PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2024
·
IF 4.2
Min Liao,Minghao Jiang,Xumiao Wang,Wei Hu,Ning Zhao,Haiqun Cao
Acetyl-CoA carboxylase (ACCase)-inhibiting herbicides are among the most commonly used herbicides to control grassy weeds, especially Leptochloa chinensis , in rice fields across China. Herein, we collected a suspected resistant (R) population of L. chinensis (HFLJ16) from Lujiang county in Anhui Province. Whole plant dose response tests showed that, compared with the susceptible (S) population, the R population showed high resistance to cyhalofop-butyl (22-fold) and displayed cross-resistance to metamifop (9.7-fold), fenoxaprop- P -ethyl (18.7-fold), quizalofop- P -ethyl (7.6-fold), clodinafop-propargyl (12-fold) and clethodim (8.4-fold). We detected an amino acid substitution (Cys-2088-Arg) in the ACCase of resistant L. chinensis . However, ACCase gene expression levels were not significantly different ( P > 0.05) between R plants and S plants, without or with cyhalofop-butyl treatment. Furthermore, pretreatment with piperonyl butoxide (PBO, a cytochrome P450 monooxygenase (CYP450) inhibitor) or 4-chloro-7-nitrobenzoxadiazole (NBD-Cl, a glutathione-S-transferase (GST) inhibitor), inhibited the resistance of the R population to cyhalofop-butyl significantly (by approximately 60% and 26%, respectively). Liquid chromatography tandem mass spectrometry analysis showed that R plants metabolized cyhalofop-butyl and cyhalofop acid (its metabolite) significantly faster than S plants. Three CYP450 genes, one GST gene, and two ABC transporter genes were induced by cyhalofop-butyl and were overexpressed in the R population. Overall, GST-associated detoxification, CYP450 enhancement, and target-site gene mutation are responsible for the resistance of L. chinensis to cyhalofop-butyl.
研究领域:
植物科学
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分子生物学
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杂草科学
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除草剂抗性
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DOI
PubMed
高影响因子
Reproductive Sciences
·
2024
·
IF 2.6
Zhou Nan,Lv Wenqiang,Chen Linna,Chen Kexin,He Qing,Xie Guangyan,Ma Jiachen,Cao Yijuan,Zhang Bei,Zhou Xueyan
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. This study aimed to investigate the therapeutic effects and mechanism of Jujuboside A on PCOS using a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. Estrogen and androgen homeostasis was evaluated in serum from both clinical samples and PCOS mice. The stages of the estrous cycle were determined based on vaginal cytology. The ovarian morphology was observed by stained with hematoxylin and eosin. Moreover, we analyzed protein expression of cytochrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2) and aryl hydrocarbon receptor (AhR) in ovary and KGN cells. Molecular docking, immunofluorescence, and luciferase assay were performed to confirm the activation of AhR by Jujuboside A. Jujuboside A effectively alleviated the disturbance of estrogen homeostasis and restored ovarian function, leading to an improvement in the occurrence and progression of PCOS. Furthermore, the protective effect of JuA against PCOS was dependent on increased CYP1A2 levels regulated by AhR. Our findings suggest that Jujuboside A improves estrogen disorders and may be a potential therapeutic agent for the treatment of PCOS. Graphical Abstract
研究领域:
内分泌学
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药理学
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生殖生物学
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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 SCIENCE & TECHNOLOGY
·
2019
·
IF 7.149
Jian Zhou,Zhengshuang Yang,Qing Liu,Yiman Liu,Menglin Liu,Tiecheng Wang,Lingyan Zhu
As emerging alternatives of legacy perfluoroalkyl substances, perfluorophosphinates (PFPiAs) and perfluorophosphonates (PFPAs) are widely applied in industrial and agricultural fields and are supposed to be large partitioned to soil and highly persistent. It is of particular interest to understand their transfer from roots to shoots and transformation in plants, such as wheat. The results of hydroponic experiments indicated that C6/C6 PFPiA, C8/C8 PFPiA, perfluorooctanophosphonic acid (PFOPA), and perfluorohexaphosphonic acid (PFHxPA) were quickly adsorbed on the epidermis of wheat root (Triticum aestivum L.), which was driven by their hydrophobicity. A small fraction of the accumulated PFPiAs and PFPAs in the wheat root was subjected to absorption via an active process dependent on H+-ATPase. PFHxPA, which has the smallest molecular weight and medium hydrophilicity (log Kow < 4), displayed the strongest absorption efficiency via the water and anion channels and had the highest translocation potential from roots to shoots in wheat. C6/C6 and C8/C8 PFPiAs experienced phase I metabolism in wheat, although at a low rate, to form more persistent PFHxPA and PFOPA, respectively, as well as 1H-perfluorohexane (1H-PFHx) and 1H-perfluorooctane (1H-PFO), which were regulated by cytochrome P450 in wheat root. As a result, exposure to PFPiAs in roots ultimately caused the accumulation of more persistent PFPAs in the above-ground parts of plants, raising concerns on their potential risks on human health.
