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Article(id=1201096920883225142, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201096916940579367, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-0934, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1690819200000, receivedDateStr=2023-08-01, revisedDate=1695225600000, revisedDateStr=2023-09-21, acceptedDate=null, acceptedDateStr=null, onlineDate=1764293421239, onlineDateStr=2025-11-28, pubDate=1712851200000, pubDateStr=2024-04-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764293421239, onlineIssueDateStr=2025-11-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764293421239, creator=13701087609, updateTime=1764293421239, updator=13701087609, issue=Issue{id=1201096916940579367, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='4', pageStart='789', pageEnd='1100', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764293420298, creator=13701087609, updateTime=1764293534792, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1201097397242912862, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201096916940579367, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1201097397242912863, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201096916940579367, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1028, endPage=1039, ext={EN=ArticleExt(id=1201096921801777750, articleId=1201096920883225142, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Mechanistic investigation on the hypoglycemic effect of Panax notoginseng saponins in type 2 diabetic mice based on plasma metabolomics, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Plasma metabolomics combined experimental verification was employed for investigating of the hypoglycemic effect of Panax notoginseng saponins (PNS) on type 2 diabetes mellitus (T2DM) mice. Forty C57BL/6J mice were randomly divided into control and experimental groups after one week of adaptive feeding. The mice in control group were fed conventionally, and the T2DM model was established in mice of the experimental group by intraperitoneal injection of streptozotocin following twelve weeks of feeding on a high-fat diet (HFD). All experiments were approved by the Ethical Committee Experimental Animal Center of North Sichuan Medical College (NSMC2022023). After the failure cases during modeling were eliminated, the remaining mice were randomly divided into model group (T2DM), low dose [200 mg·kg-1·d-1] and high dose [300 mg·kg-1·d-1] PNS groups. Mice in normal and model groups were given equal amounts of normal saline by gavage. The mice were administered intragastrically with PNS for 6 weeks, and their body weight, food intake, water intake and fasting blood glucose (FBG) were measured weekly. Oral glucose tolerance test (OGTT) was performed at the 5th week of administration. The changes of liver functions and blood lipids were detected by collecting blood from eyeballs. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were detected in the blood and the activity of glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) were analyzed in the liver by kit, respectively. Subsequently, the changes in plasma endogenous metabolites from each group were determined based on metabolomics, and the pathway enrichment analysis of differential metabolites was performed using KEGG database. NF-κB signaling pathway, TNF-α and IL-6 in liver were detected by western blot, respectively. The results showed that T2DM mice were successfully constructed. High dose of panax notoginseng saponins (HPNS) can reduce the FBG in T2DM mice while low dose of PNS (LPNS) has no significant effect on FBG. HPNS improves the liver function, reduces the levels of blood lipids, TNF-α and IL-6, and increases the activity of GSH-Px, CAT and SOD in liver of T2DM mice. Metabolomics results showed that 45 metabolites were significantly changed in the plasma of model group compared with control, and 20 metabolites were significantly changed after HPNS treatment. Pathway enrichment indicated that arachidonic acid metabolism, linoleic acid metabolism, glutathione metabolism and carnitine synthesis were changed in the blood of T2DM mice, and HPNS improved the abnormal metabolism of arachidonic acid and linoleic acid in T2DM mice. Western blot showed that HPNS could inhibit the NF-κB pathway and reduce the expression of TNF-α and IL-6 in the liver of T2DM mice, suggesting that PNS may exert the antidiabetic effect by inhibiting NF-κB pathway, regulating arachidonic acid and linoleic acid metabolism to reduce inflammatory factors and oxidative stress, improve liver function in T2DM mice.

, correspAuthors=Jin-xia CHANG, Wen-hu LIU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Jin-hua ZHANG, Han-xiang LIU, Yu-xuan LIU, Min WU, Jin-xia CHANG, Wen-hu LIU), CN=ArticleExt(id=1201096928168731565, articleId=1201096920883225142, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=基于血浆代谢组学探究三七总皂苷对2型糖尿病小鼠的降糖作用, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

基于血浆代谢组学结合实验验证研究三七总皂苷(Panax notoginseng saponins, PNS) 对2型糖尿病(type 2 diabetes mellitus, T2DM) 小鼠的降糖作用。将40只C57BL/6J小鼠随机分为对照组和实验组, 对照组常规饲养, 实验组高脂饲料喂养12周后, 经腹腔注射链脲佐菌素(streptozotocin, STZ) 建立T2DM模型, 所有动物实验经川北医学院实验动物伦理委员会批准(批准号: NSMC2022023)。造模成功小鼠随机分为模型组(T2DM)、低剂量[200 mg·kg-1·d-1] 和高剂量[300 mg·kg-1·d-1] 三七总皂苷组, 灌胃6周, 每周监测小鼠体重、摄食量、进水量和空腹血糖值(fasting blood glucose, FBG), 灌胃第5周进行口服糖耐量实验(oral glucose tolerance test, OGTT)。摘眼球采血检测肝脏功能及血脂; 试剂盒检测血液肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α) 和白介素-6 (interleukin-6, IL-6) 的水平及肝脏中抗氧化系统谷胱甘肽过氧化物酶(glutathione peroxidase, GSH-Px)、过氧化氢酶(catalase, CAT) 和超氧化物歧化酶(superoxide dismutase, SOD) 的活性。基于代谢组学研究血浆中内源性代谢物变化; 使用KEGG数据库通路富集分析; Western blot检测肝脏NF-κB通路及TNF-α和IL-6的表达。结果显示, T2DM小鼠构建成功; 高剂量三七总皂苷(high Panax notoginseng saponins, HPNS) 能够降低T2DM小鼠的空腹血糖, 低剂量三七总皂苷(low Panax notoginseng saponins, LPNS) 对空腹血糖无显著影响。HPNS能够改善T2DM小鼠肝脏功能, 降低血脂及血液TNF-α和IL-6的水平, 增加肝脏GSH-Px、CAT和SOD的活性。代谢组学结果显示, 模型组血浆中45种代谢物变化显著, HPNS治疗后20种代谢物显著变化且向正常组转归。通路富集表明, 花生四烯酸代谢、亚油酸代谢、谷胱甘肽代谢及肉碱合成在T2DM小鼠血液中改变, HPNS可改善T2DM小鼠血液中花生四烯酸和亚油酸异常代谢。Western blot表明, HPNS能够抑制T2DM小鼠NF-κB通路, 降低TNF-α和IL-6的表达, 提示PNS可能通过抑制NF-κB通路; 调节花生四烯酸和亚油酸代谢, 降低炎性因子和氧化应激水平, 改善肝脏功能发挥降低血糖的作用。

, correspAuthors=常晋霞, 刘文虎, authorNote=null, correspAuthorsNote=
*常晋霞, E-mail: ;
刘文虎, E-mail:
