eLife
·
2024
·
IF 6.4
Tian Yuan,Yifan Wang,Yuchen Jin,Hui Yang,Shuai Xu,Heng Zhang,Qian Chen,Na Li,Xinyue Ma,Huifang Song,Chao Peng,Ze Geng,Jie Dong,Guifang Duan,Qi Sun,Yang Yang,Fan Yang,Zhuo Huang
Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidine’s blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6’s N- and C-termini binding to Slack’s C-terminus and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slack’s C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of ‘Slack as an isolated target’ for anti-epileptic drug discovery efforts and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy.
研究领域:
神经科学
·
药理学
·
分子生物学
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DOI
PubMed
高影响因子
LANGMUIR
·
2014
·
IF 4.384
Dongmei Cui,Li Mi,Xuan Xu,Jusheng Lu,Jing Qian,Songqin Liu
Cytochrome P450 enzymes (cyt P450s) with an active center of iron protoheme are involved in most clinical drugs metabolism process. Herein, an electrochemical platform for the investigation of drug metabolism in vitro was constructed by immobilizing cytochrome P450 2D6 (CYP2D6) with cyt P450 reductase (CPR) on graphene modified glass carbon electrode. Direct and reversible electron transfer of the immobilized CYP2D6 with the direct electron transfer constant of 0.47 s–1 and midpoint potential of -0.483 V was obtained. In the presence of substrate tramadol, the electrochemical-driven CYP2D6 mediated catalytic behavior toward the conversion of tramadol to o-demethyl-tramadol was confirmed. The Michaelis–Menten constant (Kmapp) and heterogeneous reaction rate constant during the metabolism of tramadol were calculated to be 23.85 μM and 1.96 cm s–1, respectively. The inhibition effect of quinidine on CYP2D6 catalyze-cycle was also investigated. Furthermore, this system was applied to studying the metabolism of other drugs.
研究领域:
生物化学
·
药物代谢
·
电化学分析
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产品关联
DOI
PubMed
高影响因子
ANALYST
·
2023
·Vol. 148
·期 6
·1322-1329
·
IF 4.2
Chunyan Zhang,Yifeng Fan,Liangliang Cai,Xiaofei Ma
The discovery of novel chiral selectors always fascinates us. This work describes the chiral separation performances of a new chiral selector (kasugamycin, KAS) in capillary electrophoresis (CE) for six pairs of stereoisomers, including ephedrine and pseudoephedrine, quinine and quinidine, cinchonine and cinchonidine, and amlodipine, promethazine and ofloxacin enantiomers. Kasugamycin, an aminoglycoside antibiotic in agriculture, shows significant biological activity against rice blast with low toxicity. As it turns out, this new chiral selector possesses good CE compatibility and stereoselectivity towards model analytes. In this work, we systematically investigated several separation parameters including kasugamycin concentration, buffer pH, separation voltage and the composition of the buffer solution. A detailed discussion about the chiral recognition mechanism was made based on Statistical Product and Service Solution (SPSS) analysis, NMR experiments (1D and 2D) and molecular modeling. This is the first time that kasugamycin is utilized as a chiral selector in CE, and the development of new chiral selectors from agricultural or veterinary antibiotics deserves more attention.
研究领域:
分析化学
·
药学
·
色谱学
·
农业化学
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产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2024
·
IF 4.2
Xiaoyi Huo,Yinna Wang,Zheming Liu,Jia Liu,Hang Zhu,Yong Zhou,Yilong Man,Xiaomao Zhou,Haihao Ma
The slowpoke channel responds to the intracellular calcium concentration and the depolarization of the cell membrane. It plays an important role in maintaining the resting potential and regulating the homeostasis of neurons, but it can also regulate circadian rhythm, sperm capacitation, ethanol tolerance, and other physiological processes in insects. This renders it a potentially useful target for the development of pest control strategies. There are relatively few studies on the slowpoke channels in lepidopteran pests, and their pharmacological properties are still unclear. So, in this study, the slowpoke gene of Plutella xylostella ( Pxslo ) was heterologous expressed in HEK293T cells, and the I-V curve of the slowpoke channel was measured by whole cell patch clamp recordings. Results showed that the slowpoke channel could be activated at −20 mV with 150 μM Ca 2+ . The subsequent comparison of the electrophysiological characteristics of the alternative splicing site E and G deletions showed that the deletion of the E site enhances the response of the slowpoke channel to depolarization, while the deletion of the G site weakens the response of the slowpoke channel to depolarization. Meanwhile, the nonspecific inhibitors TEA and 4-AP of the Kv channels, and four pesticides were tested and all showed an inhibition effect on the PxSlo channel at 10 or 100 μM, suggesting that these pesticides also target the slowpoke channel. This study enriches our understanding of the slowpoke channel in Lepidopteran insects and can aid in the development of relevant pest management strategies.
