INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Rui Lv,Houkang Cao,Mingli Zhong,Jianzhao Wu,Shiyuan Lin,Bo Li,Dongyu Chen,Zhiyuan Zhang,Kefeng Zhang,Ya Gao
Alcoholic fatty liver disease (AFLD) is characterized by excessive lipid accumulation in the liver. This study aimed to investigate the protective effects and mechanisms of Polygala fallax Hemsl polysaccharides (PFPs) on AFLD. PFPs were purified and structurally characterized. An AFLD model was established in mice using alcohol and a high-fat diet. A significant reduction in hepatic steatosis was observed following PFPs treatment, evidenced by decreased fat deposition in liver tissues. Additionally, PFPs reduced various liver injury markers, increased levels of antioxidant enzymes, and improved significantly liver function. RNA sequencing revealed that PFPs improved lipid and CYP450 metabolic pathway abnormalities in AFLD mice. Furthermore, PFPs activated the AMPK pathway, reducing lipid accumulation and enhancing lipid metabolism. A HepG2 cell model treated with ethanol and oleic acid showed significant biochemical improvements with PFPs pretreatment, including reduced lipid accumulation and lower reactive oxygen species (ROS) levels. To further elucidate the AMPK and PFPs correlation in AFLD, an AMPK inhibitor (compound C) was used. In vitro and in vivo qRT-PCR and Western blot results confirmed that PFPs protected against AFLD by activating AMPK phosphorylation, regulating lipid synthesis, and inhibiting lipid accumulation. PFPs also modulated CYP2E1 and oxidative stress-related gene expression, affecting liver metabolism.
研究领域:
药理学
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肝病学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2022
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IF 7.129
Junjie Zhao,Yehui Luan,Yanan Chen,Linli Cheng,Qianxi Qin
Antibiotic residue has become an emerging environmental contaminant, while the toxicological effects and underlying mechanisms caused by the co-exposure to multiple veterinary antibiotics were rarely studied. In this study, male Sprague Dawley rats were exposed to monensin (M) (1, 2, 10 mg/(kg·body weight (BW)) combined with sulfamethazine (S) (60, 120, 600 mg/(kg·BW)) or single drugs for 28 consecutive days. The body weight, hematological and blood biochemical parameters, organ coefficients, and histopathology were analyzed to discover their combined toxicity effect. Transcriptomic analysis was used to reveal the possible mechanisms of their joint toxicity. Compared with the control group, the weight gain rate was significantly reduced in the H-M+S and H-S, and alkaline phosphatase in H-M+S was significantly increased. Furthermore, relative liver and kidneys weight was significantly increased, and the liver of H-M+S showed more severe lesions in histopathological analysis. For H-M+S, H-M and H-S, transcriptomic results showed that 344, 246, and 99 genes were differentially expressed, respectively. The Gene Ontology terms mainly differ in sterol biosynthetic process and steroid hydroxylase activity. The Kyoto Encyclopedia of Genes and Genome pathways showed abnormal retinol metabolism, metabolism of xenobiotics by cytochrome P450, and drug metabolism-cytochrome 450; the common 30 genes were screened from the network of protein-protein interaction. The results showed that mixed contamination of M and S produces hepatotoxicity by interfering with linoleic acid metabolism, retinol metabolism and CYP450 enzyme-dominated drug metabolism. Further analysis showed that Cyp1a2, Cyp2c61, Ugt1a3, and Ugt1a5 might be the key genes. These findings could provide more evidence for investigating the toxic effects and metabolism of mixed antibiotics contamination in mammals.
研究领域:
毒理学
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药理学
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分子生物学
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环境科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Shouchun Xiao,Jingna Cui,Jiaxing Yang,Haonan Hou,Jianing Yao,Xiaoran Ma,Li Zheng,Fanrong Zhao,Xueke Liu,Donghui Liu,Zhiqiang Zhou,Peng Wang
Famoxadone is a chiral fungicide frequently found in the environment and agricultural products. However, the health risks of famoxadone enantiomers are not well understood. This study investigated the stereoselective cytotoxicity and metabolic behavior of famoxadone enantiomers in mammals. Results showed that R -famoxadone was 1.5 times more toxic to HepG2 cells than S -famoxadone. R -famoxadone induced more pronounced ferroptosis compared to S -famoxadone. It caused greater upregulation of genes related to iron transport and lipid peroxidation, and greater downregulation of genes related to peroxide clearance. Furthermore, R -famoxadone induced more severe lipid peroxidation and reactive oxygen species (ROS) accumulation through ACSL4 activation and GPX4 inhibition. Additionally, the bioavailability of R -famoxadone in mice was six times higher than that of S -famoxadone. Liver microsome assays, cytochrome P450 (CYP450) inhibition assays, human recombinant CYP450 assays, and molecular docking suggested that the lower binding affinities of CYP2C8, CYP2C19, and CYP2E1 for R -famoxadone caused its preferential accumulation. Overall, R -famoxadone poses a higher risk than S -famoxadone due to its greater cytotoxicity and persistence. This study provides the first evidence of ferroptosis-induced stereoselective toxicity, offering insights for the comprehensive health risk assessment of chiral famoxadone and valuable references for the application of high-efficiency, low-risk pesticide enantiomers.