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School of Basic Medical Sciences & Forensic Medical, North Sichuan Medical College, Nanchong 637100, China), AuthorCompanyExt(id=1201096928617522128, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, companyId=1201096928596550605, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.川北医学院, 基础医学与法医学院, 四川 南充 637100)])], figs=[ArticleFig(id=1201096933663269148, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=EN, label=null, caption=null, figureFileSmall=JNTKzUWTVDlGrX1yBjvfqA==, figureFileBig=K7isrgDO8vzRzKssSrv9og==, tableContent=null), ArticleFig(id=1201096933772321059, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=CN, label=Figure 1, caption= The effect of PNS on body weight (A), food intake (B), water intake (C) and FBG (D) in mice with T2DM. <i>n =</i> 8, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i> ± <i>s</i>. T2DM <i>vs</i> Con, <sup>#</sup><i>P</i> < 0.05, <sup>##</sup><i>P</i> < 0.01, <sup>###</sup><i>P</i> < 0.001; HPNS <i>vs</i> T2DM, <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01. Con: Control; T2DM: Type 2 diabetes mellitus; PNS: <i>Panax notoginseng</i> saponins; FBG: Fasting blood glucose; HPNS: High <i>Panax notoginseng</i> saponins , figureFileSmall=JNTKzUWTVDlGrX1yBjvfqA==, figureFileBig=K7isrgDO8vzRzKssSrv9og==, tableContent=null), ArticleFig(id=1201096934095282489, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=EN, label=null, caption=null, figureFileSmall=pQkr5D0+g7cZaYimolhe8Q==, figureFileBig=mTzK9fg4gAqhnzEyFCp3bA==, tableContent=null), ArticleFig(id=1201096934221111617, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=CN, label=Figure 2, caption= The effects of PNS on the glucose tolerance of T2DM mice. A: Detection of FBG by OGTT test in mice; B: AUC in OGTT test. <i>n</i> = 8, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i> ± <i>s</i>. T2DM <i>vs</i> Con, <sup>###</sup><i>P</i> < 0.001; HPNS <i>vs</i> T2DM, <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001. OGTT: Oral glucose tolerance test; AUC: The area under the curve , figureFileSmall=pQkr5D0+g7cZaYimolhe8Q==, figureFileBig=mTzK9fg4gAqhnzEyFCp3bA==, tableContent=null), ArticleFig(id=1201096934380495180, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=EN, label=null, caption=null, figureFileSmall=mn2TQVfleOTRiuY0fBHIeg==, figureFileBig=QOX0MxfuLTP+f4JD4QjwmQ==, tableContent=null), ArticleFig(id=1201096934518907225, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=CN, label=Figure 3, caption= The effects of PNS on the blood lipids (A) and liver enzyme (B) of T2DM mice. <i>n</i> = 8, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i> ± <i>s</i>. T2DM <i>vs</i> Con, <sup>##</sup><i>P</i> < 0.01, <sup>###</sup><i>P</i> < 0.001; HPNS <i>vs</i> T2DM, <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01. TC: Total cholesterol; TG: Triglyceride; LDL-C: Low density lipoprotein cholesterin; HDL-C: High density lipoprotein cholesterin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase , figureFileSmall=mn2TQVfleOTRiuY0fBHIeg==, figureFileBig=QOX0MxfuLTP+f4JD4QjwmQ==, tableContent=null), ArticleFig(id=1201096934648930658, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=EN, label=null, caption=null, figureFileSmall=OAgjJ1CC7qiLPBfyqez82Q==, figureFileBig=nbFhJBTNvWRxQyu2T2sjLQ==, tableContent=null), ArticleFig(id=1201096934757982575, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=CN, label=Figure 4, caption= The effects of PNS on activities of GSH-Px (A), SOD (B) and CAT (C) in liver of T2DM mice. <i>n =</i> 8, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i> ± <i>s</i>. T2DM <i>vs</i> Con, <sup>###</sup><i>P</i> < 0.001; HPNS <i>vs</i> T2DM, <sup>*</sup><i>P</i> < 0.05. GSH-Px: Glutathione peroxidase; SOD: Superoxide dismutase; CAT: Catalase , figureFileSmall=OAgjJ1CC7qiLPBfyqez82Q==, figureFileBig=nbFhJBTNvWRxQyu2T2sjLQ==, tableContent=null), ArticleFig(id=1201096934904783226, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=EN, label=null, caption=null, figureFileSmall=wk5Py++0cUqBNEvEWXjhrA==, figureFileBig=cIwF+QBnD5UY8mpq09RDog==, tableContent=null), ArticleFig(id=1201096936091771273, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=CN, label=Figure 5, caption= PNS decrease blood inflammatory factors IL-6 (A) and TNF-<i>α</i> (B) levels in T2DM mice. <i>n</i> = 8, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i> ± <i>s</i>. T2DM <i>vs</i> Con, <sup>###</sup><i>P</i> < 0.001; HPNS <i>vs</i> T2DM, <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01. TNF-<i>α</i>: Tumor necrosis factor-<i>α</i>; Interleukin-6: IL-6 , figureFileSmall=wk5Py++0cUqBNEvEWXjhrA==, figureFileBig=cIwF+QBnD5UY8mpq09RDog==, tableContent=null), ArticleFig(id=1201096936200823183, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=EN, label=null, caption=null, figureFileSmall=3YiTaNu62b1kfZpHBYmWYg==, figureFileBig=U3Jiu/S3UlsRuAOxhJMjAw==, tableContent=null), ArticleFig(id=1201096936318263704, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=CN, label=Figure 6, caption= Data quality control analysis. A, B: PCA-X one-dimensional line plots; C, D: Spearman's correlation coefficients , figureFileSmall=3YiTaNu62b1kfZpHBYmWYg==, figureFileBig=U3Jiu/S3UlsRuAOxhJMjAw==, tableContent=null), ArticleFig(id=1201096936444092832, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=EN, label=null, caption=null, figureFileSmall=1pE5V99fdPQOzqQMacNgsQ==, figureFileBig=IUh7Ix8crPqYe14KbqkwzQ==, tableContent=null), ArticleFig(id=1201096936553144744, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=CN, label=Figure 7, caption= Multivariate statistical analysis of plasma metabolomics. A, D: PCA score plots of T2DM and control groups in ESI+ and ESI-, respectively; B, E: PLS-DA score plots of T2DM and control groups in ESI+ and ESI-, respectively; C, F: Permutation test plots of T2DM and control groups; G, H: PCA score plots of T2DM, control and HPNS groups in ESI+ and ESI-, respectively , figureFileSmall=1pE5V99fdPQOzqQMacNgsQ==, figureFileBig=IUh7Ix8crPqYe14KbqkwzQ==, tableContent=null), ArticleFig(id=1201096936683168180, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=EN, label=null, caption=null, figureFileSmall=ivBINzuKOdlndTmh+hpYhg==, figureFileBig=FHYglTqQJk/yZM5++eJd9g==, tableContent=null), ArticleFig(id=1201096936792220091, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=CN, label=Figure 8, caption= MS/MS spectral fragments of typical metabolites are confirmed by matching the standard library. A: Arachidonic acid; B: Docosahexaenoic acid , figureFileSmall=ivBINzuKOdlndTmh+hpYhg==, figureFileBig=FHYglTqQJk/yZM5++eJd9g==, tableContent=null), ArticleFig(id=1201096936947409352, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=EN, label=null, caption=null, figureFileSmall=XiZI6fXzDGEPTAvkAL2Kxw==, figureFileBig=rg477ndQucrgC0VuCMgHjw==, tableContent=null), ArticleFig(id=1201096937064849872, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=CN, label=Figure 9, caption= Heat map visualization of differential metabolites. A: T2DM <i>vs</i> Con; B: HPNS <i>vs</i> T2DM , figureFileSmall=XiZI6fXzDGEPTAvkAL2Kxw==, figureFileBig=rg477ndQucrgC0VuCMgHjw==, tableContent=null), ArticleFig(id=1201096937186484699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=EN, label=null, caption=null, figureFileSmall=8LqP2PMq/WLbGgXbCfNRSA==, figureFileBig=2nsIuot28d65SVc4ZNNZlw==, tableContent=null), ArticleFig(id=1201096937295536614, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=CN, label=Figure 