研究领域:
环境科学
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植物生理学
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毒理学
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2024
·Vol. 52
·期 8
·911-918
·
IF 4.4
Jingyu Zhang,Weiwei Li,Ying Liu,Yan He,Zihao Cheng,Ximei Li,Yu Chen,Aihua Zhang,Ying Peng,Jiang Zheng
Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute exposure of arsenite on activities of cytochrome P450 enzymes and pharmacokinetic behaviors of drugs in rats. Midazolam, tolbutamide, metoprolol, omeprazole, caffeine, and chlorzoxazone, the probe substrates for cytochrome P450 (CYP) s3A, 2C6, 2D, 2C11, 1A, and 2E, were selected as probe drugs for the pharmacokinetic study. Significant decreases in areas under the curves of probe substrates were observed in rats after consecutive 30-day exposure to As at 12 mg/kg. Microsomal incubation study showed that the subacute exposure to arsenite resulted in little change in effects on the activities of P450 enzymes examined. However, everted gut sac study demonstrated that such exposure induced significant decreases in intestinal absorption of these drugs by both passive diffusion and carrier-mediated transport. In addition, in vivo study showed that the arsenite exposure decreased the rate of peristaltic propulsion. The decreases in intestinal permeability of the probe drugs and peristaltic propulsion rate most likely resulted in the observed decreases in the internal exposure of the probe drugs. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents coadministered resulting from the observed drug–drug interactions.
研究领域:
毒理学
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药理学
·
药学
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DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2018
·
IF 3.44
Xuegui Wang,Xing Xiang,Huiling Yu,Shuhua Liu,Yong Yin,Peng Cui,Yaqiong Wu,Jing Yang,Chunxian Jiang,Qunfang Yang
The beet armyworm Spodoptera exigua , a major pest affecting numerous cultivated crops in China, has developed a serious resistance to many traditional chemical insecticides . The resistance levels of the field-collected populations from different districts in Sichuan Province, China, to nine insecticides were detected with a diet-incorporation bioassay. Compared to the Lab-ZN strain, five (in 2014) and three (in 2016) field populations displayed either high or extremely high levels of resistance to beta-cypermethrin. All the field populations collected in 2014 were susceptible to emamectin benzoate, hexaflumuron, methoxyfenozide, chlorantraniliprole, cyantraniliprole and indoxacarb but exhibited low or moderate levels of resistance to abamectin . The resistances of field populations collected in 2016 were significantly higher than two years earlier, especial for chlorantraniliprole and cyantraniliprole with RRs rising from 173.4- to 582.6-fold and 175.3- to 287.6-fold, respectively, even though the field populations had retained moderate or low levels of resistance to chlorpyrifos and hexaflumuron. The synergism experiment revealed that the resistance of the LS16 population to beta-cypermethrin may be mainly related to cytochrome P450 monooxygenases (P450s), which was responsible for the highest increase ratio of 37.97-fold, for piperonyl butoxide , rather than either carboxylesterase (CarE) or glutathione S-transferase (GST). The cytochrome P450 ethoxycoumarin O -deethylase activity of the LS16 population was also the strongest among the treatments ( P < 0.05). Non-denaturing polyacrylamide gel electrophoresis (native PAGE) indicated that enhanced E11, E13 and E15-E16 bands in the LS16 population likely contribute to the development of resistance to beta-cypermethrin.
