Combination of LC/MS and GC/MS based metabolomics to study the hepatotoxic effect of realgar nanoparticles in rats

Zhang, Mohan; Chen, Jiaqing; Guo, Huimin; Li, Rui-Ting; Gao, Yiqiao; Tian, Yuan; Zhang, Zunjian; Huang, Yin

doi:10.1016/s1875-5364(17)30098-5

Cited by 15 publications

(11 citation statements)

References 39 publications

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“…We dried the extracts with nitrogen flow at 37 °C and redissolved them with methanol before metabolomic analysis. Sample preparation and methods of instruments were based on our previous studies [49,50,51], as shown in the Supplementary Materials.…”

Section: Methodsmentioning

confidence: 99%

Untargeted Metabolomics Study of the In Vitro Anti-Hepatoma Effect of Saikosaponin d in Combination with NRP-1 Knockdown

Hou

Zhang

et al. 2019

Molecules

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Saikosaponin d (SSd) is one of the main active ingredients in Radix Bupleuri. In our study, network pharmacology databases and metabolomics were used in combination to explore the new targets and reveal the in-depth mechanism of SSd. A total of 35 potential targets were chosen through database searching (HIT and TCMID), literature mining, or chemical similarity predicting (Pubchem). Out of these obtained targets, Neuropilin-1 (NRP-1) was selected for further research based on the degree of molecular docking scores and novelty. Cell viability and wound healing assays demonstrated that SSd combined with NRP-1 knockdown could significantly enhance the damage of HepG2. Metabolomics analysis was then performed to explore the underlying mechanism. The overall difference between groups was quantitatively evaluated by the metabolite deregulation score (MDS). Results showed that NRP-1 knockdown exhibited the lowest MDS, which demonstrated that the metabolic profile experienced the slightest interference. However, SSd alone, or NRP-1 knockdown in combination with SSd, were both significantly influenced. Differential metabolites mainly involved short- or long-chain carnitines and phospholipids. Further metabolic pathway analysis revealed that disturbed lipid transportation and phospholipid metabolism probably contributed to the enhanced anti-hepatoma effect by NRP-1 knockdown in combination with SSd. Taken together, in this study, we provided possible interaction mechanisms between SSd and its predicted target NRP-1.

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Section: Methodsmentioning

confidence: 99%

Untargeted Metabolomics Study of the In Vitro Anti-Hepatoma Effect of Saikosaponin d in Combination with NRP-1 Knockdown

Hou

Zhang

et al. 2019

Molecules

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“…Some reports have shown that Realgar can cause the disorders of lipids metabolism in rats and mice ( Zhang et al, 2019 ; Zhang et al, 2017 ), Pearson’s correlation analysis from kidney samples also indicated that the perturbation of lipids metabolism may play an important role in the nephrotoxicity induced by Realgar. In this study, the increased levels of lysophosphatidylcholine (LPC) and lysophosphatidyl ethanolamine (LPE) were detected in kidney tissue aqueous extracts after Realgar treatment.…”

Section: Discussionmentioning

confidence: 98%

“…This consists of the holistic thinking of TCMs and metabolomics techniques are extremely suitable for evaluating the toxicity of traditional Chinese medicines and exploring the mechanisms ( Wang et al, 2011 ). Recently, studies on the toxicological effects of Realgar or Realgar-containing medicines have been reported, and have mainly focused on hepatotoxicity ( Zhang et al, 2017 ) and neurotoxicity ( Zhang et al, 2019 ). However, less metabolic analysis of nephrotoxicity has been reported.…”

Section: Introductionmentioning

confidence: 99%

A Metabolic Profiling Study of Realgar-Induced Acute Kidney Injury in Mice

Zhang

Feng

et al. 2021

Front. Pharmacol.