10, caption= Pathway enrichment and quantitative analysis. <i>n</i> = 8, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i> ± <i>s</i>. A: Altered metabolic pathways in T2DM group; B: Altered metabolic pathways in T2DM group after PNS treatment; C, D: The quantification of metabolites of arachidonic acid and linoleic acid metabolism pathways. T2DM <i>vs</i> Con, <sup>#</sup><i>P</i> < 0.05, <sup>##</sup><i>P</i> < 0.01, <sup>###</sup><i>P</i> < 0.001; HPNS <i>vs</i> T2DM, <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=8LqP2PMq/WLbGgXbCfNRSA==, figureFileBig=2nsIuot28d65SVc4ZNNZlw==, tableContent=null), ArticleFig(id=1201096937429754349, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=EN, label=null, caption=null, figureFileSmall=Gg3QbCKzHJN5CTpTaNjapQ==, figureFileBig=EWHg+0tx5AIeJKYIpG2byg==, tableContent=null), ArticleFig(id=1201096937568166391, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=CN, label=Figure 11, caption= Analysis of NF-<i>κ</i>B pathway, TNF-<i>α</i> and IL-6 by Western blot. <i>n</i> = 8, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i> ± <i>s</i>. A, C: The detection expression of TNF-<i>α</i>, IL-6, NF-<i>κ</i>B and I<i>κ</i>B<i>α</i> in control, T2DM and PNS treatment mice liver; B, D: Quantitative analysis of these protein levels by using image J software. T2DM <i>vs</i> Con, <sup>#</sup><i>P</i> < 0.05, <sup>##</sup><i>P</i> < 0.01; HPNS <i>vs</i> T2DM, <sup>*</sup><i>P</i> < 0.05 , figureFileSmall=Gg3QbCKzHJN5CTpTaNjapQ==, figureFileBig=EWHg+0tx5AIeJKYIpG2byg==, tableContent=null), ArticleFig(id=1201096937706578429, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
NoMetaboliteFormulaTheoretical MW (m/z)Calculated MW (m/z)ppmtR/minTrend
T2DM vs ConHPNS vs T2DM
1L-AcetylcarnitineC9H17NO4203.115 82203.116 111.434.39↓*↑*
2PropionylcarnitineC10H19NO4217.151 43217.152 625.487.55↓*—
3Glutamic acidC5H9NO4147.025 21147.026 7510.473.29↓**—
4Arachidonic acidC20H32O2304.263 23304.264 664.7015.20↑***↓***
5Uric acidC5H4N4O3168.028 32168.028 491.016.07↑***—
6HexanoylcarnitineC13H26NO4260.349 81260.348 91-3.4611.34↓*—
7PalmitoylcarnitineC23H46NO4400.342 14400.345 829.1915.46↓*↑**
8DecanoylcarnitineC17H33NO4315.240 97315.241 120.4813.98↓*↑*
9N6, N6, N6-Trimethyl-L-lysineC9H20N2O2188.152 48188.152 570.483.17↑*—
10NiacinamideC6H6N2O122.047 65122.048 365.825.76↓*—
11cAMPC10H12N5 O6P329.052 53329.052 750.678.045↓*—
12GlutathioneC10H17N3 O6S307.083 87307.083 57-0.985.37↓***—
13CholineC5H14NO104.100 52104.100 06-4.423.22↑**—
14TaurineC2H7NO3S125.014 73125.014 891.283.27↓***↑*
15Aspartic acidC4H7NO4133.037 51133.037 731.653.26↓**—
16GSSGC20H32N6 O12S2612.151 93612.153 312.257.41↓*—
17Prostaglandin F2bC20H34O5354.240 66354.243 167.0615.03↑***↓**
18Aminoadipic acidC6H11NO4161.068 82161.069 041.373.55↑**—
19N6-Acetyl-L-lysineC8H16N2O3188.116 12188.116 331.123.72↑*—
20TryptophanC11H12N2O2204.089 93204.072 07-4.219.98↑*—
21Kynurenic acidC10H7NO3189.052 61189.052 891.4812.23↑**—
228, 11, 14-Eicosatrienoic acidC20H34O2306.255 96306.256 230.8818.54↓**↑*
23Prostaglandin C2C20H30O4334.194 41334.196 686.7916.05↑**↓***
2414, 15-DiHETrEC20H34O4338.213 66338.216 909.5816.38↑***—
25Coenzyme Q1C14H18O4250.120 54250.118 08-9.8414.16↓**↑**
26PC (16:0/16:0)C40H80NO8P733.562 15733.265 915.1316.64↑*—
27Prostaglandin E2C20H32O5352.224 92352.228 9811.5319.59↑***↓***
2820-HETEC20H32O3320.235 11320.230 49-14.4315.42↑***↓***
29Palmitoleic acidC16H30O2254.224 63254.224 42-0.8317.83↓***—
30Pantothenic acidC9H17NO5219.110 76219.111 051.329.37↓*—
3113, 14-Dihydro-15-keto-PGE2C20H32O5352.224 93352.225 341.1613.91↑*—
32Indoleacrylic acidC11H9NO2187.066 38187.067 053.5812.05↓***↑*
33Testosterone sulfateC19H28O5S368.165 74368.163 53-6.0015.36↑**—
34TetrahydrocorticosteroneC21H35O5350.245 71350.242 43-9.3614.62↑**↑*
35Oleic acidC18H34O2282.255 93282.255 24-2.4416.73↓***↑***
36Pentadecanoic acidC15H30O2242.224 64242.224 36-1.1616.29↑***↓***
37Xanthurenic acidC10H7NO4205.037 57205.036 99-2.839.02↑*—
38Eicosapentaenoic acidC20H30O2302.224 69302.224 24-1.4916.08↓***↑***
39Tridecylic acidC13H26O2214.193 37214.192 76-2.8515.74↑*—
40Docosahexaenoic acidC22H32O2328.240 28328.239 70-1.7716.64↓**↑***
413-MethylhistidineC7H11N3O2169.085 13169.084 25-5.204.48↑*—
42Tetradecanedioic acidC14H26O4258.183 11258.183 05-0.2312.55↓*↑*
4311, 12-DiHETrEC20H34O4338.245 73338.234 53-3.5515.44↑*—
4419, 20-DiHDPAC22H34O4362.245 75362.245 790.1114.91↓**↑**
45Indoleacetic acidC10H9NO2175.066 36175.066 08-1.6011.99↓**↑*
), ArticleFig(id=1201096937836601861, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920883225142, language=CN, label=Table 1, caption=

Altered metabolites in the T2DM and after PNS treatment. *P < 0.05, **P < 0.01, ***P < 0.001

, figureFileSmall=null, figureFileBig=null, tableContent=
NoMetaboliteFormulaTheoretical MW (m/z)Calculated MW (m/z)ppmtR/minTrend
T2DM vs ConHPNS vs T2DM
1L-AcetylcarnitineC9H17NO4203.115 82203.116 111.434.39↓*↑*
2PropionylcarnitineC10H19NO4217.151 43217.152 625.487.55↓*—
3Glutamic acidC5H9NO4147.025 21147.026 7510.473.29↓**—
4Arachidonic acidC20H32O2304.263 23304.264 664.7015.20↑***↓***
5Uric acidC5H4N4O3168.028 32168.028 491.016.07↑***—
6HexanoylcarnitineC13H26NO4260.349 81260.348 91-3.4611.34↓*—
7PalmitoylcarnitineC23H46NO4400.342 14400.345 829.1915.46↓*↑**
8DecanoylcarnitineC17H33NO4315.240 97315.241 120.4813.98↓*↑*
9N6, N6, N6-Trimethyl-L-lysineC9H20N2O2188.152 48188.152 570.483.17↑*—
10NiacinamideC6H6N2O122.047 65122.048 365.825.76↓*—
11cAMPC10H12N5 O6P329.052 53329.052 750.678.045↓*—
12GlutathioneC10H17N3 O6S307.083 87307.083 57-0.985.37↓***—
13CholineC5H14NO104.100 52104.100 06-4.423.22↑**—
14TaurineC2H7NO3S125.014 73125.014 891.283.27↓***↑*
15Aspartic acidC4H7NO4133.037 51133.037 731.653.26↓**—
16GSSGC20H32N6 O12S2612.151 93612.153 312.257.41↓*—
17Prostaglandin F2bC20H34O5354.240 66354.243 167.0615.03↑***↓**
18Aminoadipic acidC6H11NO4161.068 82161.069 041.373.55↑**—
19N6-Acetyl-L-lysineC8H16N2O3188.116 12188.116 331.123.72↑*—
20TryptophanC11H12N2O2204.089 93204.072 07-4.219.98↑*—
21Kynurenic acidC10H7NO3189.052 61189.052 891.4812.23↑**—
228, 11, 14-Eicosatrienoic acidC20H34O2306.255 96306.256 230.8818.54↓**↑*
23Prostaglandin C2C20H30O4334.194 41334.196 686.7916.05↑**↓***
2414, 15-DiHETrEC20H34O4338.213 66338.216 909.5816.38↑***—
25Coenzyme Q1C14H18O4250.120 54250.118 08-9.8414.16↓**↑**
26PC (16:0/16:0)C40H80NO8P733.562 15733.265 915.1316.64↑*—
27Prostaglandin E2C20H32O5352.224 92352.228 9811.5319.59↑***↓***
2820-HETEC20H32O3320.235 11320.230 49-14.4315.42↑***↓***
29Palmitoleic acidC16H30O2254.224 63254.224 42-0.8317.83↓***—
30Pantothenic acidC9H17NO5219.110 76219.111 051.329.37↓*—
3113, 14-Dihydro-15-keto-PGE2C20H32O5352.224 93352.225 341.1613.91↑*—
32Indoleacrylic acidC11H9NO2187.066 38187.067 053.5812.05↓***↑*
