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基于血浆代谢组学的附子脂溶性生物碱对佐剂性关节炎模型大鼠的毒性作用机制研究
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| 篇名： | 基于血浆代谢组学的附子脂溶性生物碱对佐剂性关节炎模型大鼠的毒性作用机制研究 |
| TITLE： | |
| 摘要： | 目的：研究附子脂溶性生物碱对佐剂性关节炎（AIA）模型大鼠的毒性作用机制。方法：将40只大鼠随机分为空白组（超纯水）、模型组（超纯水）和附子脂溶性生物碱低、高剂量组（12.5、35 mg/kg），每组10只。除空白组外，其余各组大鼠均于右后足垫部位注射0.1 mL完全弗氏佐剂复制AIA模型。造模19 d后开始灌胃给药，每天1次。连续给药14 d后，采用超高效液相色谱-线性离子阱/静电场轨道阱结合高分辨质谱技术分离并鉴定血浆中内源性代谢物，然后对数据进行主成分分析（PCA）和偏最小二乘判别分析（PLS-DA），通过变量投影重要度值（VIP）＞1和P值（＜0.05）筛选血浆中的差异代谢物；并根据差异代谢物查阅京都基因与基因组百科全书数据库，推测附子脂溶性生物碱对AIA大鼠的毒性作用机制。结果：共鉴定出57个血浆代谢物，并确定了L-脯氨酸、6-羟基烟酸、腺苷等11个差异代谢物。AIA造模后可引起大鼠血浆中L-脯氨酸和尿苷酸含量显著降低（P＜0.05或P＜0.01），脱氧胞苷含量显著升高（P＜0.01）。低剂量附子脂溶性生物碱给药后可使模型大鼠血浆中腺苷和L-脯氨酸含量显著降低（P＜0.05或P＜0.01），血浆中脱氧胆酸含量显著升高（P＜0.05）；而高剂量附子脂溶性生物碱给药后可使模型大鼠血浆中6-羟基烟酸、腺苷、肉碱、L-脯氨酸、N-甲酰氨基苯甲酸含量显著降低（P＜0.05或P＜0.01），血浆中脱氧胆酸、L-精氨酸、脱氧胞苷、L-赖氨酸含量显著升高（P＜0.05或P＜0.01）。结论：低剂量附子脂溶性生物碱对AIA模型大鼠的毒性较小；高剂量附子脂溶性生物碱对AIA模型大鼠的毒性作用可能与其引起胆汁分泌异常及赖氨酸生物合成及嘌呤、嘧啶、色氨酸、脯氨酸、精氨酸代谢紊乱有关。 |
| ABSTRACT： | OBJECTIVE：To study the toxicity mechanism of lipid-soluble alkaloids of Aconitum carmichaeli to adjuvant-induced arthritis （AIA） model rats. METHODS： Totally 40 rats were randomly divided into blank group （ultrapure water）， model group （ultrapure water） and A. carmichaeli lipid-soluble alkaloids low-dose and high-dose groups （12.5， 35 mg/kg）， with 10 rats in each group. Except for blank group， rats in other groups were given complete Freund’s adjuvant 0.1 mL on the right hind paw to induce AIA model. 19 d after modeling， they were given relevant medicine intragastrically， once a day. After 14 d of administration， endogenous metabolites were separated and identified from plasma by UPLC-LTQ/Orbitrap MS. Then， the collected data were analyzed by principal component analysis （PCA） and partial least squares-discriminant analysis （PLS-DA）. Variable importance projection （VIP）＞1 and P value （＜0.05） were used to screen differential metabolites in plasma. Retrieving the database of Kyoto Encyclopedia of Genes and Genomes according to the differential metabolites，the toxic mechanism of A. carmichaeli liposoluble alkaloids to AIA rats were speculated. RESULTS： A total of 57 plasma metabolites were indentified， and 11 differential metabolites such as L-proline， 6-hydroxynicotinic acid and adenosine were identified. After inducing AIA model， the plasma contents of L-proline and uridylic acid were decreased significantly （P＜0.05 or P＜0.01）， and the content of deoxycytidine was increased significantly （P＜0.01）. Low dose of A. carmichaeli lipid-soluble alkaloids could decrease the plasma contents of adenosine and L-proline in rats （P＜0.05 or P＜0.01）， while the plasma contents of deoxycholic acid was increased significantly （P＜0.05）. High dose of A. carmichaeli lipid-soluble alkaloids could decrease the plasma contents of 6-hydroxynicotinic acid， adenosine， carnitine， L-proline， N-formylaminobenzoic acid were decreased significantly （P＜0.05 or P＜0.01）， while the plasma contents of deoxycholic acid， L-arginine， deoxycytidine and L-lysine were increased significantly （P＜0.05 or P＜0.01）. CONCLUSIONS： The toxicity of low-dose of A. carmichaeli lipid-soluble alkaloids to AIA model rats is less； the toxicity of high-dose of A. carmichaeli lipid-soluble alkaloids to AIA model rats may be related to abnormal bile secretion， lysine biosynthesis and metabolic disorders of purine， pyrimidine， tryptophan， proline and arginine. |
| 期刊： | 2019年第30卷第1期 |
| 作者： | 谢运飞，李芸霞，刘美辰，周忆梦，王彪，彭成 |
| AUTHORS： | XIE Yunfei，LI Yunxia，LIU Meichen，ZHOU Yimeng，WANG Biao，PENG Cheng |
| 关键字： | 附子；脂溶性生物碱；代谢组学；佐剂性关节炎；毒性机制；大鼠 |
| KEYWORDS： | Aconitum carmichaeli； Lipid-soluble alkaloids； Metabolomics； Adjuvant-induced arthritis model； Toxic mechanism； Rat |
| 阅读数： | 387 次 |
| 本月下载数： | 8 次 |
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