研究领域:
昆虫学
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药理学
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分子生物学
·
害虫管理
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2024
·
IF 7.6
Guangcai Ma,Kan Ma,Jing Zhang,Xianglong Zhao,Qiuyi Wang,Yewen Chen,Jiayu Lu,Xiaoxuan Wei,Xueyu Wang,Haiying Yu
The escalating focus on the environmental occurrence and toxicology of emerging pollutants underscores the imperative need for a profound exploration of their metabolic transformations mediated by human CYP450 enzymes. Such investigations have the potential to unravel the intricate metabolite profiles, substantially altering the toxicological outcomes. In this study, we integrated the computational simulations with in vitro metabolism experiments to investigate the metabolic activity and mechanism of an emerging pollutant, 1,3,5-tris(2,3-dibromopropyl)-1,3,5-triazinane-2,4,6-trione (TDBP-TAZTO), catalyzed by human CYP450s. The results highlight the important contributions of CYP2E1, 3A4 and 2C9 to the biotransformation of TDBP-TAZTO, leading to the identification of four distinct metabolites. The effective binding conformations governing biotransformation reactions of TDBP-TAZTO within active CYP450s are unveiled. Structural instability of primary hydroxyTDBP-TAZTO products suggests three potential outcomes: (1) generation of an alcohol metabolite through successive debromination and reduction reactions, (2) formation of a dihydroxylated metabolite through secondary hydroxylation by CYP450, and (3) production of an N-dealkylated metabolite via decomposition and isomerization reactions in the aqueous environment. The formation of a desaturated debrominated metabolite may arise from H-abstraction and barrier-free Br release during the primary oxidation, potentially competing with the generation of hydroxyTDBP-TAZTO. These findings provide detailed mechanistic insight into TDBP-TAZTO biotransformation by CYP450s, which can enrich our understanding of the metabolic fate and associated health risk of this chemical.
研究领域:
环境科学
·
毒理学
·
计算生物学
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产品关联
DOI
PubMed
高影响因子
npj Science of Food
·
2024
·Vol. 8
·期 1
·1-12
·
IF 6.3
Zhang Meng,Du Pengfei,Xiao Yirong,Liu Hao,Wang Meixue,Zhang Yumei,Chen Xin
Sodium dehydroacetate (DHA-Na), a widely used preservative, can induce sex-differentiated coagulation disorders primarily resulting from its metabolism. However, the underlying mechanisms remain poorly understood. Here, we identified several Cytochrome P450 (CYP450) sub-enzymes involved in sex differences related to DHA-Na metabolism, along with two related DHA-Na metabolites. CYP1A2, CYP3A2, and CYP2D1 were primarily responsible for DHA-Na metabolism, which was stronger in male rats than in female rats. Inhibition of these isoforms separately resulted in the DHA-Na metabolic capacity in male rats becoming equal to, or even weaker than, that in female rats. Furthermore, Cyp1a2, Cyp3a2, Cyp2d1 , and Cyp2c11 expression was higher in male rats than in female rats, suggesting these enzymes are related to exhibited sex differences in DHA-Na metabolism. Moreover, 3-glycoloyl-6-methy-2,3-dihydropyran-2,4-dione (C 8 H 8 O 5 ) and 3-imino-6-methyl-2,3-dihydropran-2,4dione (C 6 H 5 O 3 N) were identified as the two main DHA-Na metabolites. These findings provide crucial insights into potential mechanisms underlying sex differences in DHA-Na metabolism and its metabolites in rats.
