scholarly journals Lipidomics Analysis Indicates Disturbed Hepatocellular Lipid Metabolism in Reynoutria multiflora-Induced Idiosyncratic Liver Injury

2020 ◽  
Vol 11 ◽  
Author(s):  
Xiaofang Wu ◽  
Yating Zhang ◽  
Jiaqi Qiu ◽  
Ya Xu ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Liver Injury ◽  
Rat Liver ◽  
High Performance ◽  
Phospholipid Metabolism ◽  
Polygonum Multiflorum ◽  
Drug Induced ◽  
Metabolic Characteristics ◽  
Lipid Biomarker ◽  
Q Exactive

The root of Reynoutria multiflora (Thunb.) Moldenke (syn.: Polygonum multiflorum Thunb., HSW) is a distinguished herb that has been popularly used in traditional Chinese medicine (TCM). Evidence of its potential side effect on liver injury has accumulated and received much attention. The objective of this study was to profile the metabolic characteristics of lipids in injured liver of rats induced by HSW and to find out potential lipid biomarkers of toxic consequence. A lipopolysaccharide (LPS)-induced rat model of idiosyncratic drug-induced liver injury (IDILI) was constructed and evident liver injury caused by HSW was confirmed based on the combination of biochemical, morphological, and functional tests. A lipidomics method was developed for the first time to investigate the alteration of lipid metabolism in HSW-induced IDILI rat liver by using ultra-high-performance liquid chromatography/Q-exactive Orbitrap mass spectrometry coupled with multivariate analysis. A total of 202 characterized lipids, including phosphatidylcholine (PC), lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE), lysophosphatidylethanolamine (LPE), sphingomyelin (SM), phosphatidylinositol (PI), lysophosphatidylinositol (LPI), phosphatidylserine (PS), phosphoglycerols (PG), and ceramide (Cer), were compared among groups of LPS and LPS + HSW. A total of 14 out 26 LPC, 22 out of 47 PC, 19 out of 29 LPE, 16 out of 36 PE, and 10 out of 15 PI species were increased in HSW-treated rat liver, which indicated that HSW may cause liver damage via interfering the phospholipid metabolism. The present work may assist lipid biomarker development of HSW-induced DILI and it also provide new insights into the relationships between phospholipid perturbation and herbal-induced idiosyncratic DILI.

scholarly journals High-Throughput Identification of Organic Compounds from Polygoni Multiflori Radix Praeparata (Zhiheshouwu) by UHPLC-Q-Exactive Orbitrap-MS

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3977
Author(s):  
Shaoyun Wang ◽  
Xiaozhu Sun ◽  
Shuo An ◽  
Fang Sang ◽  
Yunli Zhao ◽  
...  
Keyword(s):  
High Performance ◽  
Chemical Constituents ◽  
Water Extract ◽  
Ethanol Extract ◽  
In Vivo Studies ◽  
Polygonum Multiflorum ◽  
Q Exactive ◽  
Orbitrap Ms

Polygoni Multiflori Radix Praeparata (PMRP), as the processed product of tuberous roots of Polygonum multiflorum Thunb., is one of the most famous traditional Chinese medicines, with a long history. However, in recent years, liver adverse reactions linked to PMRP have been frequently reported. Our work attempted to investigate the chemical constituents of PMRP for clinical research and safe medication. In this study, an effective and rapid method was established to separate and characterize the constituents in PMRP by combining ultra-high performance liquid chromatography with hybrid quadrupole-orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap-MS). Based on the accurate mass measurements for molecular and characteristic fragment ions, a total of 103 compounds, including 24 anthraquinones, 21 stilbenes, 15 phenolic acids, 14 flavones, and 29 other compounds were identified or tentatively characterized. Forty-eight compounds were tentatively characterized from PMRP for the first time, and their fragmentation behaviors were summarized. There were 101 components in PMRP ethanol extract (PMRPE) and 91 components in PMRP water extract (PMRPW). Simultaneously, the peak areas of several potential xenobiotic components were compared in the detection, which showed that PMRPE has a higher content of anthraquinones and stilbenes. The obtained results can be used in pharmacological and toxicological research and provided useful information for further in vitro and in vivo studies.

Idiosyncratic drug-induced liver injury linked to Polygonum multiflorum: A case study by pharmacognosy

2017 ◽  
Vol 23 (8) ◽  
pp. 625-630 ◽  
Author(s):  
Chun-yu Li ◽  
Qin He ◽  
Dan Gao ◽  
Rui-yu Li ◽  
Yun Zhu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Polygonum Multiflorum ◽  
Drug Induced ◽  
Drug Induced Liver Injury

scholarly journals Quantitative Transcriptional Biomarkers of Xenobiotic Receptor Activation in Rat Liver for the Early Assessment of Drug Safety Liabilities

2020 ◽  
Vol 175 (1) ◽  
pp. 98-112 ◽  
Author(s):  
Alexei A Podtelezhnikov ◽  
James J Monroe ◽  
Amy G Aslamkhan ◽  
Kara Pearson ◽  
Chunhua Qin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Injury ◽  
Drug Development ◽  
Rat Liver ◽  
Stress Responses ◽  
Receptor Activation ◽  
Linear Modeling ◽  
Early Assessment ◽  
Drug Induced ◽  
Additional Qualification