研究领域:
昆虫学
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害虫管理
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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
DRUG METABOLISM AND DISPOSITION
·
2025
·
IF 4
Xiyue Huang,Lei Zhou,Huixian Chen,Xiaowei Sun,Mengyi Cao,Yangming Zhang,Dewen Li,Xuelin Zhu,Fajun Nan,Xiaoyan Chen
Hydroxamic acid is an excellent metal ion chelating group and is used commonly in the design of histone deacetylase (HDAC) inhibitors. Despite its utility, the hydroxamic acid group suffers from poor metabolic stability and undergoes rapid conversion to carboxylic acid, a process that has generally been described as hydrolytic metabolism. By using the HDAC inhibitor, bisthianostat as a model drug, this study provided novel insights into the role of cytochrome P450 (P450) enzymes in the metabolism of the hydroxamic acid group into the carboxylic acid metabolite (M351). The primary formation of M351 was observed in liver microsomes after incubating bisthianostat with different human liver, intestinal and plasma fractions. Chemical inhibition experiments further indicated that P450 enzyme-mediated oxidation was the main pathway for generation of M351, with hydrolysis making a minor contribution. 18 O-labeling isotope experiments and Griess assays demonstrated that the peroxoferric species of P450 enzymes acted as a nucleophile, attacking the carbonyl carbon of hydroxamic acid, leading to the formation of carboxylic acid and reactive nitrogen species. The metabolism of eight hydroxamic acid derivatives in human liver microsomes indicated that P450 enzymes exhibited substrate specificity in catalyzing the conversion of hydroxamic acids to carboxylic acids. Molecular docking results further revealed that oxidative metabolism occurred when the hydroxamic acid group was in appropriate proximity to the P450 catalytic center. Overall, this study demonstrated the important role of P450 enzymes in hydroxamic acid metabolism and provided valuable insights for future rational design and clinical applications of hydroxamic acid-based drugs.
研究领域:
药理学
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生物化学
·
药物代谢
·
酶学
·
分子生物学
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药物化学
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DOI
PubMed
高影响因子
CHEMOSPHERE
·
2019
·
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
·
毒理学
·
生物化学
·
微生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Shuaishuai Xing,Xu Tang,Leyan wang,Jun Wang,Bingbing Lv,Xiaolong Wang,Can Guo,Ye Zhao,Feng Feng,Wenyuan Liu,Yao Chen,Haopeng Sun
Most recently, worldwide interest in butyrylcholinesterase (BChE) as a potential target for treating Alzheimer's disease (AD) has increased. In this study, the previously obtained selective BChE inhibitors with benzimidazole-oxadiazole scaffold were further structurally modified to increase their aqueous solubility and pharmacokinetic (PK) characteristics. S16 – 1029 showed improved solubility (3280 μM, upgraded by 14 times) and PK parameters, including plasma exposure (AUC 0-inf = 1729.95 ng/mL*h, upgraded by 2.6 times) and oral bioavailability (F po = 48.18%, upgraded by 2 times). S16 – 1029 also displayed weak or no inhibition against Cytochrome P450 (CYP450) and human ether a-go-go related gene ( h ERG) potassium channel. In vivo experiments on tissue distribution revealed that S16 – 1029 could cross the blood-brain barrier (BBB) and reach the central nervous system (CNS). In vivo cognitive improvement efficacy and good in vitro target inhibitory activity ( eq BChE IC 50 = 11.35 ± 4.84 nM, h BChE IC 50 = 48.1 ± 11.4 nM) were also assured. The neuroprotective effects against several AD pathology characteristics allowed S16 – 1029 to successfully protect the CNS of progressed AD patients. According to the findings of this study, altering molecular planarity might be a viable strategy for improving the drug-like property of CNS-treating drugs.
