DOI: 10.14109/j.cnki.xyylc.2024.07.10
Xian-ming QIU, Wen DAI, Quan-zhen WANG, Fei-hu ZHANG, Li KONG, Zhi-ming JIANG, Lei ZHOU. Berberine ameliorates intestinal injury in sepsis by regulating Nrf2/HO-1 pathway[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (7) : 535 -540 . DOI: 10.14109/j.cnki.xyylc.2024.07.10
正文
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脓毒症是常见的急危重症病种，因感染诱发宿主全身炎症反应综合征以及免疫反应异常调节，最终引起宿主器官功能障碍，进而危及生命[1]。脓毒症诱发内源性和外源性炎症刺激破坏肠道屏障，增强上皮通透性，导致全身性炎症反应和脏器功能损伤的发生[2]。小檗碱（berberine）是一种植物生物碱，存在于多种植物的根和树皮中，包括黄连（金线）、小檗（俄勒冈葡萄）和小檗（树姜黄）。小檗碱具有多种药理作用，包括抗癌、抗糖尿病、抗肥胖、抗高脂血症、心脏保护、空间记忆改善、免疫抑制特性，以及抗氧化和抗炎症活性[3]。
小檗碱可以改善肠道炎症，减少炎症细胞浸润，修复肠黏膜屏障[4]。研究表明小檗碱能通过调控氧化/抗氧化相关介质来改善脓毒症炎症反应。核因子E2相关因子2（Nrf2）/血红素加氧酶-1（HO-1）通路为重要的抗氧化应激信号途径，该通路可改善脓毒症诱导的肾、肺、肠急性损伤[5]。本研究观察小檗碱通过Nrf2/HO-1通路对脓毒症肠损伤的影响及可能的作用机制。
材料与方法
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药物、试剂与仪器
小檗碱（纯度：HPLC≥98%）购自美国MCE公司。大鼠HO-1、白细胞介素（IL）-1β、肿瘤坏死因子-α（TNF-α）、IL-6、二胺氧化酶（DAO）、肠脂肪酸结合蛋白（iFABP）ELISA试剂盒均购自天津安诺瑞康生物技术有限公司，Anti-Nrf2兔多克隆抗体购自杭州华安生物技术有限公司，Anti-HO-1兔多克隆抗体购自美国Cell Signaling Technology公司，Anti-IL-1β兔多克隆抗体购自英国Abcam公司，丙二醛（MDA）检测试剂盒、BCA蛋白浓度测定试剂盒、超氧化物歧化酶（SOD）检测试剂盒均购自北京索莱宝科技有限公司。电动组织匀浆器（上海净信实业发展有限公司），移液器（德国艾本德有限公司），1658040型垂直电泳槽、Chemidoc化学发光凝胶成像系统（美国Bio-Rad公司），Stratos高速冷冻离心机（赛默飞世尔有限公司），Bio Tek EpochME酶标仪（宝特伯美国有限公司）。
实验动物
8周龄雄性SD大鼠40只，体重180~220 g，购自济南朋悦实验动物繁育有限公司，动物合格证号：SCXK（鲁）2019-0003。标准饲料，专人单笼饲养1周。实验前12 h禁食，自由饮水。本实验经过山东第一医科大学第一附属医院伦理委员会审查批准（［2022］动伦审字S681）。
建模与分组
采用随机数字表法随机将大鼠分为5组，假手术组，模型组，小檗碱低、中、高剂量（25、50、100 mg·kg-1）组，均n=8。小檗碱各剂量组灌胃给予对应剂量每日1次，假手术组大鼠给予同等剂量生理盐水（每100 g体重2 mL）灌胃。在第7日灌胃2 h后，模型组和小檗碱各剂量组采用盲肠结扎穿孔（CLP）法造脓毒症大鼠模型：3%戊巴比妥钠30 mg·kg-1腹腔内注射麻醉，切口取上腹部正中部位，取出盲肠，分离盲肠远端1/3处用线结扎，用针穿2孔，然后挤出少许肠内容物于腹腔内，回纳盲肠，后分层缝合腹腔，术后6 h成模。假手术组开腹后，探查腹腔后关腹，其他操作相同。术后22 h小檗碱组继续给予对应剂量灌胃1次，假手术组和模型组大鼠同时间给予生理盐水灌胃。造模后24 h用3%戊巴比妥30 mg·kg-1腹腔注射麻醉大鼠，腹主动脉取血后分离血清用于ELISA检测。于近回盲端取回肠组织约5 cm，清洗后分为3份，用于病理学检查、Western blot及-80 ℃冰箱备用。
肠组织病理学改变
于10%甲醇水溶液中固定72 h，常规处理后经HE染色，镜下观察病理学变化，并依据Chiu’s评分标准[6]。1分为正常肠黏膜绒毛；2分为绒毛顶端黏膜下出现间隙，毛细血管充血；3分为肠黏膜下间隙扩大，肠黏膜与黏膜下层分离；4分为黏膜与黏膜下层分离延伸到肠绒毛两侧；5分为绒毛变钝，固有膜及其血管暴露，炎性组织浸润；6分为固有层消化崩解，出血或溃疡形成。
