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采用靶向神经酰胺组学方法评估[药物名称]引起的潜在肝损伤的潜在生物标志物。

Assessing potential liver injury induced by using potential biomarkers via targeted sphingolipidomics.

机构信息

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China.

出版信息

Pharm Biol. 2022 Dec;60(1):1578-1590. doi: 10.1080/13880209.2022.2099908.

DOI:10.1080/13880209.2022.2099908
PMID:35949191
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9377235/
Abstract

CONTEXT

Thunb. (Polygonaceae) (PM) can cause potential liver injury which is typical in traditional Chinese medicines (TCMs)-induced hepatotoxicity. The mechanism involved are unclear and there are no sensitive evaluation indicators.

OBJECTIVE

To assess PM-induced liver injury, identify sensitive assessment indicators, and screen for new biomarkers using sphingolipidomics.

MATERIALS AND METHODS

Male Sprague-Dawley (SD) rats were randomly divided into four groups (control, model with low-, middle- and high-dose groups,  = 6 each). Rats in the three model groups were given different doses of PM (i.g., low/middle/high dose, 2.7/8.1/16.2 g/kg) for four months. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the plasma and liver were quantitatively analyzed. Fixed liver tissue sections were stained with haematoxylin and eosin and examined under a light microscope. The targeted sphingolipidomic analysis of plasma was performed using high-performance liquid chromatography tandem mass spectrometry.

RESULTS

The maximal tolerable dose (MTD) of PM administered intragastrically to mice was 51 g/kg. Sphingolipid profiling of normal and PM-induced liver injury SD rats revealed three potential biomarkers: ceramide (Cer) (d18:1/24:1), dihydroceramide (d18:1/18:0)-1-phosphate (dhCer (d18:1/18:0)-1P) and Cer (d18:1/26:1), at 867.3-1349, 383.4-1527, and 540.5-658.7 ng/mL, respectively. A criterion for the ratio of Cer (d18:1/24:1) and Cer (d18:1/26:1) was suggested and verified, with a normal range of 1.343-2.368 (with 95% confidence interval) in plasma.

CONCLUSIONS

Three potential biomarkers and one criterion for potential liver injury caused by PM that may be more sensitive than ALT and AST were found.

摘要

背景

菝葜（百合科）（PM）可引起潜在的肝损伤，这是中药（TCM）引起肝毒性的典型特征。其涉及的机制尚不清楚，也没有敏感的评估指标。

目的

使用神经节苷脂组学评估 PM 诱导的肝损伤，确定敏感的评估指标，并筛选新的生物标志物。

材料和方法

雄性 Sprague-Dawley（SD）大鼠随机分为四组（对照组、低、中、高剂量组，每组 6 只）。三组模型大鼠分别给予不同剂量的 PM（低/中/高剂量，2.7/8.1/16.2 g/kg），连续给药 4 个月。定量分析血浆和肝脏中丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平。用苏木精和伊红染色固定的肝组织切片，在光镜下检查。采用高效液相色谱串联质谱法对血浆进行靶向神经节苷脂组学分析。

结果

PM 灌胃给予小鼠的最大耐受剂量（MTD）为 51 g/kg。正常和 PM 诱导的肝损伤 SD 大鼠的神经节苷脂谱分析显示了三个潜在的生物标志物：神经酰胺（Cer）（d18:1/24:1）、二氢神经酰胺（d18:1/18:0）-1-磷酸（dhCer（d18:1/18:0）-1P）和 Cer（d18:1/26:1），分别为 867.3-1349、383.4-1527 和 540.5-658.7 ng/mL。建议并验证了 Cer（d18:1/24:1）与 Cer（d18:1/26:1）比值的标准，其血浆正常范围为 1.343-2.368（95%置信区间）。

结论

发现了三种可能比 ALT 和 AST 更敏感的 PM 引起潜在肝损伤的潜在生物标志物和一个标准。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/297efa5e3946/IPHB_A_2099908_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/66fa3020e83d/IPHB_A_2099908_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/b9529f92179c/IPHB_A_2099908_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/e186b5e671d6/IPHB_A_2099908_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/88b5c219eda7/IPHB_A_2099908_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/c652147bc67a/IPHB_A_2099908_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/f08239c98351/IPHB_A_2099908_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/297efa5e3946/IPHB_A_2099908_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/66fa3020e83d/IPHB_A_2099908_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/b9529f92179c/IPHB_A_2099908_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/e186b5e671d6/IPHB_A_2099908_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/88b5c219eda7/IPHB_A_2099908_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/c652147bc67a/IPHB_A_2099908_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/f08239c98351/IPHB_A_2099908_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f221/9377235/297efa5e3946/IPHB_A_2099908_F0007_C.jpg

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