TOXICOLOGY MECHANISMS AND METHODS
·
2015
·
IF 1.517
Chongshan Dai,Shusheng Tang,Daowen Li,Kena Zhao,Xilong Xiao
Quinocetone (QCT), a new quinoxaline 1,4-dioxides, has been used as antimicrobial feed additive in China. Potential genotoxicity of QCT was concerned as a public health problem. This study aimed to investigate the protective effect of curcumin on QCT-induced oxidative stress and genotoxicity in human hepatocyte L02 cells. Cell viability and intracellular reactive oxygen species (ROS), biomarkers of oxidative stress including superoxide dismutase (SOD) activity and glutathione (GSH) level were measured. Meanwhile, comet assay and micronucleus assay were carried out to evaluate genotoxicity. The results showed that, compared to the control group, QCT at the concentration ranges of 2–16 μg/mL significantly decreased L02 cell viability, which was significantly attenuated with curcumin pretreatment (2.5 and 5 μM). In addition, QCT significantly increased cell oxidative stress, characterized by increases of intracellular ROS level, while decreased endogenous antioxidant biomarkers GSH level and SOD activity (all p < 0.05 or 0.01). Curcumin pretreatment significantly attenuated ROS formation, inhibited the decreases of SOD activity and GSH level. Furthermore, curcumin significantly reduced QCT-induced DNA fragments and micronuclei formation. These data suggest that curcumin could attenuate QCT-induced cytotoxicity and genotoxicity in L02 cells, which may be attributed to ROS scavenging and anti-oxidative ability of curcumin. Importantly, consumption of curcumin may be a plausible way to prevent quinoxaline 1,4-dioxides-mediated oxidative stress and genotoxicity in human or animals.
研究领域:
毒理学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL PROLIFERATION
·
2023
·
IF 8.5
Yun Lv,Ziyan Rao,Lulu Liu,Jun Jia,Chenyang Wu,Jun Xu,Yuanyuan Du,Yinan Liu,Bei Liu,Jihang Shi,Guangya Li,Dongyu Zhao,Hongkui Deng
Derivation of human hepatocytes from pluripotent stem cells in vitro has important applications including cell therapy and drug discovery. However, the differentiation of pluripotent stem cells into hepatocytes in vitro was not well recapitulated the development of liver. Here, we developed a differentiation protocol by mimicking the two-stage development of hepatoblasts, which permits the efficient generation of hepatic progenitor cells from chemically induced pluripotent stem cells (hCiPSCs). Single-cell RNA sequencing (scRNA-seq) indicates the similarity between hepatoblasts differentiated in vitro and in vivo. Moreover, hCiPSC-derived hepatic progenitor cells can further differentiate into hepatocytes that are similar to primary human hepatocytes with respect to gene expression and key hepatic functions. Our results demonstrate the feasibility of generating hepatic progenitor cells and hepatocytes from hCiPSCs with high efficiency and set the foundation for broad translational applications of hCiPSC-derived hepatocytes.
研究领域:
干细胞研究
·
分子生物学
·
再生医学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2021
·
IF 10.588
Lingfei Zhu,Xiaohan Huang,Zhenhua Li,Gang Cao,Xuanjin Zhu,Shaohua She,Tenghao Huang,Gang Lu
Increasing use of organophosphorus flame retardants (OPFRs) has aroused great concern to their uncertain environment risk, especially to human health risk. In our study, hepatotoxicity screening of six aryl-OPFRs, potential hepatotoxicity mechanism of 2-ethylhexyldiphenyl phosphate (EHDPP) using RNA-sequencing and its metabolites were investigated in human hepatocytes (L02). The toxicity results demonstrated that EHDPP should be prioritized for further research with the highest toxicity. Further RNA-seq results through GO and KEGG enrichment analysis indicated that exposure to 10 mg/L of EHDPP significantly affected energy homeostasis , endoplasmic reticulum (ER) stress, apoptosis, cell cycle, and inflammation response in cells. The top 12 hub genes were validated by RT-qPCR and conformed to be mainly related to glycolysis and ER stress, followed by cell cycle and inflammation response. Western blot, apoptosis detection, glycolysis stress test, and cell cycle analysis were further performed to verify the above main pathways. Additionally, it was found in the metabolism experiment that detoxification of EHDPP by phase I and phase II metabolism in cells wasn’t significant until 48 h with a metabolic rate of 6.12%. EHDPP was stable and still dominated the induction of toxicity. Overall, this study provided valuable information regarding the toxicity and potential metabolism pathway of EHDPP.