研究领域:
毒理学
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药理学
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分子生物学
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环境科学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Jie Du,Xiaodong Chen,Yongshun Zhao,Tingting Zhao,Dalong Wang,Zujia Chen,Changyuan Wang,Qiang Meng,Jialin Yao,Huijun Sun,Kexin Liu,Jingjing Wu
CYP46A1 is a brain-specific enzyme responsible for cholesterol homeostasis. Inhibition of CYP46A1 activity serves as a therapeutic target for excitatory neurotoxicity. Sesame is a common medicine and food resource; its component lignans possess various pharmacological activities. In this study, the inhibitory effects of sesame lignans on CYP46A1 activity were investigated. Inhibition kinetics analyses revealed that sesamin and sesamolin produce mixed partial competitive inhibition of CYP46A1, while sesamol produces non-competitive inhibition. Notably, molecular simulations revealed that the sesame lignans have excellent orientations within the active cavity of CYP46A1. Importantly, the sesame lignans had high permeability coefficients and low efflux ratios. Furthermore, sesamin significantly reduced the levels of 24S-hydroxycholesterol in rat plasma and brain tissues, and down-regulated the protein expressions of CYP46A1, NMDAR2A, NMDAR2B, and HMGCR. Collectively, sesame lignans exhibit significant inhibitory effects on CYP46A1 activity, highlighting their potential therapeutic role in treating excitatory neurotoxicity.
研究领域:
药理学
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神经科学
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生物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL RESEARCH
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2024
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IF 7.7
HeLang Huang,CaiYun Xie,ZiYuan Xia,ZhaoYong Sun,YaTing Chen,Min Gou,YueQin Tang,HengLin Cui,XiaoLei Wu
Haloarchaea with the capacity to degrade alkanes is promising to deal with petroleum pollution in hypersaline environments. However, only a limited number of haloarchaeal species are investigated, and their pathway and mechanism for alkane degradation remain unclear. In this study, Halogranum rubrum RO2-11, a haloarchaeal strain, verified the ability to degrade kerosene and hexadecane in 184 g/L NaCl, with a 53% degradation rate after 9 and 4 days, respectively. Genome sequencing and gene annotation indicated that strain RO2-11 possesses a complete potential alkane-degrading pathway, of which alkane hydroxylases may include CYP450, AlmA, and LadA. Transcriptome and metabolome analyses revealed that the upregulation of related genes in TCA cycle, lysine biosynthesis, and acetylation may help improve hexadecane degradation. Additionally, an alternative degrading pathway of hexadecane based on dual-terminal β -oxidation may occur in strain RO2-11. It is likely to be the first report of alkane degradation by the genus Halogranum , which may be helpful for applications of oil-pollution bioremediation under high-salt conditions.
研究领域:
微生物学
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环境科学
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基因组学
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转录组学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2022
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IF 14.224
Yanhua Wang,You Weng,Lu Lv,Dou Wang,Guiling Yang,Yuanxiang Jin,Qiang Wang
The combined toxicity of heavy metals and pesticides to aquatic organisms is still largely unexplored. In this study, we investigated the combined impacts of cadmium (Cd) and carbofuran (CAR) on female zebrafish (F0 generation) and their following F1 generation. Results showed that mixtures of Cd and CAR induced acute synergistic effects on both zebrafish adults of the F0 generation and embryos of the F1 generation. Combined exposure to Cd and CAR could obviously alter the hepatic VTG level of females, and the individual exposures increased the relative mRNA levels of vtg1 and vtg2 . Through maternal transmission, co-exposure of Cd and CAR caused toxicity to 4-day-old larvae of the F1 generation, evidenced by the significant changes in T4 and VTG levels, CYP450 activity, and the relative transcriptional levels of genes related to the hormone, oxidative stress , and apoptosis. These effects were also reflected by the global gene expression pattern to 7-day-old larvae of F1 generation using the transcriptomic analysis, and they could also affect energy metabolism. Our results provided a more comprehensive insight into the transgenerational toxic impacts of heavy metal and pesticide mixtures. These findings highlighted that it was highly necessary to consider transgenerational exposures in the ecological risk assessment of chemical mixtures.