33Testosterone sulfateC19H28O5S368.165 74368.163 53-6.0015.36↑**—
34TetrahydrocorticosteroneC21H35O5350.245 71350.242 43-9.3614.62↑**↑*
35Oleic acidC18H34O2282.255 93282.255 24-2.4416.73↓***↑***
36Pentadecanoic acidC15H30O2242.224 64242.224 36-1.1616.29↑***↓***
37Xanthurenic acidC10H7NO4205.037 57205.036 99-2.839.02↑*—
38Eicosapentaenoic acidC20H30O2302.224 69302.224 24-1.4916.08↓***↑***
39Tridecylic acidC13H26O2214.193 37214.192 76-2.8515.74↑*—
40Docosahexaenoic acidC22H32O2328.240 28328.239 70-1.7716.64↓**↑***
413-MethylhistidineC7H11N3O2169.085 13169.084 25-5.204.48↑*—
42Tetradecanedioic acidC14H26O4258.183 11258.183 05-0.2312.55↓*↑*
4311, 12-DiHETrEC20H34O4338.245 73338.234 53-3.5515.44↑*—
4419, 20-DiHDPAC22H34O4362.245 75362.245 790.1114.91↓**↑**
45Indoleacetic acidC10H9NO2175.066 36175.066 08-1.6011.99↓**↑*
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Pathway nameMatch statusP valuePathway impact
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Glutathione metabolism1/190.4290.112
Carnitine synthesis1/160.3760.143
Oxidation of branched chain fatty acids2/210.1200.066
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Enrichment analysis of metabolic pathways in T2DM mice

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Carnitine synthesis1/160.3760.143
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Linoleic acid metabolism4/170.0080.301
Oxidation of branched chain fatty acids2/210.1200.066
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Enrichment analysis of metabolic pathways in T2DM mice after PNS treatment

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基于血浆代谢组学探究三七总皂苷对2型糖尿病小鼠的降糖作用
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张金花 1 , 刘汉湘 1 , 刘雨轩 1 , 吴敏 1 , 常晋霞 2, * , 刘文虎 1, *
药学学报 | 研究论文 2024,59(4): 1028-1039
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药学学报 | 研究论文 2024, 59(4): 1028-1039
基于血浆代谢组学探究三七总皂苷对2型糖尿病小鼠的降糖作用
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张金花1, 刘汉湘1, 刘雨轩1, 吴敏1, 常晋霞2, * , 刘文虎1, *
作者信息
  • 1.川北医学院, 药学院, 四川 南充 637100
  • 2.川北医学院, 基础医学与法医学院, 四川 南充 637100

通讯作者:

*常晋霞, E-mail: ;
刘文虎, E-mail:
Mechanistic investigation on the hypoglycemic effect of Panax notoginseng saponins in type 2 diabetic mice based on plasma metabolomics
Jin-hua ZHANG1, Han-xiang LIU1, Yu-xuan LIU1, Min WU1, Jin-xia CHANG2, * , Wen-hu LIU1, *
Affiliations
  • 1. Department of Pharmacy, North Sichuan Medical College, Nanchong 637100, China
  • 2. School of Basic Medical Sciences & Forensic Medical, North Sichuan Medical College, Nanchong 637100, China
出版时间: 2024-04-12 doi: 10.16438/j.0513-4870.2023-0934
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基于血浆代谢组学结合实验验证研究三七总皂苷(Panax notoginseng saponins, PNS) 对2型糖尿病(type 2 diabetes mellitus, T2DM) 小鼠的降糖作用。将40只C57BL/6J小鼠随机分为对照组和实验组, 对照组常规饲养, 实验组高脂饲料喂养12周后, 经腹腔注射链脲佐菌素(streptozotocin, STZ) 建立T2DM模型, 所有动物实验经川北医学院实验动物伦理委员会批准(批准号: NSMC2022023)。造模成功小鼠随机分为模型组(T2DM)、低剂量[200 mg·kg-1·d-1] 和高剂量[300 mg·kg-1·d-1] 三七总皂苷组, 灌胃6周, 每周监测小鼠体重、摄食量、进水量和空腹血糖值(fasting blood glucose, FBG), 灌胃第5周进行口服糖耐量实验(oral glucose tolerance test, OGTT)。摘眼球采血检测肝脏功能及血脂; 试剂盒检测血液肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α) 和白介素-6 (interleukin-6, IL-6) 的水平及肝脏中抗氧化系统谷胱甘肽过氧化物酶(glutathione peroxidase, GSH-Px)、过氧化氢酶(catalase, CAT) 和超氧化物歧化酶(superoxide dismutase, SOD) 的活性。基于代谢组学研究血浆中内源性代谢物变化; 使用KEGG数据库通路富集分析; Western blot检测肝脏NF-κB通路及TNF-α和IL-6的表达。结果显示, T2DM小鼠构建成功; 高剂量三七总皂苷(high Panax notoginseng saponins, HPNS) 能够降低T2DM小鼠的空腹血糖, 低剂量三七总皂苷(low Panax notoginseng saponins, LPNS) 对空腹血糖无显著影响。HPNS能够改善T2DM小鼠肝脏功能, 降低血脂及血液TNF-α和IL-6的水平, 增加肝脏GSH-Px、CAT和SOD的活性。代谢组学结果显示, 模型组血浆中45种代谢物变化显著, HPNS治疗后20种代谢物显著变化且向正常组转归。通路富集表明, 花生四烯酸代谢、亚油酸代谢、谷胱甘肽代谢及肉碱合成在T2DM小鼠血液中改变, HPNS可改善T2DM小鼠血液中花生四烯酸和亚油酸异常代谢。Western blot表明, HPNS能够抑制T2DM小鼠NF-κB通路, 降低TNF-α和IL-6的表达, 提示PNS可能通过抑制NF-κB通路; 调节花生四烯酸和亚油酸代谢, 降低炎性因子和氧化应激水平, 改善肝脏功能发挥降低血糖的作用。

三七总皂苷  /  降糖作用  /  NF-κB通路  /  花生四烯酸代谢  /  亚油酸代谢

Plasma metabolomics combined experimental verification was employed for investigating of the hypoglycemic effect of Panax notoginseng saponins (PNS) on type 2 diabetes mellitus (T2DM) mice. Forty C57BL/6J mice were randomly divided into control and experimental groups after one week of adaptive feeding. The mice in control group were fed conventionally, and the T2DM model was established in mice of the experimental group by intraperitoneal injection of streptozotocin following twelve weeks of feeding on a high-fat diet (HFD). All experiments were approved by the Ethical Committee Experimental Animal Center of North Sichuan Medical College (NSMC2022023). After the failure cases during modeling were eliminated, the remaining mice were randomly divided into model group (T2DM), low dose [200 mg·kg-1·d-1] and high dose [300 mg·kg-1·d-1] PNS groups. Mice in normal and model groups were given equal amounts of normal saline by gavage. The mice were administered intragastrically with PNS for 6 weeks, and their body weight, food intake, water intake and fasting blood glucose (FBG) were measured weekly. Oral glucose tolerance test (OGTT) was performed at the 5th week of administration. The changes of liver functions and blood lipids were detected by collecting blood from eyeballs. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were detected in the blood and the activity of glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) were analyzed in the liver by kit, respectively. Subsequently, the changes in plasma endogenous metabolites from each group were determined based on metabolomics, and the pathway enrichment analysis of differential metabolites was performed using KEGG database. NF-κB signaling pathway, TNF-α and IL-6 in liver were detected by western blot, respectively. The results showed that T2DM mice were successfully constructed. High dose of panax notoginseng saponins (HPNS) can reduce the FBG in T2DM mice while low dose of PNS (LPNS) has no significant effect on FBG. HPNS improves the liver function, reduces the levels of blood lipids, TNF-α and IL-6, and increases the activity of GSH-Px, CAT and SOD in liver of T2DM mice. Metabolomics results showed that 45 metabolites were significantly changed in the plasma of model group compared with control, and 20 metabolites were significantly changed after HPNS treatment. Pathway enrichment indicated that arachidonic acid metabolism, linoleic acid metabolism, glutathione metabolism and carnitine synthesis were changed in the blood of T2DM mice, and HPNS improved the abnormal metabolism of arachidonic acid and linoleic acid in T2DM mice. Western blot showed that HPNS could inhibit the NF-κB pathway and reduce the expression of TNF-α and IL-6 in the liver of T2DM mice, suggesting that PNS may exert the antidiabetic effect by inhibiting NF-κB pathway, regulating arachidonic acid and linoleic acid metabolism to reduce inflammatory factors and oxidative stress, improve liver function in T2DM mice.