研究领域:
毒理学
·
分子生物学
·
基因组学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF FOOD SCIENCES AND NUTRITION
·
2016
·
IF 1.451
Baogui Wang,Jing Fu,Lumin Li,Deming Gong,Xuefang Wen,Ping Yu,Zheling Zeng
Accumulation of lipids in the liver can lead to cell dysfunction and steatosis, an important factor in pathogenesis causing non-alcoholic fatty liver disease. The mechanisms related to lipid deposition in the liver, however, remain poorly understood. This study was aimed to investigate the effects of medium-chain fatty acid (MCFA) on the lipolysis and expression of lipid-sensing genes in human liver cells with steatosis. A cellular steatosis model, which is suitable to experimentally investigate the impact of fat accumulation in the liver, was established in human normal liver cells (LO2 cells) with a mixture of free fatty acids (oleate/palmitate, 2:1) at 200 μm for 24 h incubation. MCFA was found to down-regulate expression of liver X receptor-α, sterol regulatory element binding protein-1, acetyl-CoA carboxylase, fatty acid synthase, CD 36 and lipoprotein lipase in this cellular model, and have positive effects on adipose triglyceride lipase and hormone-sensitive lipase. These results suggest that MCFA may reduce lipid accumulation by regulating key lipid-sensing genes in human liver cells with steatosis.
研究领域:
肝病学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2021
·
IF 6.953
Yundi Duan,Nan Jiang,Jing Chen,Jianhua Chen
A high serum uric acid (SUA) concentration is associated with hyperuricemia (HUA) and gout. In order to obtain long-acting therapeutic effect, correction of purine metabolism at genetic level is advantageous. For this purpose, we expressed three “human-like” urate oxidases in human hepatocytes (HL-7702) by lentivirus-mediated transduction. Enzymatic assay revealed that the recombinant urate oxidases expressed in HL-7702 cells were functionally active. Electron microscopy study showed that the recombinant enzymes were localized to peroxisome and formed distinct crystalloid core structures as in other mammal cells. Although similar rate of uric acid degradation was observed for all recombinant urate oxidases, HL-7702-pLVX-UOX 83 cells and HL-7702-pLVX-UOX 214/217 cells retained more cell viability compared with HL-7702-pLVX-UOX PBC at high uric acid level. This study provides a new direction for the treatment of gout and hyperuricemia.
研究领域:
遗传学
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代谢性疾病
·
分子生物学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY MECHANISMS AND METHODS
·
2017
·
IF 1.595
Chongshan Dai,Lei Lei,Bin Li,Yang Lin,Xilong Xiao,Shusheng Tang
Furazolidone (FZD) is extensively used as the antiprotozoal and antibacterial drug in clinic. The previous study has shown that curcumin pretreatment could improve FZD induced cytotoxicity by inhibiting oxidative stress and mitochondrial apoptotic pathway. The current study aimed to investigate the potential roles of endoplasmic reticulum (ER) stress, p38 mitogen-activated protein kinases (p38 MAPK) signaling pathway in curcumin against FZD cytotoxicity by using human hepatocyte L02 cells. The results showed that curcumin could markedly attenuate FZD induced cytotoxicity. Compared with FZD alone group, curcumin pretreatment significantly reduced the expression of phospho (p)-p38, cyclin D1, p-checkpoint kinase 1 (ChK1) and breast cancer associated gene 1 (BRCA1) protein, followed to attenuate S phase arrest. Meanwhile, curcumin pretreatment prevented FZD induced ER stress, evidenced by the inhibition of glucose-regulated protein 78 and DNA damage inducible gene 153/C/EBP-homologous protein (GADD153/CHOP) protein expression. Moreover, compared with the control, FZD exposure activated the protein and mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), which were further activated by curcumin treatment. These results reveal that curcumin could prevent FZD induced cytotoxicity and S phase arrest, which may involve the activation of Nrf2/HO-1 pathway and the inhibition of p38 MAPK pathway and ER stress.