研究领域:
药理学
·
毒理学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
ACS Infectious Diseases
·
2025
·
IF 3.8
Feifei Zhao,Yizhen Zhu,Lingxiang Mao,Honghao Huang,Wei Wei,Qiangcheng Deng,Youzhi Tang,Ning Han,Zhenling Zeng
Staphylococcus aureus poses a global threat to livestock health and public health security, necessitating a novel antibiotic. Pleuromutilin, a natural antibiotic, has served as a promising foundation for developing new antibacterial agents through structural modification. This study aims to evaluate the antibacterial potential, safety, and pharmacokinetic profile of a novel pleuromutilin derivative 2-3 (22-[2-(L-prolylamino)phenylsulfanyl]-22-deoxypleuromutilin). The compound 2–3 exhibited potent antibacterial activity (MIC = 0.25 μg/mL), concentration-dependent bactericidal effects, and prolonged post-antibiotic effects (PAEs). Safety assessments revealed low cytotoxicity (CC50 = 62.63 μg/mL) and no observable hemolytic activity. In vitro metabolic studies indicated species-dependent clearance, primarily mediated by CYP3A4. Pharmacokinetic in rats showed rapid absorption and elimination, with oral and intramuscular bioavailability of 16.03% ± 8.82% and 53.36% ± 12.27%, respectively. Notably, 2–3 demonstrated superior efficacy over tiamulin in a neutropenic murine thigh infection model. Molecular docking revealed a stronger binding free energy between 2–3 and the 50S ribosomal subunit compared to tiamulin. Collectively, these results highlight 2–3 as a promising clinical candidate against S. aureus infections, characterized by enhanced efficacy and a favorable safety profile.
研究领域:
抗生素研发
·
药理学
·
微生物学
·
药物化学
·
药物代谢
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产品关联
DOI
PubMed
高影响因子
ELECTROANALYSIS
·
2012
·Vol. 24
·期 7
·1647-1654
·
IF 2.872
Li Liu,Xuecai Tan,Xiaoxue Fang,Yuexin Sun,Fuhou Lei,Zaiyin Huang
A novel cross-linker (functional abietic-type acids) for preparing highly sensitive, molecularly imprinted sensors was proposed for quinine determination. A MIP film was created on a glassy carbon electrode for determination of quinine using free radical polymerization method. The modification procedure was characterized via electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). The interaction between functional monomer and target molecule was observed by UV spectrometric methods. Under the optimal experimental conditions, the peak currents were proportional to the concentrations of quinine in the range from 8.0×10 −7 to 2.6×10 −4 M with a detection limit of 2.0×10 −8 M. Meanwhile the prepared sensor showed sensitive and selective binding sites for quinine. Determination of quinine in tonic water showed good recovery.
研究领域:
分析化学
·
生物传感技术
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产品关联
DOI
高影响因子
JOURNAL OF POLYMER RESEARCH
·
2021
·Vol. 28
·期 5
·1-10
·
IF 3.097
Lin Yali,Liu Yu,Li Siqi,Rui Lili,Ou Jiming,Wu Quanzhou,He Jianfeng
A kind of novel three-dimensionally ordered macroporous molecularly imprinted microspheres (3DMIMs) had been developed for selective recognition and separation of quinine based on the combination of colloidal crystal templating method and molecular imprinting technique. The 3DMIMs were derived from the spherical silica colloidal crystal involving a four-step templating process including infiltration of imprinted precursors, sealing of polyethylene glycol, initiation polymerization, as well as final removal of the colloidal crystal and imprinting template. The resulted 3DMIMs consisted of a three-dimensional, highly ordered and interconnected macroporous arrays with nanoscale thickness of polymer wall, in which numerous imprinted cavities were obtained. The kinetic and isothermal adsorption behavior of the 3DMIMs were investigated in detail. The results showed the 3DMIMs had a rapider mass transfer process, higher adsorption capacities and recognition specificity toward quinine compared with the traditional bulk imprinted polymers. In addition, the 3DMIMs exhibited obvious high permeability and low backpressure at high flow rate as column packing. Extraction experiments showed that the 3DMIMs could effectively separate quinine and its diastereoisomer, quinidine, directly from crude cinchona bark extract with a satisfactory selectivity and elution recovery.