Panax notoginseng saponin  /  hypoglycemic effect  /  NF-κB signaling pathway  /  arachidonic acid metabolism  /  linoleic acid metabolism
张金花, 刘汉湘, 刘雨轩, 吴敏, 常晋霞, 刘文虎. 基于血浆代谢组学探究三七总皂苷对2型糖尿病小鼠的降糖作用. 药学学报, 2024 , 59 (4) : 1028 -1039 . DOI: 10.16438/j.0513-4870.2023-0934
Jin-hua ZHANG, Han-xiang LIU, Yu-xuan LIU, Min WU, Jin-xia CHANG, Wen-hu LIU. Mechanistic investigation on the hypoglycemic effect of Panax notoginseng saponins in type 2 diabetic mice based on plasma metabolomics[J]. Acta Pharmaceutica Sinica, 2024 , 59 (4) : 1028 -1039 . DOI: 10.16438/j.0513-4870.2023-0934
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糖尿病(diabetes mellitus, DM) 是以血糖水平升高、糖脂代谢紊乱为主要特征, 且常伴有高血压、高血脂及动脉粥样硬化等多种慢性疾病的代谢型综合征。据《中国居民营养与慢性病状况报告(2020年)》显示, 中国18岁及以上人群糖尿病患病率为11.9%, 其中2型糖尿病(type 2 diabetes mellitus, T2DM) 占90%以上。近年来, T2DM发展趋向低龄化、长病程、多并发症、危害严重及医疗支出费用高等特点[1, 2]。T2DM已成为全球性严重公共卫生问题之一。
三七[Panax notoginseng (Burk.) F. H. Chen] 为五加科人参属三七的干燥根和根茎, 为中国特有名贵药材, 具有“参中之王”“南国神草”之美誉。现代药理证明, 三七具有活血化瘀、免疫调节、改善微循环及抑制炎症等功效[3-6]。三七中富含皂苷、多糖、黄酮、氨基酸等化学成分, 其中三七总皂苷(Panax notoginseng saponins, PNS) 是三七中最主要的药效组分, 也是血塞通临床使用的药用成分。据报道, 三七皂苷可通过瘦素介导的AMPKα/STAT3通路调控肠道微生物群, 促进产热和米色脂肪细胞重建, 进而抑制高脂饮食诱导的肥胖[7]。有学者认为, 三七中的单体成分人参皂苷Rb1和人参皂苷Re具有降糖和减轻糖尿病并发症的作用, 前者可促进胰岛素分泌并减少甘油三酯的积累[8], 后者与刺激大麻素I型受体和CaMKK β激活AMPK信号通路、抑制胰岛素抵抗、改善葡萄糖摄取有关[9]。然而, 迄今对三七总皂苷的降糖作用研究较少。
本实验通过60%脂肪供能纯化型饲料联合小剂量注射链脲佐菌素(streptozotocin, STZ)建立T2DM小鼠模型, 基于代谢组学结合实验验证探究PNS对T2DM小鼠的降糖作用, 并从信号通路及炎性因子角度探究PNS的降糖机制, 旨在为三七总皂苷的临床应用及开发提供实验和理论依据。
材料与方法
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实验动物  5~6周龄雄性C57BL/6J小鼠(16~20 g) 购于北京维通利华实验动物技术有限公司[合格证号: SCXK (京) 2021-0006], 动物实验遵循川北医学院动物伦理委员会的规定并通过动物实验伦理审查(批准号: NSMC2022023)。饲养于川北医学院实验动物中心, 环境温度20~26 ℃, 相对湿度~60%, 12 h明暗交替循环, 小鼠自由摄食、饮水。动物福利符合川北医学院动物实验伦理委员会之规定。
药物及主要试剂  三七总皂苷(含量≥ 90%, 批号DST200706-054) 购于成都德思特生物技术有限公司。链脲佐菌素(STZ, USP级) 购于源叶生物科技; 肿瘤坏死因子(tumor necrosis factor-α, TNF-α, E-EL-M3063) 和白介素-6 (interleukin-6, IL-6, E-EL-M0044c) 试剂盒购于Elabscuence生物科技; 丙氨酸转移酶(alanine aminotransferase, ALT, BC1555)、天冬氨酸转氨酶(aspartate aminotransferase, AST, BC1565) 试剂盒购于Solarbio生物科技。谷胱甘肽过氧化物酶(glutathione peroxidase: GSH-Px, KTB1640)、过氧化氢酶(catalase, CAT, KTB1040) 及超氧化物歧化酶(superoxide dismutase, SOD, KTB1030) 试剂盒购于Abbkine科技公司。抗体TNF-α (26405-1-AP)、IL-6 (21865-1-AP)、NF-κBp65 (10745-1-AP)、pNF-κBp65 (82335-1-RR) 和IκBα (10268-1-AP) 购于Proteintech公司。
动物分组及模型构建  40只小鼠适应性饲养1周后, 随机分为正常组(对照组, 8只) 和高脂组(high fat diet, HFD, 32只), 正常组普通饲料喂养, HFD用60%脂肪供能纯化型饲料喂养12周(江苏协同医药生物工程有限责任公司)。第13周, 小鼠禁食10 h, 正常组按0.1 mL·10g-1腹腔注射柠檬酸缓冲液, HFD组按40 mg·kg-1·d-1腹腔注射STZ, 连续5天, 末次给药1周后, 禁食12 h, 尾尖采血检测空腹血糖(fasting blood glucose, FBG), 高脂组FBG ≥ 11.1 mmol·L-1视为T2DM模型成功, FBG < 11.1 mmol·L-1的小鼠剔除实验。
给药方法  按照三七总皂苷注射剂血栓通单日剂量150 mg体表面积换算, 确定小鼠尾静脉注射的临床等效剂量为20 mg·kg-1·d-1。依据三七总皂苷口服10%生物利用度换算, 确定小鼠灌胃临床等效剂量为200 mg·kg-1·d-1。本实验按照200 mg·kg-1·d-1 (临床等效剂量) 和300 mg·kg-1·d-1 (1.5倍临床等效剂量) 灌胃。正常组和模型组给予等量生理盐水, PNS用生理盐水溶解后灌胃, 每组8只, 剂量为0.1 mL·10 g-1, 每天一次, 持续6周, 每周检测小鼠体重、摄食量、饮水量及FBG。
口服葡萄糖耐量实验  给药结束前1周, 小鼠禁食不禁水12 h, 按20 mg·10 g-1灌胃20%葡萄糖, 尾尖采血, 测定0、15、30、60、90、120 min的FBG, 绘制口服糖耐量实验(oral glucose tolerance test, OGTT) 曲线。
血液生化指标检测  给药结束后, 小鼠禁食不禁水10 h, 检测FBG。摘眼球取血于抗凝管中, 混匀, 1 500 ×g离心10 min, 取上清, 试剂盒检测TNF-α、IL-6、ALT和AST水平。全自动生化分析仪检测总胆固醇(total cholesterol, TC)、甘油三酯(triglyceride, TG)、低密度脂蛋白(low density lipoprotein cholesterin, LDL-C) 和高密度脂蛋白(high density lipoprotein cholesterin, HDL-C)。
肝脏GSH-Px、CAT及SOD检测  取肝脏30 mg, 研磨匀浆, 2 000 ×g离心20 min, 收集上清, 按试剂盒说明检测450 nm波长处OD值, 计算GSH-Px、CAT和SOD含量。
血浆非靶标代谢组学分析