研究领域:
药理学
·
毒理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2019
·
IF 2.931
Xianmei Piao,Zhongrui Liu,Yangyang Li,Dahong Yao,Liwen Sun,Baihui Wang,Yan Ma,Libo Wang,Yan Zhang
Bisphenol A (BPA) as a chemical raw material, is widely used in the manufacturing process of daily necessities. It was reported that BPA could induce oxidative stress , and catalase (CAT) can protect the body from oxidative stress. In this paper, the effect of BPA on CAT was carried out in vitro and in vivo. Firstly, we studied the effects of BPA on oxidative stress, cell viability and CAT activity in human hepatocytes, and the results of vitro experiments show that the survival rate of hepatocytes significant decreased along with the increase of BPA concentration. And when the BPA concentration was 100 μM, the hepatocyte survival decreased by 13.2%, ROS levels in the cells increased by 85%. However, the activity of intracellular CAT increased with the increasing concentration of BPA in 24 h. The results of vivo experiments showed that the activity of CAT in the high-dose group decreased by 29.1% compared with the control group. The long-term effects of BPA on rats reduced the CAT activity in liver, which reduced the resistance to oxidative stress. Meanwhile, the interaction mechanism between BPA and CAT at the molecule level was performed via multiple spectra methods and molecular docking, and the results illustrated that the structural change of CAT is mainly due to the strong combination of BPA with the residues of Trp185. In addition, the interaction mechanism between BPA and CAT were hydrophobic and electrostatic effect. This study provided experimental evidence for better understanding the toxicity of BPA.
研究领域:
毒理学
·
细胞生物学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2020
·Vol. 7
·期 21
·2002002
·
IF 15.84
Ying Wang,Ranjith Kumar Kankala,Jianting Zhang,Liuzhi Hao,Kai Zhu,Shibin Wang,Yu Shrike Zhang,Aizheng Chen
Compared to various traditional 2D approaches, the scaffold-based 3D tumor models have emerged as an effective strategy to investigate the complex mechanisms behind cancer progression and responses to drug treatments, by providing biomimetic extracellular matrix and stromal-like microenvironments including the vascular elements. Herein, the development of a 3D endothelialized hepatic tumor microtissue model based on the fusion of multicellular aggregates of human hepatocellular carcinoma cells and human umbilical vein endothelial cells cocultured in poly(lactic- co -glycolic acid)-based porous microspheres (PLGA PMs) is reported. In contrast to the conventional 2D culture, the cells within the PLGA PMs exhibit significantly higher half-maximal inhibitory concentration values against anticancer drugs, including doxorubicin and cisplatin. Furthermore, the feasibility of coculturing other cell types, such as fibroblasts (L929) and HepG2 cells, is investigated. Together, the findings emphasize the significance of engineered 3D hepatic tumor microtissue models using PLGA PM-based multicellular aggregates for drug screening applications.
研究领域:
癌症生物学
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药理学
·
组织工程
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2018
·
IF 3.831
Li Zhuo-Qing,Jiang Li-Long,Zhao Dong-Sheng,Zhou Jing,Wang Ling-Li,Wu Zi-Tian,Zheng Xian,Shi Zi-Qi,Li Ping,Li Hui-Jun
Dictamni Cortex (DC) has been reported to be associated with acute hepatitis in clinic and may lead to a selective sub-chronic hepatotoxicity in rats. Nevertheless, the potent toxic ingredient and the underlying mechanism remain unknown. Dictamnine (DTN), the main alkaloid from DC, possesses a furan ring which was suspected of being responsible for hepatotoxicity via metabolic activation primarily by CYP3A4. Herein, the present study aimed to evaluate the role of CYP3A4 in DTN-induced liver injury. The in vitro results showed that the EC50 values in primary human hepatocytes (PHH), L02, HepG2 and NIH3T3 cells were correlated with the CYP3A4 expression levels in corresponding cells. Furthermore, the toxicity was increased in CYP3A4-induced PHH by rifampicin, and CYP3A4 over-expressed (OE) HepG2 and L02 cells. Contrarily, the cytotoxicity was decreased in CYP3A4-inhibited PHH and CYP3A4 OE HepG2 and L02 cells inhibited by ketoconazole (KTZ). In addition, the hepatotoxicity of DTN in enzyme induction/inhibition mice was further investigated in the aspects of biochemistry, histopathology, and pharmacokinetics. Administration of DTN in combination with KTZ resulted in attenuated liver injury, including lower alanine transaminase and aspartate transaminase activities and greater AUC and Cmax of serum DTN, whereas, pretreatment with dexamethasone aggravated the injury. Collectively, our findings illustrated that DTN-induced hepatotoxicity correlated well with the expression of CYP3A4, namely inhibition of CYP3A4 alleviated the toxicity both in vitro and in vivo, and induction aggravated the toxicity effects.