研究领域:
药理学
·
神经科学
·
药物化学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENT INTERNATIONAL
·
2024
·
IF 10.3
Zhengyuan Gao,Chenggang Gu,Xiuli Fan,Lezu Shen,Zhihua Jin,Fang Wang,Xin Jiang
The extensive use of sulfonylurea herbicides has raised major concerns regarding their long-term soil residues and agroecological risks despite their role in agricultural protection. Microbial degradation is an important approach to remove sulfonylureas, whereas understanding the associated biodegradation mechanisms, enzymes, and physiological responses remains incomplete. Based on the rapid biodegradation of nicosulfuron by typical fungal isolate Talaromyces flavus LZM1, the dependency on cellular accumulation and environmental conditions, e.g. pH and nutrient supplies, was shown in the study. The biodegradation of nicosulfuron occurred intracellularly and followed the cascade of reactions including hydrolysis, Smile contraction rearrangement, hydroxylation, and opening of the pyrimidine ring. Besides 2-amino-4,6-dimethoxypyrimidine (ADMP) and 2-aminosulfonyl-N,N-dimethylnicotinamide (ASDM), numerous products and intermediates were newly identified and the structural forms of methoxypyrimidine and sulfonylurea bridge contraction rearrangement are predicted to be more toxic than nicosulfuron. The biodegradation should be enzymatically regulated by glycosylphosphatidylinositol transaminase (GPI-T) and P450s, which were manifested with the significant upregulation in proteomics. It is the first time that the hydrolysis of nicosulfuron into ADMP and ASDM have been associated with GPI-T. The integrated pathways of biodegradation were further elucidated through the involvement of various active enzymes. Except for the enzymatic catalysis, the physiological responses verified by metabolo-proteomics were critical not only to regulate material synthesis, uptake, utilization, and energy transfer but also to maintain antioxidant homeostasis, biodegradability, and tolerance of nicosulfuron by the differentially expressed metabolites, such as acetolactate synthase and 3-isopropylmalate dehydratase. The obtained results would help understand the biodegradation mechanism of sulfonylurea from chemicobiology and enzymology and promote the use of fungal biodegradation in pollution rehabilitation.
研究领域:
环境微生物学
·
生物化学
·
酶学
·
土壤学
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产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2024
·
IF 6.7
Yang Yang,Yifan Li,Qinhui Xie,Bo Jiang,Junbo Li,Yunfei Xie,Wei Ji
Biomimetic cytochrome P450 for chemical activation of environmental carcinogens is an efficient in vitro model for evaluating their mutagenicity and ultimately acquiring the metabolites that cannot be easily accessed by conventional routes of organic synthesis. Different kinds of mutagen derived from polyaromatic hydrocarbons (PAHs) by metalloporphyrin/oxidant model systems have been reported, but the underlying molecular mechanisms are poorly understood. Herein, we have for the first time demonstrated an effective surface-enhanced Raman scattering (SERS) protocol to study the dynamics and biomimetic metabolic behaviors of pyrene (Pyr) in the presence of various oxygen donors. Quantitative information on the relative concentration of Pyr and its metabolites in the biomimetic system can be extracted from the SERS spectra. On the basis of our results, we conclude that the oxidative metabolism of Pyr is highly influenced by the types and concentrations of oxygen donors, leading to the formation of 1-hydroxypyrene and dioxygenated products. Besides, the addition of an appropriate amount of an organic solvent can promote the formation of secondary oxidation products. These results offer valuable insights into the dynamics of PAHs metabolism and the regulation of their metabolic pathways in biomimetic activation. In comparison to traditional liquid chromatography–mass spectrometry, the present SERS approach is more suitable for high-throughput evaluation of the metabolic process and kinetics of PAHs. We anticipate that this approach will enable a more general and comprehensive tracking of metabolic dynamics and molecular mechanisms involved in the biomimetic activation of other xenobiotics, such as procarcinogens, promutagens, and drugs.