样本制备  按常规方法制备小鼠血浆样本, 保存于-80 ℃备用。用前于4 ℃解冻, 取100 µL血浆, 加入300 µL预冷甲醇-乙腈-水体系(5∶3∶2, V/V), 涡旋, -20 ℃放置1 h, 14 000 ×g离心10 min, 取上清, 冻干, 残渣保存于-80 ℃。分析前加入100 µL乙腈-水(乙腈∶水=1∶1, V/V) 复溶, 涡旋, 14 000 ×g离心10 min, 上清供质谱检测。取等量待检样本(20 µL), 混合作为质控。
色谱条件  Vanquish (美国Thermo Fisher Scientific) 超高效液相色谱仪搭载Waters ACQUITY UPLC HSS T3 (100 mm × 2.1 mm, 1.8 μm) 色谱柱(美国Waters)。流动相A为水(含5 mmol·L-1乙酸铵和5 mmol·L-1乙酸), 流动相B为乙腈, 梯度洗脱(1~11 min, 2% B; 11~15.4 min, 维持98% B; 15.4~15.6 min, 98%~2% B; 15.6~21 min, 维持2% B; 流速200 nL·min-1。自动进样器温度4 ℃; 进样体积2 µL。
参照中国药典(2020版) 一部对血塞通制剂中三七总皂苷检测方法。取对照品(已标示三七皂苷R1、人参皂苷Rg1、人参皂苷Re、人参皂苷Rb1和人参皂苷Rd含量)和供试品(含三七总皂苷25 mg) 适量, 精密称定, 加入70%甲醇完全溶解, 精密取对照品和供试品溶液各10 μL, 注入Waters 2695-2996高效液相色谱仪。色谱柱为Ultimate® XB-C18 (250 mm × 4.6 mm, 5 μm), 柱温35 ℃, 流动相A为乙腈, 流动相B为水, 洗脱梯度: 0~20 min, 20% A; 20~45 min, 20%~46% A; 45~55 min, 46%~55% A; 55~60 min, 维持55% A; 60~64 min, 55%~90% A; 流速1.5 mL·min-1, 检测波长203 nm。
质谱条件  Orbitrap Exploris 120质谱仪(Xcalibur, 美国Thermo Fisher Scientific) 采用FullScan MS2模式进行一级、二级数据采集。离子传输管温度320 ℃; 喷雾电压4.0 kV (Pos) 和-3.5 kV (Neg); 鞘气流速50 arb, 辅助气流速15 arb, Full MS分辨率60 000, MS/MS分辨率15 000, 碰撞能10/30/60。
数据分析及差异代谢物筛选  质谱数据经Proteo Wizard转为mzXML格式, 经XCMS软件峰对齐、峰识别、峰过滤、峰匹配、峰面积提取及保留时间校正。生成包括质荷比m/z、保留时间(tR) 及面积的数据矩阵; 过滤缺失值超过50%的变量; 利用K临近法(K = 10) 填充剩余缺失值, 总面积法归一化。根据质控计算各变量的变异系数(coefficient of variation, CV), 将CV大于30%的变量剔除。
将所得数据矩阵导入MetaboAnalyst 5.0 (https://www.metaboanalyst.ca/) 作多变量分析, 变量经均值中心化和Pareto scaling标度化, 采用非监督主成分分析(principal component analysis, PCA) 建立分类模型, 观察样本间聚类趋势及离群样本; 采用偏最小二乘判别分析(partial least squares discriminant analysis, PLS-DA) 建立代谢物浓度与样本间模型, 并对模型200次置换检验, R2表示模型稳定性, Q2表示模型预测能力。依据PLS-DA模型变量投影重要性(variable important in projection, VIP) 筛选对模型分组贡献较大的变量(VIP > 1), 依据显著性水平和倍数变化(fold change, FC) 筛选差异变量, 视VIP > 1、FC ≥ 1.5或FC ≤ 0.67且P < 0.05的变量为差异变量。根据变量质荷比m/z、ppm及MS/MS谱图匹配鉴定代谢物, 依据人类代谢组学数据库(The Human Metabolome Database, HMDB) 数据库剔除外源性、药源性化合物。
通路富集分析  将差异代谢物导入MetaboAnalyst 5.0数据库进行通路富集分析, 富集方法为Fisher's exact test; 拓扑学方法为relative-betweeness centrality; 数据库为京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes, KEGG)。
Western blot检测蛋白质的表达  取小鼠肝脏约30 mg, 冰上解冻用预冷PBS洗2次, 加入150 µL RIPA裂解液, 组织匀浆至完全裂解, 12 000 ×g离心10 min, 取上清, BCA法测蛋白浓度。取适量蛋白, 变性、聚丙烯酰胺凝胶电泳、转膜、封闭、4 ℃孵育一抗至过夜、洗膜、常温孵育二抗、洗膜、显影。Image J灰度值分析, GraphPad Prism 8.0作图。
统计学分析  使用SPSS 26.0软件统计学分析, 数据用均数±标准差(x ± s) 表示。多组间比较用单因素方差分析, 组间两两比较用LSD法, P < 0.05表示差异具有统计学意义。
结果
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1 高效液相色谱检测三七总皂苷主要成分及含量
结果显示, 三七总皂苷的主要成分为三七皂苷R1、人参皂苷Rg1、人参皂苷Re、人参皂苷Rb1和人参皂苷Rd。按标示量计算, 三七皂苷R1、人参皂苷Rg1、人参皂苷Re、人参皂苷Rb1和人参皂苷Rd含量分别为6.96%、34.29%、2.65%、31.34%和10.19%, 符合中国药典(2020版) 对血塞通有效成分之规定。
2 三七总皂苷对小鼠体重、摄食量、饮水量及空腹血糖的影响
给药期间, 每周检测小鼠体重、摄食量、饮水量及FBG变化。结果显示, 正常组体重相对稳定且趋于增加, 模型组、高剂量和低剂量PNS组体重呈下降趋势。给药5周后, 模型组与正常组相比, 差异具有统计学意义(P < 0.05), 高、低剂量组与模型组相比无显著变化(图 1A)。与正常组相比, 模型组摄食量显著增加(P < 0.001)。给药4周后, 高剂量组摄食量减少, 但与模型组相比差异无统计学意义; 低剂量组摄食量随给药时间变化不明显(图 1B)。与正常组相比, 模型组饮水量显著增加(P < 0.001), 给药5周后高剂量组饮水量减少, 6周后相比模型组差异具有统计学意义(P < 0.05), 低剂量组与模型组相比无显著差异(图 1C)。给药前, 模型组、高剂量和低剂量组的FBG分别为16.28 ± 0.72、16.11 ± 1.02和16.15 ± 0.64 mmol·L-1。与正常组相比, 模型组FBG显著增加(P < 0.001), 给药6周后高剂量组FBG为14.58 ± 1.63 mmol·L-1, 与模型组相比差异具有统计学意义(P < 0.01), 低剂量组FBG为15.61 ± 1.29 mmol·L-1, 与模型组相比差异无统计学意义(图 1D)。综上, 高剂量PNS对T2DM小鼠具有降糖作用, 而低剂量的降糖作用不明显。因此, 后续仅对高剂量PNS降糖作用研究。
3 三七总皂苷改善T2DM小鼠口服糖耐量
糖耐量显示, 20%葡萄糖灌胃后, 正常组15 min内FBG迅速上升, 15 min时达峰值17.98 ± 2.85 mmol·L-1, 15~30 min内FBG快速下降至8.01 ± 1.51 mmol·L-1, 120 min降为4.43 ± 0.32 mmol·L-1。模型组和高剂量组前15 min内FBG快速上升, 15~30 min内缓慢上升, 30 min时达到峰值, 分别为32.97 ± 1.07和30.05 ± 1.24 mmol·L-1, 之后FBG缓慢降低, 120 min分别为25.28 ± 1.77和20.19 ± 2.44 mmol·L-1 (图 2A)。与正常组相比, 模型组各时间点的FBG显著增加(P < 0.001); 除15 min时间点外, 高剂量组FBG较模型组显著降低(P < 0.05) (图 2A)。模型组AUC较正常组显著增加(P < 0.001), 高剂量组AUC较模型组显著降低(P < 0.01) (图 2B), 表明模型组小鼠糖耐量受损, 高剂量PNS可改善T2DM小鼠的糖耐量。