研究领域:
药理学
·
毒理学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Yun Luo,Ningbo Geng,Shuai Sun,Lin Cheng,Shuangshuang Chen,Haijun Zhang,Jiping Chen
Polycyclic aromatic hydrocarbons (PAHs) and Chlorinated PAHs (Cl-PAHs) are ubiquitous environmental contaminants. The toxicological information of anthracene (Ant) and its chlorinated derivatives is quite limited. In this study, an integrated metabolomic and transcriptomic analysis approach was adopted to assess the toxic effects triggered by Ant and its chlorinated derivatives, 2-chloroanthracene (2-ClAnt) and 9,10-dichloroanthracen (9,10-Cl 2 Ant), at human-relevant levels on human normal hepatocyte L02 cells. The cell viability test showed no significant effects on the viability of L02 cells exposed to Ant, 2-ClAnt and 9,10-Cl 2 Ant at doses of 5–500 nM for 24 h. However, based on transcriptomic analysis, Ant, 2-ClAnt and 9,10-Cl 2 Ant exposure at human-relevant levels obviously perturbed global gene expression in L02 cells and induced the differential expression of several genes related to cancer development. As the number of genes related to cancer development altered by 9,10-Cl 2 Ant is the largest, 9,10-Cl 2 Ant posed greater risks of tumor development than Ant and 2-ClAnt did. Metabolomics analysis demonstrated that Ant, 2-ClAnt and 9,10-Cl 2 Ant caused significant metabolic perturbation in L02 cells. Pathway enrichment analysis indicated that Ant, 2-ClAnt and 9,10-Cl 2 Ant mainly perturbed the lipid metabolism and nucleotide metabolism pathway. However, 9,10-Cl 2 Ant caused a wider perturbation to metabolic pathways than Ant and 2-ClAnt did. In addition, dysregulation of nucleotide metabolism perturbed by Ant, 2-ClAnt and 9,10-Cl 2 Ant may be associated with the genomic instability and further carcinogenesis.
研究领域:
环境毒理学
·
分子生物学
·
基因组学
·
代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2018
·
IF 3.432
Li-Long Jiang,Yan Jiang,Dong-Sheng Zhao,Ya-Xi Fan,Qiong Yu,Ping Li,Hui-Jun Li
1,3,8-Trihydroxy-6-methylanthraquinone (emodin), a widely existing natural product in herbal medicines, has been reported to be hepatotoxic, but the exact underlying mechanism is still not fully understood. The objective of the present study was to evaluate the role of CYP3A and glutathione (GSH) in emodin-induced liver injury. Primary human hepatocytes were exposed to emodin with and without addition of CYP3A inducer/inhibitor and GSH synthesis inhibitor. It was found that emodin-mediated cytotoxicity increased when CYP3A was activated and GSH was depleted. Hepatotoxicity induced by emodin in rats by activation/inhibition of CYP3A and depletion of GSH was further investigated. Administration of emodin in combination with l-buthionine sulfoximine (BSO) or dexamethasone (DEX) resulted in aggravated liver injury, whereas pretreatment with ketoconazole (KTZ) suppressed the side effects caused by emodin. In addition, plasma exposure of emodin and its glucuronide metabolite were measured by ultraperformance liquid chromatography triple quadrupole mass spectrometry. Emodin and its glucuronide were lower in BSO-, DEX-, and KTZ-co-treated rats compared with those administered with emodin alone. In conclusion, these mentioned results suggested that CYP3A induction and GSH depletion might be involved in hepatotoxicity induced by emodin. This study may help to understand the risk factors and the mechanism of hepatotoxicity of emodin in humans.
研究领域:
药理学
·
毒理学
·
药学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2022
·
IF 8.025
Weihong Jing,Mingyue Jiang,Xiaoxue Fu,Jiaxin Yang,Lu Chen,Feng Leng,Ping Xu,Wenyan Huang,Chao Yu,Zhangyou Yang
Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease closely related to obesity, which has become a global health problem. However, current pharmacological therapies for NAFLD are limited by potential side effects, low effectiveness and poor aqueous solubility. Herein, we designed functionalized drug-albumin nanocomposites ( [email protected] NPs), which were prepared by self-assembly of the anti-obesity small-molecule drug (BAM15) and bovine serum albumin (BSA), for treatment of NAFLD. The proposed [email protected] NPs not only improve aqueous solubility and half-life of BAM15 but also exhibit hepatic-targeted capacity and an increased therapeutic efficacy. In vitro experiments revealed that [email protected] NPs possessed excellent biocompatibility, and improved resistance to adipogenesis and reduced lipid accumulation in human hepatocellular carcinoma cells. In vivo , [email protected] NPs showed liver targeting ability and powerful anti-obesity effects without altering body temperature or affecting food intake, and could effectively alleviate hepatic steatosis and improve therapeutic efficacy for NAFLD treatment. The above findings demonstrated that [email protected] NPs potentially served as a safe and effective drug for NAFLD treatment.
研究领域:
药理学
·
纳米技术
·
肝病学
·
代谢疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）