Abstract The robust transcriptional plasticity of liver mediated through xenobiotic receptors underlies its ability to respond rapidly and effectively to diverse chemical stressors. Thus, drug-induced gene expression changes in liver serve not only as biomarkers of liver injury, but also as mechanistic sentinels of adaptation in metabolism, detoxification, and tissue protection from chemicals. Modern RNA sequencing methods offer an unmatched opportunity to quantitatively monitor these processes in parallel and to contextualize the spectrum of dose-dependent stress, adaptation, protection, and injury responses induced in liver by drug treatments. Using this approach, we profiled the transcriptional changes in rat liver following daily oral administration of 120 different compounds, many of which are known to be associated with clinical risk for drug-induced liver injury by diverse mechanisms. Clustering, correlation, and linear modeling analyses were used to identify and optimize coexpressed gene signatures modulated by drug treatment. Here, we specifically focused on prioritizing 9 key signatures for their pragmatic utility for routine monitoring in initial rat tolerability studies just prior to entering drug development. These signatures are associated with 5 canonical xenobiotic nuclear receptors (AHR, CAR, PXR, PPARα, ER), 3 mediators of reactive metabolite-mediated stress responses (NRF2, NRF1, P53), and 1 liver response following activation of the innate immune response. Comparing paradigm chemical inducers of each receptor to the other compounds surveyed enabled us to identify sets of optimized gene expression panels and associated scoring algorithms proposed as quantitative mechanistic biomarkers with high sensitivity, specificity, and quantitative accuracy. These findings were further qualified using public datasets, Open TG-GATEs and DrugMatrix, and internal development compounds. With broader collaboration and additional qualification, the quantitative toxicogenomic framework described here could inform candidate selection prior to committing to drug development, as well as complement and provide a deeper understanding of the conventional toxicology study endpoints used later in drug development.

scholarly journals Application of a Rat Liver Drug Bioactivation Transcriptional Response Assay Early in Drug Development That Informs Chemically Reactive Metabolite Formation and Potential for Drug-induced Liver Injury

2020 ◽  
Vol 177 (1) ◽  
pp. 281-299 ◽  
Author(s):  
James J Monroe ◽  
Keith Q Tanis ◽  
Alexei A Podtelezhnikov ◽  
Truyen Nguyen ◽  
Sam V Machotka ◽  
...  
Keyword(s):  
Liver Injury ◽  
Rat Liver ◽  
Stress Responses ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Drug Candidate ◽  
Related Factor ◽  
Nuclear Factor ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Abstract Drug-induced liver injury is a major reason for drug candidate attrition from development, denied commercialization, market withdrawal, and restricted prescribing of pharmaceuticals. The metabolic bioactivation of drugs to chemically reactive metabolites (CRMs) contribute to liver-associated adverse drug reactions in humans that often goes undetected in conventional animal toxicology studies. A challenge for pharmaceutical drug discovery has been reliably selecting drug candidates with a low liability of forming CRM and reduced drug-induced liver injury potential, at projected therapeutic doses, without falsely restricting the development of safe drugs. We have developed an in vivo rat liver transcriptional signature biomarker reflecting the cellular response to drug bioactivation. Measurement of transcriptional activation of integrated nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1) electrophilic stress, and nuclear factor erythroid 2-related factor 1 (NRF1) proteasomal endoplasmic reticulum (ER) stress responses, is described for discerning estimated clinical doses of drugs with potential for bioactivation-mediated hepatotoxicity. The approach was established using well benchmarked CRM forming test agents from our company. This was subsequently tested using curated lists of commercial drugs and internal compounds, anchored in the clinical experience with human hepatotoxicity, while agnostic to mechanism. Based on results with 116 compounds in short-term rat studies, with consideration of the maximum recommended daily clinical dose, this CRM mechanism-based approach yielded 32% sensitivity and 92% specificity for discriminating safe from hepatotoxic drugs. The approach adds new information for guiding early candidate selection and informs structure activity relationships (SAR) thus enabling lead optimization and mechanistic problem solving. Additional refinement of the model is ongoing. Case examples are provided describing the strengths and limitations of the approach.

scholarly journals Screening of Quality Markers During the Processing of Reynoutria multiflora Based on the UHPLC-Q-Exactive Plus Orbitrap MS/MS Metabolomic Method

2021 ◽  
Vol 12 ◽  
Author(s):  
Junqi Bai ◽  
He Su ◽  
Youling Liang ◽  
Xuhua Shi ◽  
Juan Huang ◽  
...  
Keyword(s):  
High Performance ◽  
High Resolution Mass Spectrometry ◽  
Polygonum Multiflorum ◽  
Multivariate Statistical ◽  
Processing Times ◽  
Quality Markers ◽  
Q Exactive ◽  
Group 2 ◽  
Q Exactive Plus ◽  
Orbitrap Ms