4 三七总皂苷对T2DM小鼠血脂及肝酶的影响
肝脏是机体糖脂代谢的主要场所, 肝脏对胰岛素的敏感性降低将导致糖脂代谢异常, 肝功能受损。另一方面, 糖代谢异常诱发机体脂代谢紊乱, 导致胰岛素抵抗。与正常组相比, 模型组TC、TG、LDL-C显著增加(P < 0.001), HDL-C显著降低(P < 0.01); AST和ALT显著增加(P < 0.001) (图 3A、B)。与模型组相比, 高剂量组TC、LDL-C和AST降低, 差异具有统计学意义(P < 0.05), 而TG、HDL-C和ALT具有向正常组转归的趋势(图 3A、B), 提示PNS对模型组血脂及肝酶有改善作用。
5 三七总皂苷对T2DM小鼠肝脏GSH-Px、SOD和CAT活性的影响
氧化-抗氧化系统失调是导致机体活性氧累积的重要诱因, 进而导致氧化应激, 而后者在胰岛素抵抗和糖尿病发生发展中起关键作用[10]。结果显示, 与正常组相比, 模型组肝脏抗氧化酶GSH-Px、SOD和CAT显著降低(P < 0.001)。给药6周后, 与模型组相比, 高剂量组GSH-Px和CAT活性增加(P < 0.05), SOD变化不显著(图 4), 提示PNS降低了T2DM小鼠肝脏氧化应激水平。
6 三七总皂苷降低T2DM小鼠血液炎症因子
炎症反应是导致胰岛素抵抗的关键因素, 也是糖尿病发生发展的机制之一[11, 12]。与正常组相比, 模型组血液中炎症因子TNF-α和IL-6水平显著增加(P < 0.001) (图 5A), PNS治疗后TNF-α和IL-6水平降低, 与模型组相比差异具有统计学意义(P < 0.05) (图 5B)。
7 小鼠血浆代谢组学研究
7.1 质控分析
正负离子下质控样本的变异系数偏差在±2 std (图 6A、B)。各样本间的相关性系数大于0.95 (图 6C、D), 表明检测系统稳定可靠。
7.2 代谢轮廓分析
基于模式识别对正常组和模型组小鼠血浆进行代谢轮廓分析。PCA结果显示, 组间样本分离明显, 组内聚集良好(图 7A、D)。PLS-DA表明, 正离子模式的R2Y和Q2分别为0.85和0.78 (图 7B); 负离子模式的R2Y和Q2分别为0.82和0.69 (图 7E), 表明模型可靠。置换检验表明, 正负模式下, R2Y建模值与真实值构成的回归线截距分别为0.930和0.921; Q2建模值与真实值构成的回归线截距分别为-0.219和-0.244 (图 7C、F), 表明PLS-DA模型无过拟合。PCA显示, 正负模式下高剂量组代谢轮廓介于正常组与模型组之间(图 7G、H), 提示PNS对T2DM小鼠异常代谢具有改善作用。
7.3 潜在差异代谢物的筛选
代谢物的鉴定通过标准品库和HMDB数据库代谢物的MS/MS谱图匹配识别, 鉴定的代谢物须满足MW实测值-MW理论值 < △15 ppm, 代表性代谢物的MS/MS谱图匹配如图 8A、B所示。根据PLS-DA模型下VIP > 1.0、倍数变化FC ≥ 1.50或≤ 0.67且P < 0.05筛选潜在差异代谢物45个。与正常组相比, 22个代谢物在模型组中显著增加, 23个代谢物显著降低(表 1), 代谢物的趋势变化如图 9A, PNS治疗后花生四烯酸(arachidonic acid, AA)、前列腺素类物质(prostaglandin, PGs)、肉碱衍生物及脂肪酸等20个代谢物水平显著改变且向正常组转归(图 9B), 提示这些代谢物在PNS对T2DM小鼠降糖中发挥了关键性作用。
7.4 通路富集及定量分析
将45个差异代谢物导入MetaboAnalyst 5.0数据库作通路富集分析, 根据P值及通路影响值(pathway impact, PI), 显示模型组花生四烯酸代谢(P = 1.73E-5, PI = 0.293)、亚油酸代谢(P = 0.008, PI = 0.301) 显著变化, 与肝脏功能相关的谷胱甘肽代谢以及与线粒体能量代谢相关的肉碱合成显示较高的PI, 分别为0.112和0.143 (图 10A, 表 2)。PNS治疗后花生四烯酸代谢(P = 0.001, PI = 0.279)、亚油酸代谢显著变化(P = 0.008, PI = 0.301) (图 10B, 表 3)。定量结果显示, 花生四烯酸通路中, 模型组AA、PGE2、PGF2β、PGC2、20-HETE、11, 12-DiHETrE和14, 15-DiHETrE较正常组显著增加, 而谷胱甘肽显著减少(P < 0.05)。PNS治疗后AA、PGE2、20-HETE、PGF2β和PGC2向正常组转归, 谷胱甘肽、11, 12-DiHETrE和14, 15-DiHETrE具有向正常组转归的趋势(图 10C)。同样, PNS治疗后亚油酸代谢途径中相关代谢物水平向正常组转归(图 10D), 提示PNS可能通过花生四烯酸和亚油酸途径调节T2DM小鼠的异常代谢。
8 三七总皂苷对T2DM小鼠肝脏炎性分子及NF-κB信号通路的影响
为探明PNS对T2DM小鼠炎症的影响, 采用Western blot检测了肝组织中TNF-α、IL-6及NF-κB通路的变化(图 11A、C)。结果显示, 与正常组相比, 模型组TNF-α和IL-6表达显著增加(P < 0.05), pNF-κBp65/NF-κBp65在胞浆中减少, 核中增加(P < 0.05)。PNS治疗后模型组TNF-α和IL-6的表达显著降低(P < 0.05), 胞浆中pNF-κBp65/NF-κBp65增加, 核中减少(P < 0.05), 对IκBα的表达无显著变化(图 11B、D), 表明PNS对T2DM小鼠肝脏NF-κB通路具有抑制作用, 且能够降低TNF-α和IL-6的表达。
讨论
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皂苷是三七中的重要有效组分, 也是三七成分研究最为系统的活性物质。研究表明, 三七皂苷中的人参皂苷Rb1和Re具有降糖和减轻糖尿病并发症的作用[8, 9]。然而, 三七总皂苷是否具有降糖作用尚不明确。血塞通是三七总皂苷制剂的通用药名, 具有活血祛瘀、通脉活络、调节微循环之功效。根据中国药典2020版对血塞通制剂有效成分含量要求, 三七总皂苷中三七皂苷R1、人参皂苷Rg1、人参皂苷Re、人参皂苷Rb1及人参皂苷Rd的含量分别不得低于5.00%、25.00%、2.50%、27.00%和5.00%。为确保三七总皂苷中单体皂苷含量符合要求, 本实验对市售三七总皂苷含量检测, 显示三七皂苷R1、人参皂苷Rg1、人参皂苷Re、人参皂苷Rb1和人参皂苷Rd含量分别为6.96%、34.29%、2.65%、31.34%和10.19%, 各成分含量符合中国药典(2020版) 规定。
在糖尿病动物模型制备中, STZ的用量及给药方法与糖尿病分型密切相关。单次大剂量(170~200 mg·kg-1) 注射STZ可导致小鼠胰岛β细胞功能破坏, 为T1DM理想造模方法[13, 14]; 若先使用高脂饲料喂养小鼠, 再多次小剂量(30~70 mg·kg-1) 注射STZ, 可破坏部分胰岛β细胞功能, 导致外周组织对胰岛素敏感性降低, 为T2DM理想造模方法[13-15]。本实验采用60%脂肪供能纯化型饲料喂养C57BL/6J小鼠12周, 小鼠表现为体型肥胖, 反应迟钝, 高血脂等特征, 再用40 mg·kg-1的STZ连续腹腔注射5天。此法高效、可控、模型稳定且成功率高达90%, 模型小鼠FBG超过15 mmol·L-1, 且小鼠无死亡。