血清DAO、iFABP、HO-1、TNF-α、IL-6、IL-1β含量
大鼠腹主动脉采血后立即离心后取血清，根据ELISA试剂盒说明书步骤检测血清DAO、iFABP、HO-1、IL-1β、IL-6和TNF-α的含量，操作按试剂盒说明书进行。
肠组织MDA含量及SOD活性
留取100 mg肠组织，加入生理盐水制备为10%组织匀浆，离心后取上清液500 μL，应用硫代巴比妥酸比色分析法测定MDA含量，应用黄嘌呤氧化酶法测定SOD活性。
HO-1通路相关蛋白表达
新鲜肠组织称重后按照1∶10（g·mL-1）的比例放入RIPA强裂解液中，使用电动匀浆器将其充分研磨，后置于冰上裂解30 min，裂解过程中反复涡旋混匀。12 000×g 4 ℃高速离心15 min后收集上清液并使用BCA蛋白试剂盒测量总蛋白浓度。各组样本经SDS-PAGE凝胶电泳分离，转到PVDF膜上，用5%的脱脂奶粉室温封闭1 h，TBST缓冲液洗膜3次，与HO-1（1∶1 000）、Nrf2（1∶1 000）、IL-1β（1∶1 000）、GAPDH（1∶2 000）一抗在4 ℃冰箱的摇床上孵育过夜，TBST洗膜3次，然后与荧光二抗（1∶10 000）在4 ℃下避光孵育过夜，用化学发光凝胶成像系统将结果可视化，并测定条带灰度值，以目的蛋白与GAPDH的灰度值比值表示蛋白的相对表达量。
统计学分析
应用SPSS Statistic 26和GraphPad Prism 8.0软件对实验数据进行统计分析及作图。符合正态分布的计量资料以（）表示，组间比较采用单因素方差分析，方差齐性采用LSD检验。若方差不齐则用秩和检验。P<0.05表示有显著差异。
结果
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一般情况
模型组大鼠在造模后3 h可见到竖毛、蜷缩、反应迟钝、发热寒战等表现。假手术组大鼠行为表现未见异样。小檗碱组大鼠以上表现较模型组轻微，不同剂量组之间未见明显差异。
肠组织病理损伤及评分
与假手术组相比，模型组大鼠肠组织镜下可见黏膜萎缩，绒毛破坏，上皮细胞坏死，炎症细胞大量浸润。小檗碱中、高剂量组肠组织细胞的损伤表现及炎症细胞浸润情况较模型组轻，见图1。与假手术组相比，模型组肠组织病理学评分显著增高（1.25±0.89 vs. 4.12±0.64, P<0.01）。与模型组相比，小檗碱中、高剂量组肠道损伤评分均显著降低（分别为2.38±0.52和1.88±0.64，P<0.01），小檗碱低剂量组无显著差异（3.75±0.71，P>0.05）。
血清DAO、iFABP含量
与假手术组相比，模型组DAO和iFABP含量显著升高（P<0.01）。与模型组相比，小檗碱高剂量组DAO和iFABP含量均显著降低（P<0.05），小檗碱中剂量组血清iFABP含量显著降低（P<0.05），呈剂量依赖趋势。见表1。
肠组织氧化应激相关指标
与假手术组相比，模型组MDA含量显著升高，SOD活性降低（P<0.01）。与模型组相比，小檗碱中、高剂量组大鼠MDA含量降低（P<0.05），小檗碱高剂量组SOD活性升高（P<0.01），见表1。
血清HO-1、TNF-α、IL-1β、IL-6含量
与假手术组相比，模型组血清HO-1及TNF-α、IL-1β、IL-6含量均显著升高（P<0.01）。与模型组相比，小檗碱中、高剂量组血清HO-1含量升高（P<0.01），TNF-α、IL-6、IL-1β含量降低（P<0.05），呈剂量依赖趋势。见表2。
肠组织HO-1、Nrf2、IL-1β蛋白表达
与假手术组相比，模型组肠组织IL-1β、HO-1、Nrf2蛋白表达显著上调（P<0.01）。与模型组相比，小檗碱各剂量组HO-1、Nrf2蛋白表达显著升高，呈剂量依赖性，小檗碱高剂量组IL-1β蛋白表达显著降低（P<0.05）。见表3，图2。
讨论
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脓毒症的高死亡率与肠上皮屏障功能损伤有着密切关系。因此，探寻脓毒症肠黏膜屏障损伤的关键环节，需找到阻断脓毒症发生发展的有效手段。本研究发现盲肠结扎术后24 h大鼠血清DAO、iFABP含量升高，血清炎症因子水平上升，肠组织病理显示肠道明显受损，表明盲肠结扎穿孔法成功制备了脓毒症肠道损伤大鼠模型。