研究领域:
材料科学
·
药物化学
✓ 已验证
产品关联
DOI
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Hanqing Chen,Shuang Zhou,Meilin Zhu,Bing Wang,Wei Chen,Lingna Zheng,Meng Wang,Weiyue Feng
Gold nanoparticles (GNPs) have been used as a potential bioactive platform for drug delivery due to their unique optical and thermal characteristics. Liver is the main organ in orchestrating physiological homeostasis through metabolization of drugs and detoxification of exogenous substances. Therefore, it is crucial to deeply understand the mechanism of nanoparticle–liver interaction and the potential hepatic effects of GNPs in vivo . In this study, we studied the hepatic impacts of the intravenously injected polyethyleneimine (PEI)-modified GNPs (PEI-GNPs) on the expression of hepatic drug-metabolic enzymes and sterol responsive element binding protein 1c (SREBP-1c)-mediated de novo lipogenesis in mice for 24 h and 1 week. PEI-GNP accumulation in the liver is associated with increased liver inflammation, as evidenced by the gene expression of pro-inflammatory cytokines. Moreover, the GNP-induced hepatotoxicity in mice is partly due to liver inflammation–triggered disruption in the function of drug-metabolic enzymes, including hepatic uptake and efflux transporters, cytochrome P450 (CYP450), and UDP-glucuronosyltransferases (UGTs). The study provides evidence that it is necessary to consider the nanomaterial–liver interaction and manipulate the surface chemistry of GNPs prior to biomedical application of nanoparticles.
研究领域:
纳米技术
·
药理学
·
毒理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2020
·Vol. 48
·期 10
·1074-1083
·
IF 3.231
Yingchun Chen,Cui Li,Yaodong Yi,Weijuan Du,Huidi Jiang,Su Zeng,Hui Zhou
Dehydrocorydaline (DHC), one of the main active components of Corydalis yanhusuo, is an important remedy for the treatment of coronary heart disease. Our previous study revealed a higher unbound concentration of DHC in the heart than plasma of mice after oral administration of C. yanhusuo extract or DHC, but the underlying uptake mechanism remains unelucidated. In our investigations, we studied the transport mechanism of DHC in transgenic cells, primary neonatal rat cardiomyocytes, and animal experiments. Using quantitative real-time polymerase chain reaction and Western blotting, we found that uptake transporters expressed in the mouse heart include organic cation transporter 1/3 (OCT1/3) and carnitine/organic cation transporter 1/2 (OCTN1/2). The accumulation experiments in transfected cells showed that DHC was a substrate of OCT1 and OCT3, with Km of 11.29 ± 3.3 and 8.96 ± 3.7 μM, respectively, but not a substrate of OCTN1/2. Additionally, a higher efflux level (1.71-fold of MDCK-mock) of DHC was observed in MDCK-MDR1 cells than in MDCK-mock cells. Therefore, DHC is a weak substrate for MDR1. Studies using primary neonatal rat cardiomyocytes showed that OCT1/3 inhibitors (quinidine, decynium-22, and levo-tetrahydropalmatine) prevented the accumulation of DHC, whereas OCTN2 inhibitors (mildronate and l-carnitine) did not affect its accumulation. Moreover, the coadministration of OCT1/3 inhibitors (levo-tetrahydropalmatine, THP) decreased the concentration of DHC in the mouse heart. Based on these findings, DHC may be accumulated partly by OCT1/3 transporters and excreted by MDR1 in the heart. THP could alter the distribution of DHC in the mouse heart.
研究领域:
药理学
·
心脏病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2020
·
IF 7.182
Ziming Zheng,Yu Zhang,Yuxuan Liu,Jinglin Wang,Zheng Cui,Xianglin Pan,Yan Liu,Wenqi Tang,Kaiping Wang
Lentinan (LNT), a typical triple helix β-glucan, has been widely used as drug and biomaterial. However, its pharmacokinetics in vivo is rarely reported, which severely limits its further development and application. The aim of this study is to establish a sensitive method for detecting LNT in biosamples and to evaluate the plasma level, tissue distribution and metabolic degradation of LNT in rats. 5-([4,6-Dichlorotriazin-2-yl] amino) fluorescein (DTAF) was labelled to LNT. After purification and identification, FLNT was intravenously administered to rats at dose of 32 mg/kg. LNT was predominantly incorporated into the liver and liver microsomes were used to study the degradation mechanism of LNT in the liver. The results showed that two cytochrome P450 (CYP450) enzymes subtypes (CYP2D6 and CYP2C9), as well as epoxide hydrolase, were involved in the metabolic degradation of LNT. These findings provide a pharmacokinetic reference for further study and application of LNT and other β-glucans.
研究领域:
药理学
·
生物化学
·
分子生物学
✓ 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）