研究领域:
环境毒理学
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水生生物学
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分子生物学
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生态毒理学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2018
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IF 2.831
Zhe Wang,Wei Sun,Zheng-Feng Lin,Rui Sun,Cheng-Ke Huang,Wei-Jian Ye,Yao-Yao Dong,Xiao-Dan Zhang,Rui-Jie Chen
Drug-drug interactions (DDIs) are thought to be associated with the inhibition of cytochrome P450 activities. The cocktail method with analysis of the metabolism of two or more probe drugs is used to determine CYP450 activities. In this study, we established a UHPLC-MS/MS method for simultaneous quantitation of four CYP450 probe drugs (phenacetin, omeprazole, metoprolol and midazolam) and their metabolites (acetaminophen, 5′-hydroxy omeprazole, α-hydroxy metoprolol and 1′-hydroxy midazolam) in rat plasma. Sample preparation by plasma protein precipitation was combined with a liquid-liquid extraction method. The separation was carried out on a ZORBAX Eclipse Plus C18 Rapid Resolution High Definition column with a gradient elution, using water containing 0.1% formic acid (A) and acetonitrile (B) in a run time of only 3.0 min. Detection was conducted with a 6420 series triple-quadrupole tandem mass spectrometer, using ESI in positive ion mode with multiple reaction monitoring (MRM). The calibration curves were linear over the concentration range 10–5000 ng/mL for phenacetin, omeprazole, metoprolol and midazolam, and 1–500 ng/mL for their metabolites. Intra- and inter-day precisions were within 15%, and the accuracies were in the range of 87–112%. The method was successfully applied to the pharmacokinetic study of probe drugs/metabolites and DDIs with 3-n-butylphthalide (NBP) after administration of a single oral dose of phenacetin, omeprazole, metoprolol and midazolam in rats.
研究领域:
药理学
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分析化学
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临床医学
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
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2022
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IF 8.943
Meng-Yuan Li,Run-Dong Zhang,Yi-Xing Lin,Qi-Wen Li,Qiu-Yue Zhao,Zong-Xi Zhao,Zhong-Ming Ling,Long-Fei Shu,Min Zhang,Li-Xin Hu,Yi-Jing Shi,Guang-Guo Ying
The biotransformation of sulfamonomethoxine (SMM) was studied in an aerobic granular sludge (AGS) system to understand the role of sorption by microbial cells and extracellular polymeric substances (EPS) and the role of functional microbe/enzyme biodegradation. Biodegradation played a more important role than adsorption, while microbial cells covered with tightly bound EPS (TB-EPS) showed higher adsorption capacity than microbial cells themselves or microbial cells covered with both loosely bound EPS (LB-EPS) and TB-EPS. The binding tests between EPS and SMM and the spectroscopic analyses (3D-EEM, UV–Vis, and FTIR) were performed to obtain more information about the adsorption process. The data showed that SMM could interact with EPS by combining with aromatic protein compounds, fulvic acid-like substances, protein amide II, and nucleic acids . Batch tests with various substances showed that SMM removal rates were in an order of NH 2 OH (60.43 ± 2.21 μg/g SS) > NH 4 Cl (52.96 ± 0.30 μg/g SS) > NaNO 3 (31.88 ± 1.20 μg/g SS) > NaNO 2 (21.80 ± 0.42 μg/g SS). Hydroxylamine and hydroxylamine oxidoreductase (HAO) favored SMM biotransformation and the hydroxylamine-mediated biotransformation of SMM was more effective than others. In addition, both ammonia monooxygenase (AMO) and CYP450 were able to co-metabolize SMM. Analysis of UPLC-QTOF-MS indicated the biotransformation mechanisms, revealing that acetylation of arylamine, glucuronidation of sulfonamide, deamination, SO 2 extrusion, and δ cleavage were the five major transformation pathways. The detection of TP202 in the hydroxylamine-fed Group C indicated a new biotransformation pathway through HAO. This study contributes to a better understanding of the biotransformation of SMM.