胰岛素抵抗与炎症因子关系密切, 高水平的炎性因子可造成胰岛β细胞功能受损, 导致胰岛素抵抗。因此, 炎症被认为是诱发糖尿病的重要致病因素[12]。临床上, 可见糖尿病患者血液中急性期反应产物和炎性因子水平的增加, 高水平的炎性因子通过“cross-talk”对胰岛素信号传导起抑制作用, 诱导胰岛素抵抗[12, 16]。IL-6和TNF-α是重要的细胞因子, 可由免疫细胞和脂肪细胞产生, 在炎症和免疫反应中起核心调控作用。高水平的IL-6使肝脏处于应激状态, 分泌大量急性反应蛋白, 激活血管内皮和脂肪组织急性相反应, 产生胰岛素抵抗[17]。此外, IL-6还可通过促进胰岛β淋巴细胞分化, 促使IgG高表达, 激活杀伤性T淋巴细胞, 导致胰岛β细胞功能破坏, 加重胰岛素抵抗[18]。同样, TNF-α可直接作用于胰岛素信号转导系统, 干扰其正常信号, 降低机体对胰岛素的敏感性。TNF-α还可以通过刺激糖皮质激素、胰高血糖素、儿茶酚胺等其他激素的分泌, 加快糖尿病进程[19]。众所周知, NF-κB是机体调节炎症反应的重要核因子, 可被TNF-α和IL等多种因子激活, 活化的NF-κB促进p65快速入核, 进一步促进TNF-α、IL-6及IL-1β的释放, 加重并持续放大炎症反应, 造成肝功异常, 导致机体对胰岛素敏感性降低[20]。反之, 炎性因子可通过活化的NF-κB信号诱导氧化应激, 降低GSH-Px、SOD和CAT表达, 破坏机体氧化-还原稳态[21]。与文献一致[18-21], 模型组NF-κB信号被激活, IL-6和TNF-α的水平增加, 且GSH-Px、SOD和CAT表达降低, PNS干预后NF-κB信号被抑制, TNF-α和IL-6水平降低, 肝脏GSH-Px和CAT表达增加, 肝功能改善, 提示PNS可能通过抑制NF-κB信号, 降低了炎性因子水平, 进而改善肝脏功能发挥了降糖作用。
花生四烯酸是机体必需多不饱和脂肪酸, 对机体血糖的调节具有双向性, 其机制与其代谢产生的炎性因子有关。细胞水平, 低于15 µmol·L-1的花生四烯酸能够促进胰岛β细胞生长, 30 µmol·L-1花生四烯酸能够抑制细胞生长, 超过100 µmol·L-1的花生四烯酸可导致胰岛β细胞功能损伤[22]。代谢层面, 花生四烯酸经COX-2和LOX途径代谢生成的前列腺素类(prostaglandin Gs, PGs) 和羟基二十碳四烯酸类(hydroxyeicosatetraenoic acids, HETEs) 物质, 能够直接破坏胰岛β细胞, 减少胰岛素分泌, 降低机体对胰岛素的敏感性, 其机制可能与致炎因子PGs的过量累积导致的胰岛β细胞凋亡有关[23]。另一方面, 花生四烯酸经P450单加氧酶代谢途径生成的环氧二十碳三烯酸类(epoxyeicosatrienoic acids, EETs)可促进胰岛素信号转导, 增强胰岛素的敏感性, 降低血糖[24]。本实验中, 模型组小鼠血液中花生四烯酸浓度较正常小鼠增加了3.14倍, 且模型组前列腺素途径代谢物PGE2、PGF2β和PGC2, 以及LOX途径代谢物20-HETE、14, 15-DiHETrE和11, 12-DiHETrE的水平均明显增加。通路富集证实, 花生四烯酸代谢在模型组中显著变化且具有高的通路影响值。PNS不仅降低花生四烯酸、PGE2、20-HETE、PGF2β及PGC2的水平, 而且对花生四烯酸的异常代谢具有调节作用, 提示PNS可能通过调控花生四烯酸代谢中COX-2和LOX途径, 降低炎性因子水平, 保护胰岛β细胞功能发挥了降糖作用。遗憾的是, 本实验代谢组学检测到的EETs物质较少(可能与样本采集、检测技术及手段有关)。因此, 目前的数据尚不能预判PNS是否通过P450单加氧酶途径调控了花生四烯酸代谢。
亚油酸对清理血管胆固醇及甘油三脂发挥重要作用, 被称为“血管清道夫”。亚油酸异常减少会导致脂质堆积、代谢异常, 诱发高血脂症及肥胖等多种疾病[25]。大数据显示, 血液中亚油酸水平与T2DM风险呈负相关, 且高水平的亚油酸不仅对合并高胆固醇血症的T2DM患者具有改善作用, 而且可恢复糖尿病患者受损的内皮细胞功能, 降低甘油三酯水平并抑制血小板聚集[26]。结果显示, T2DM小鼠血液中亚油酸代谢通路异常, 其通路代谢物, 包括eicosapentaenoic acid、8, 11, 14-eicosatrienoic acid和docosahexaenoic acid (DHA) 的水平降低, 而PNS可提高模型组中这些代谢物的水平, 推测PNS降血脂作用可能与改善亚油酸异常代谢有关。
作为线粒体脂肪酸β-氧化的特定底物, 酰基肉碱对维持正常肝功能具有重要作用。酰基肉碱与脂肪酸结合使脂肪酸以酰基肉碱形式通过线粒体膜完成β氧化, 为机体提供能量。线粒体功能损伤时, 酰基肉碱对脂肪酸转运能力降低, 游离脂肪酸累积, 造成肝毒性。因此, 酰基肉碱可作为肝功是否正常的预判指标[27], 不仅如此, 酰基肉碱还可提高T2DM的早期预测效能[28]。代谢组学表明, 模型组乙酰肉碱、丙酰肉碱、己酰肉碱、棕榈酰肉碱和癸酰肉碱的水平显著降低, 且肉碱合成途径异常, PNS干预可提高乙酰肉碱、癸酰肉碱和棕榈酰肉碱的水平, 这对于改善肝脏功能, 提高机体能量供应, 调节糖脂代谢发挥了作用。
肝脏是机体糖脂代谢的重要器官, 当机体处于高糖状态时, 糖代谢紊乱, 糖耐量减退, 诱发胰岛素抵抗[18]。反之, 糖尿病的发生提高了机体氧化应激水平, 过度的氧化应激加速了糖尿病的进程, 导致肝功能受损[29]。代谢组学表明, 模型组中还原性谷胱甘肽、牛磺酸、辅酶Q1降低, 且肝脏中GSH-Px和CAT表达减少, PNS既提高了牛磺酸、辅酶Q1的水平, 又降低了ALT和AST的水平, 而且增加肝脏GSH-Px和CAT的活性, 推测PNS的降糖作用可能与降低肝脏氧化应激水平, 调节肝脏代谢及改善肝功能有关。
综上所述, PNS可能通过抑制NF-κB信号, 调节花生四烯酸和亚油酸代谢, 以降低炎性反应、改善肝脏功能发挥降糖降脂作用。本研究为三七总皂苷临床治疗T2DM提供了实验依据, 也为三七总皂苷的开发利用提供理论依据。
作者贡献: 刘文虎负责实验设计、数据分析、文章撰写及修改; 张金花、刘汉湘、刘雨轩、吴敏完成实验部分; 常晋霞负责部分数据分析及文章修改。
利益冲突: 本文不存在任何利益冲突。
基金
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  • 国家级大学生创新创业项目(202210634038)
  • 四川省应用基础科研项目(2019YJ0378)
  • 川北医学院重点发展项目(CBY22-ZDA01)
  • 南充市市校合作项目(18SXHZ0402)
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doi: 10.16438/j.0513-4870.2023-0934
  • 接收时间：2023-08-01
  • 首发时间：2025-11-28
  • 出版时间：2024-04-12
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  • 收稿日期：2023-08-01
  • 修回日期：2023-09-21
基金
国家级大学生创新创业项目(202210634038)
四川省应用基础科研项目(2019YJ0378)
川北医学院重点发展项目(CBY22-ZDA01)
南充市市校合作项目(18SXHZ0402)
作者信息
    1.川北医学院, 药学院, 四川 南充 637100
    2.川北医学院, 基础医学与法医学院, 四川 南充 637100

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*常晋霞, E-mail: ;
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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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