研究领域:
环境科学
·
分析化学
·
生物化学
·
毒理学
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2019
·Vol. 10
·期 10
·1-14
·
IF 5.959
Li Zhongwen,Wu Jun,Wang Lei,Han Weifang,Yu Juan,Liu Xin,Wang Yukai,Zhang Ying,Feng Guihai,Li Wei,Stacey Glyn Nigel,Gu Qi,Hu Baoyang,Wang Liu,Zhou Qi,Hao Jie
Hepatocytes have been successfully generated from human pluripotent stem cells (hPSCs). However, the cost-effective and clinical-grade generation of hepatocytes from hPSCs still need to be improved. In this study, we reported the production of functional hepatocytes from clinical-grade human embryonic stem cells (hESCs) under good manufacturing practice (GMP) requirements. We sequentially generated primitive streak (PS), definitive endoderm (DE), hepatoblasts and hepatocyte-like cells (HLCs) from hESCs in the different stages with completely defined reagents. During hepatoblast differentiation, dimethyl sulfoxide (DMSO), transferrin, L-ascorbic acid 2-phosphate sesquimagnesium salt hydrate (Vc-Mg), insulin, and sodium selenite were used instead of cytokines and FBS/KOSR. Then, hepatoblasts were differentiated into HLCs that had a typical hepatocyte morphology and possessed characteristics of mature hepatocytes, such as metabolic-related gene expression, albumin secretion, fat accumulation, glycogen storage, and inducible cytochrome P450 activity in vitro. HLCs integrated into the livers of Tet-uPA Rag2 –/– Il2rg –/– (URG) mice, which partially recovered after transplantation. Furthermore, a series of biosafety-related experiments were performed to ensure future clinical applications. In conclusion, we developed a chemically defined system to generate qualified clinical-grade HLCs from hESCs under GMP conditions. HLCs have been proven to be safe and effective for treating liver failure. This efficient platform could facilitate the treatment of liver diseases using hESC-derived HLCs transplantation.
研究领域:
干细胞生物学
·
再生医学
·
肝病治疗
·
移植学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Tao Ai,Siyu Yao,Yuanyuan Yu,Kai Peng,Ling Jin,Xifen Zhu,Haijun Zhou,Jiahui Huang,Jianteng Sun,Lizhong Zhu
Sulfonamide antibiotics, extensively used in human and veterinary therapy, accumulate in agroecosystem soils through livestock manure and sewage irrigation. However, the interaction between sulfonamides and rice plants remains unclear. This study investigated the transformation behavior and toxicity of sulfamethoxazole (SMX) and its main metabolite, N4-acetyl-sulfamethoxazole (NASMX) in rice. SMX and NASMX were rapidly taken up by roots and translocated acropetally. NASMX showed higher accumulating capacity, with NASMX concentrations up to 20.36 ± 1.98 μg/g (roots) and 5.62 ± 1.17 μg/g (shoots), and with SMX concentrations up to 15.97 ± 2.53 μg/g (roots) and 3.22 ± 0.789 μg/g (shoots). A total of 18 intermediate transformation products of SMX were identified by nontarget screening using Orbitrap-HRMS, revealing pathways such as deamination, hydroxylation, acetylation, formylation, and glycosylation. Notably, NASMX transformed back into SMX in rice, a novel finding. Transcriptomic analysis highlights the involvements of cytochrome P450 (CYP450), acetyltransferase (ACEs) and glycosyltransferases (GTs) in these biotransformation pathways. Moreover, exposure to SMX and NASMX disrupts TCA cycle, amino acid, linoleic acid, nucleotide metabolism, and phenylpropanoid biosynthesis pathways of rice, with NASMX exerting a stronger impact on metabolic networks. These findings elucidate the sulfonamides' metabolism, phytotoxicity mechanisms, and contribute to assessing food safety and human exposure risk amid antibiotic pollution.
研究领域:
环境科学
·
植物生理学
·
药理学
·
分子生物学
·
毒理学
✓ 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）