研究领域:
环境科学
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微生物学
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生物技术
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化学工程
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
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2022
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IF 8.943
Yingjie Liu,Zhongxiang Chen,Shanwei Li,Lu Ding,Xiaofeng Wei,Shicheng Han,Peng Wang,Yanchun Sun
Di-(2-ethylhexyl) phthalate (DEHP) is one of the most extensively utilized plasticizers in the plastic manufacturing process. It is widely used in various fields due to its low cost and excellent effect. Although there is evidence that DEHP is harmful to animal and human health, DEHP-induced gill toxicity in aquatic organisms is inconclusive, and its mechanism has not been fully elucidated. Here, we investigated the effects of DEHP acute exposure on crucian carp gills at environmentally relevant concentrations of 20, 100, and 500 μg/L. Multi-omics profiling and biochemical assays were employed to characterize the potential toxicological mechanisms. The results showed that acute exposure to 100 and 500 μg/L of DEHP leads to oxidative stress in gills, as evidenced by overproduction of reactive oxygen species (ROS), increased antioxidant enzyme activity , and the transformation of glutathione from reduced to oxidized form, resulting in lipid peroxidation. Integrative analysis of transcriptomics and metabolomics indicated that increased purine metabolism was the potential source of increased ROS. Moreover, lipid metabolism disorder, including arachidonic acid metabolism, induces inflammation. Further, DEHP causes the imbalance of the CYP enzyme system in the gill, and DEHP-induced gill toxicity in crucian carp was associated with interference with CYP450 homeostasis . Taken together, this study broadens the molecular understanding of the DEHP-induced gill toxicity in aquatic organisms and provides novel perspectives for assessing the effects of DEHP on target and non-target aquatic organisms in the environment.
研究领域:
环境毒理学
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水生生物学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
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2019
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IF 5.108
Shuyan Zhao,Bohui Wang,Zhe Zhong,Tianqi Liu,Tiankun Liang,Jingjing Zhan
Perfluorooctane sulfonamide (FOSA) is known as a key intermediate of perfluorooctane sulfonic acid (PFOS) precursors, which can be frequently detected in the environment and biota. FOSA could be bioaccumulated in earthworms from soil, but the contributions of enzymes and gut microbes involved in the biotransformation of FOSA in earthworms have not been identified. Therefore, the effects of enzyme inhibitors and intestinal microflora on biotransformation of FOSA in earthworms were investigated in the present study. FOSA was biotransformed to form PFOS by earthworms obtained from in vivo and in vitro tests. The addition of FOSA had significantly positive effects on cytolchrome P450 (CYP450) and glutathione- s -transferase (GST) activities, suggesting CYP450 and GST are likely involved in the enzymatic transformation. In addition, both 1-Aminobenzotriazole (ABT) and ezatiostat hydrochloride (TLK199), which were selected to inhibit the CYP and GST enzymes, respectively, demonstrated inhibition effects on biotransformation of FOSA in earthworms with a dose-dependent relationship. However, the concentrations of FOSA weren't changed by the bacteria isolated from worm gut, suggesting that gut bacteria did not contribute to FOSA biotransformation in earthworms. The results of this study confirm that the transformation of FOSA in earthworms is mediated mainly by enzymes rather than by gut microbes.
研究领域:
环境科学
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毒理学
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生物化学
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微生物学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
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2024
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IF 10.8
Xiu Huang,Yong Li,Zhao Shu,Li Huang,Qian Liu,Guibin Jiang
Plastic pollution is a significant environmental concern globally. Plastics are normally considered chemically inert and resistant to biodegradation. Although many papers have reported enzyme-induced biodegradation of plastics, these studies are primarily limited to enzymes of microbial origin or engineered enzymes. This study reveals that poly(ethylene terephthalate) (PET, ∼6000 Da and 100 kDa) particles and plastic bottle debris (PBD, 24.9 kDa) can be efficiently degraded by a mammal-origin natural phase II metabolic isozyme, glutathione S-transferase (GST), under mild conditions. The degradation efficiency of PET plastics reached 98.9%, with a degradation rate of 2.6 g·L–1·h–1 under ambient or physiological conditions at 1 atm. PET plastics can be degraded by GST with varying environmental or biological factors (i.e., temperature, light irradiation, pH, and presence of humic acid or protein). We suggest a novel mechanism for PET degradation other than hydrolysis, i.e., the mechanism of cleavage and release of PET plastic monomers via nitridation and oxidation. This finding also reveals a novel function of GST, previously thought to only degrade small molecules (<1000 Da). This method has been successfully applied in real human serum samples. Additionally, we have tested and confirmed the ability to degrade PET of a mammal-origin natural digestive enzyme (trypsin) and a human-derived natural metabolic enzyme (CYP450). Overall, our findings provide a potential new route to plastic pollution control and contribute to our understanding of the metabolism and fate of plastics in organisms.
研究领域:
环境科学
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生物化学
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生物技术
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酶学
✓ 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）