iFABP是一种存在于肠黏膜微绒毛顶端的蛋白，组织特异性高，生理状态下不存在于体循环中。当消化道受到各种原因的损伤后，黏膜通透性发生改变，iFABP释放入血，因此，iFABP可以作为肠道缺血的生物标志物[7]，并与急性胰腺炎[8]和脑膜炎球菌血症[9]等一些危重疾病引起的肠道损伤的严重程度相关。DAO是一种催化组胺等二胺类发生氧化反应的酶，在肠缺血、炎症及类似应激的患者中组胺样二胺含量升高[10]。本研究采用Chiu’s评估法对脓毒症大鼠肠道上皮组织损伤进行评估，根据HE染色结果可看到脓毒症严重损伤肠道上皮组织，小檗碱中、高剂量组肠黏膜层上皮细胞脱落减轻，炎症细胞浸润减少，血清DAO、iFABP含量均降低，再次证明小檗碱保护肠黏膜屏障的作用，而且高剂量组的保护作用更强。
机体一旦发生脓毒症，巨噬细胞、中性粒细胞等炎症细胞和局部产生的TNF-α、IL-1β等炎症因子入血，诱导IL-6、IL-8的产生，引起炎症瀑布式的级联反应，造成炎症介质过多释放，破坏了肠上皮细胞间正常的紧密连接[11]。氧化应激和炎症可以互为因果。MDA、SOD是常见的氧化应激标志物[12]，控制过度的炎症反应，可以改善肠屏障功能，降低肠上皮细胞通透性，进而提高脓毒症整体存活率[13]。本研究结果显示，模型组血清炎症因子含量增加，肠组织中IL-1β高表达，MDA含量升高，SOD活性降低，而小檗碱各剂量组炎症因子含量及表达均有不同程度地降低，MDA含量降低，而SOD活性升高，说明小檗碱可以抑制脓毒症大鼠肠道炎症及氧化应激水平，提高肠道抗氧化能力。
Nrf2是自身抗氧化应激调节因子，在生理条件下，Nrf2位于细胞质，与kelch样环氧氯丙烷相关蛋白1（Keap1）结合，并且不断被泛素化降解。一旦机体出现损伤，Nrf2与Keap1分离释放并转移到细胞核中，通过与Nrf2结合抗氧化反应元件（ARE）相互结合，增加抗氧化基因的转录，从而起到抗氧化应激的作用[14]。HO-1的激活是细胞对氧化应激的适应性反应[15]。本研究发现，假手术组大鼠肠组织核Nrf2、HO-1蛋白表达较低，模型组核内Nrf2及HO-1表达增高，提示模型组大鼠肠组织内抗氧化应激系统也同时激活，但却不足以对抗过度升高的氧化应激，从而出现肠黏膜损伤，这与LI等[16]的研究结果一致。小檗碱中、高剂量组肠组织中核内Nrf2及HO-1蛋白表达进一步升高，提示小檗碱可能通过激活Nrf2/HO-1通路提高脓毒症肠道抗氧化水平，进而抑制了炎症因子表达。
综上所述，小檗碱可能通过Nrf2/HO-1通路抑制脓毒症大鼠炎症因子的释放，减轻机体炎症反应、改善脓毒症肠损伤。
基金
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  • 国家重点研发计划资助项目(2018YFC2002000)
  • 国家自然科学基金面上项目(81974545)
  • 中国民族医药学会科研项目(2021Z1041-370104)
  • 山东省中医药科技发展计划(2019-0390)
文献
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参考文献 引证文献
排序方式：
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2024年第43卷第7期
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doi: 10.14109/j.cnki.xyylc.2024.07.10
  • 接收时间：2023-06-26
  • 首发时间：2026-03-13
  • 出版时间：2024-07-25
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  • 收稿日期：2023-06-26
  • 录用日期：2024-05-06
基金
国家重点研发计划资助项目(2018YFC2002000)
国家自然科学基金面上项目(81974545)
中国民族医药学会科研项目(2021Z1041-370104)
山东省中医药科技发展计划(2019-0390)
作者信息
    1.山东第一医科大学第一附属医院/山东省千佛山医院 重症医学科，山东 济南　250014
    2.滨州医学院附属烟台分院 急诊医学科，山东 烟台　264100
    3.山东中医药大学附属医院 急诊中心，山东 济南　250014
    4.山东中医药大学第一临床医学院，山东 济南　250399

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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