The root of Reynoutria multiflora (Thunb.) Moldenke (syn: Polygonum multiflorum Thunb.) is a distinguished herb that has been popularly used in traditional Chinese medicine. The raw Reynoutria multiflora (RRM) should be processed by steaming before use, and the processing time is not specified in the processing specification. Our previous studies showed that the efficacy and toxicity of processed Reynoutria multiflora (PRM) at different processing times were inconsistent. A comprehensive identification method was established in this study to find a quality marker of raw Reynoutria multiflora (RRM) and processed Reynoutria multiflora (PRM) with different processing times. Metabolomics based on ultra-high-performance liquid chromatography tandem quadrupole/electrostatic field orbitrap high-resolution mass spectrometry (UHPLC-Q-Exactive plus orbitrap MS/MS) was used in this study. Using the CD.2 software processed database, multivariate statistical analysis methods coupled with cluster analysis and heatmap were implemented to distinguish between RRMs and PRMs with different processing times. The results showed that RRM and PRMs processed for 4, 8, 12, and 18 h cluster into group 1, and PRM processed for 24 and 32 h into group 2, indicating that it can effectively distinguish between the two groups and twenty potential markers, made the highest contributions to the observed chemical differences between two groups. Among them, tetrahydroxystilbene-O-hexoside-O-galloyl and sucrose can be used to identify PRM processed for 24 h. Therefore, the properties of RRM changed after 24 h of processing, and the quality markers were screened to distinguish RRM and PPM. It can also be used as an important control technology for the processing of RM, which has wide application prospects.

scholarly journals Metabolomics Profiling and Diagnosis Biomarkers Searching for Drug-Induced Liver Injury Implicated to Polygonum multiflorum: A Cross-Sectional Cohort Study

2020 ◽  
Vol 7 ◽  
Author(s):  
Ying Huang ◽  
Xu Zhao ◽  
Zi-teng Zhang ◽  
Shuai-shuai Chen ◽  
Shan-shan Li ◽  
...  
Keyword(s):  
Liver Injury ◽  
Decision Tree ◽  
High Efficiency ◽  
High Resolution Mass Spectrometry ◽  
Classification Model ◽  
Plasma Metabolites ◽  
Polygonum Multiflorum ◽  
Drug Induced ◽  
Cross Sectional ◽  
Drug Induced Liver Injury

Aim: The diagnosis of drug-induced liver injury (DILI) remains a challenge and the cases of Polygonum multiflorum Thunb. (PM) induced DILI (PM-DILI) have received much attention This study aimed to identify a simple and high-efficiency approach to PM-DILI diagnosis via metabolomics analysis.Methods: Plasma metabolites in 13 PM-DILI patients were profiled by liquid chromatography along with high-resolution mass spectrometry. Meanwhile, the metabolic characteristics of the PM-DILI were compared with that of autoimmune hepatitis (AIH), hepatitis B (HBV), and healthy volunteers.Results: Twenty-four metabolites were identified to present significantly different levels in PM-DILI patients compared with HBV and AIH groups. These metabolites were enriched into glucose, amino acids, and sphingolipids metabolisms. Among these essential metabolites, the ratios of P-cresol sulfate vs. phenylalanine and inosine vs. bilirubin were further selected using a stepwise decision tree to construct a classification model in order to differentiate PM-DILI from HBV and AIH. The model was highly effective with sensitivity of 92.3% and specificity of 88.9%.Conclusions: This study presents an integrated view of the metabolic features of PM-DILI induced by herbal medicine, and the four-metabolite decision tree technique imparts a potent tool in clinical diagnosis.

scholarly journals Drug-Induced Liver Injury: Twenty Five Cases of Acute Hepatitis Following Ingestion of Polygonum multiflorum Thunb

Gut and Liver ◽  
2011 ◽  
Vol 5 (4) ◽  
pp. 493-499 ◽  
Author(s):  
Kyoung Ah Jung ◽  
Hyun Ju Min ◽  
Seung Suk Yoo ◽  
Hong Jun Kim ◽  
Su Nyoung Choi ◽  
...  
Keyword(s):  
Liver Injury ◽  
Acute Hepatitis ◽  
Polygonum Multiflorum ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Effects of Steroids on Fetal Rat Liver

1969 ◽  
Vol 27 ◽  
pp. 350-351
Author(s):  
F. G. Zaki
Keyword(s):  
Liver Injury ◽  
Rat Liver ◽  
Fetal Liver ◽  
Dosage Level ◽  
Maternal Plasma ◽  
Methyl Prednisolone ◽  
Fetal Rat ◽  
Toxic Agents ◽  
Fetal Rat Liver ◽  
Neonatal Liver

Fetal and neonatal liver injury induced by agents circulating in maternal plasma, even though well recognized, its morphological manifestations are not yet established. As part of our studies of fetal and neonatal liver injury induced by maternal nutritional disorders, metabolic impairment and toxic agents, the effects of two anti-inflammatory steroids have been recently inves tigated.Triamcinolone and methyl prednisolone were injected each in a group of rats during pregnancy at a-dosage level of 2 mgm three times a week. Fetal liver was studied at 18 days of gestation. Litter size and weight markedly decreased than those of control rats. Stillbirths and resorption were of higher incidence in the triamcinolone group than in those given the prednisolone.

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