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Realgar has been used as a type of mineral drug that contains arsenic for thousands of years. Previous studies have shown that Realgar-induced acute kidney injury is associated with abnormal metabolism, but the underlying mechanism is poorly understood. The aim of this study is to investigate the metabolic changes in serum and kidney tissues of mice exposed to Realgar by using a metabolomic approach and explore the molecular mechanisms of acute kidney injury induced by Realgar. Forty mice were randomly divided into four groups: Control group, 0.5-, 1.0, and 2.0 g/kg Realgar group. After 1 week, the body weight and kidney weight of the mice were measured. The serum and kidney samples were used for LC-MS spectroscopic metabolic profiling. Principal component analysis (PCA), correlation analysis, and pathway analysis were used to detect the nephrotoxic effects of Realgar. Body weight decreased significantly in the 2.0 g/kg group, and the kidney weight index also showed a dose-dependent increase in Realgar. The PCA score plot showed the serum and kidney tissue metabolic profile of mice exposed to 2.0 g/kg Realgar separated from the control group, while the lower-doses of 0.5 g/kg and 1.0 g/kg Realgar shown a similar view to the Control group. Thirty-three metabolites and seventeen metabolites were screened and identified in the serum and kidney of mice in a dose-dependent manner. respectively. Correlation analysis showed a strong correlation among these metabolites. Amino acid metabolism, lipid metabolism, glutathione metabolism, and purine metabolism pathways were found to be mainly associated with Realgar nephrotoxicity. This work illustrated the metabolic alterations in Realgar-induced nephrotoxic mice through a metabolomic approach.

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“…It has been reported that the alcohol extracted portion of LSW-ET is the main effective portion of LSW against tumors (Chen et al, 2018). However, LSW contains realgar and venenum bufonis, whichh has been queried for its safety (Zhang et al, 2017a). In order to reduce the damage of toxic substances to the body, it is very important to develop a drug targeting method.…”

Section: Discussionmentioning

confidence: 99%

Nanoparticle-Encapsulated Liushenwan Could Treat Nanodiethylnitrosamine-Induced Liver Cancer in Mice by Interfering With Multiple Critical Factors for the Tumor Microenvironment

et al. 2020

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We previously isolated an ethanol fraction of LSW (Liushenwan pill, a traditional Chinese medicine) which has been shown to prevent and treat liver cancer induced by nanodiethylnitrosamine (nanoDEN) in mice. In the present study, we utilized a highpressure microfluidics technique to generate LSW lipid nanoparticles (nano-LSW) to reduce its toxicity, and enhance its inhibitory effect on tumor growth, and further evaluate its therapeutic effect using a nanoDEN-induced mouse model of liver cancer. Our in vitro results indicated that nano-LSW-low could induce apoptosis in HepG2 cells, but exhibited low toxicity in L02 cells. Furthermore, the in vivo results indicated that nano-LSW-low exerted minimal or no damage to normal hepatocytes, kidney, and small intestine tissues. In addition, our results showed that at the 20 th week, the inflammatory infiltration in the mice in the model group increased severely, and partial pimelosis and fibrosis occurred. In contrast, the liver tissues in the mice treated with nano-LSW exhibited only slight inflammatory infiltration, without pimelosis and fibrosis. At the 30 th week, 4 out of 5 liver tissues in the model group showed hyperplastic nodules by hematoxylin and eosin (H&E) staining. However, the liver tissues in the nano-LSW treatment group did not showed hyperplastic nodules. Immunohistochemical staining showed that, in contrast to the model group, the levels of COX-2, PCNA, b-catenin, and HMGB1 protein expressions were significantly lower in the nano-LSW-low group at the 20 th and 30 th week. Compared to model group, the COX-2, TNF-a, Smad-2, and TGF-b1 mRNA levels obviously decreased in the liver tissue after the nano-LSW-low treatment. Taken together, nano-LSW-low may serve as a potent therapeutic agent for preventing liver cancer by interfering with multiple critical factors for the tumor microenvironment during oncogenesis.

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Combination of LC/MS and GC/MS based metabolomics to study the hepatotoxic effect of realgar nanoparticles in rats

Cited by 15 publications

References 39 publications

Untargeted Metabolomics Study of the In Vitro Anti-Hepatoma Effect of Saikosaponin d in Combination with NRP-1 Knockdown

Untargeted Metabolomics Study of the In Vitro Anti-Hepatoma Effect of Saikosaponin d in Combination with NRP-1 Knockdown

A Metabolic Profiling Study of Realgar-Induced Acute Kidney Injury in Mice

Nanoparticle-Encapsulated Liushenwan Could Treat Nanodiethylnitrosamine-Induced Liver Cancer in Mice by Interfering With Multiple Critical Factors for the Tumor Microenvironment

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