RSC Advances
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2023
·Vol. 13
·期 3
·1606-1616
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IF 3.9
Pei He,Haiqi Xu,Can Yang,Dehong Yu,Yi Liu,Jiana Du,Yanfang Li
Xanthine oxidase (XO) is a key target for gout treatment. Great efforts have been made towards the discovery and development of new XO inhibitors. Aureusidin (AUR), a natural compound, emerges as the second reported XO inhibitor with an aurone skeleton with an IC50 value of 7.617 ± 0.401 μM in vitro. The inhibitory mechanism of AUR against XO was explored through enzyme kinetic studies, multi-spectroscopic methods, computer simulation techniques, and ADME prediction. The results showed that AUR acts as a rapid reversible and mixed-type XO inhibitor and its binding to XO was driven by hydrogen bonding and hydrophobic interaction. Moreover, AUR presented a strong fluorescence quenching effect through a static quenching process and induced a conformation change of XO. Its binding pattern with XO was revealed through molecular docking, and its affinity toward XO was enhanced through interactions with key amino acid residues in the active pocket of XO. Further, AUR demonstrated good stability and pharmacokinetic behavior properties in molecular dynamics simulation and ADME prediction. In short, the current work clarified in depth the inhibitory mechanism of AUR on XO firstly and then provided fresh insights into its further development as a natural potent XO inhibitor with aurone skeleton.
研究领域:
药理学
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生物化学
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分子生物学
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药物化学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
·
IF 6.2
Bu-Da Su,Xiao-Meng Li,Zhi-Wei Huang,Yue Wang,Jia Shao,Yan-Yan Xu,Le-Xin Shu,Yu-Bo Li
Ochratoxin A (OTA) is a common fungal toxin frequently detected in food and human plasma samples. Currently, the physiologically based toxicokinetic (PBTK) model plays an active role in dose translation and can improve and enhance the risk assessment of toxins. In this study, the PBTK model of OTA in rats and humans was established based on knowledge of OTA-specific absorption, distribution, metabolism, and excretion (ADME) in order to better explain the disposition of OTA in humans and the discrepancies with other species. The models were calibrated and optimized using the available kinetic and toxicokinetic (TK) data, and independent test datasets were used for model evaluation. Subsequently, sensitivity analyses and population simulations were performed to characterize the extent to which variations in physiological and specific chemical parameters affected the model output. Finally, the constructed models were used for dose extrapolation of OTA, including the rat-to-human dose adjustment factor (DAF) and the human exposure conversion factor (ECF). The results showed that the unbound fraction (F up ) of OTA in plasma of rat and human was 0.02–0.04% and 0.13–4.21%, respectively. In vitro experiments, the maximum enzyme velocity (V max ) and Michaelis–Menten constant (K m ) of OTA in rat and human liver microsomes were 3.86 and 78.17 μg/g min −1 , 0.46 and 4.108 μg/mL, respectively. The predicted results of the model were in good agreement with the observed data, and the models in rats and humans were verified. The PBTK model derived a DAF of 0.1081 between rats and humans, whereas the ECF was 2.03. The established PBTK model can be used to estimate short- or long-term OTA exposure levels in rats and humans, with the capacity for dose translation of OTA to provide the underlying data for risk assessment of OTA.
研究领域:
毒理学
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药代动力学
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食品安全
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
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2019
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IF 1.984
Yueying Tao,Kunming Tian,Ji Chen,Danfeng Tan,Yan Liu,Yongai Xiong,Zehui Chen,Yingbiao Tian
This study aims to predict the active ingredients, potential targets, signaling pathways and investigate the “ingredient-target-pathway” mechanisms involved in the pharmacological action of Danshiliuhao Granule (DSLHG) on liver fibrosis. Pharmacodynamics studies on rats with liver fibrosis showed that DSLHG generated an obvious anti-liver fibrosis action. On this basis, we explored the possible mechanisms underlying its antifibrosis effect using network pharmacology approach. Information about compounds of herbs in DSLHG was collected from TCMSP public database and literature. Furthermore, the oral bioavailability (OB) and drug-likeness (DL) were screened according to ADME features. Compounds with OB≥30% and DL≥0.18 were selected as active ingredients. Then, the potential targets of the active compounds were predicted by pharmacophore mapping approach and mapped with the target genes of the specific disease. The compound-target network and Protein-Protein Interaction (PPI) network were built by Cytoscape software. The core targets were selected by degree values. Furthermore, GO biological process analysis and KEGG pathway enrichment analysis were carried out to investigate the possible mechanisms involved in the anti-hepatic fibrosis effect of DSLHG. The predicted results showed that there were 108 main active components in the DSLHG formula. Moreover, there were 192 potential targets regulated by DSLHG, of which 86 were related to liver fibrosis, including AKT1, EGFR, and IGF1R. Mechanistically, the anti-liver fibrosis effect of DSLHG was exerted by interfering with 47 signaling pathways, such as PI3K-Akt, FoxO signaling pathway, and Ras signaling pathway. Network analysis showed that DSLHG could generate the antifibrosis action by affecting multiple targets and multiple pathways, which reflects the multicomponent, multitarget, and multichannel characteristics of traditional Chinese medicine and provides novel basis to clarify the mechanisms of anti-liver fibrosis of DSLHG.
研究领域:
药理学
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中药学
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分子生物学
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系统生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 6.7
Youzhi Wang,Huifang Wang,Guoqing Yang,Qingjing Hao,Kan Yang,Huizhen Shen,Yulong Wang,Jinxin Wang
It is well known that chronic obstructive pulmonary disease (COPD) patients are always trapped in the vicious circle of inflammation and oxidative stress , therefore anti-inflammatory and antioxidant bifunctional agents may interrupt this vicious cycle in COPD. Phosphodiesterase 4 (PDE4) inhibitors, as anti-inflammatory drugs, have been used for COPD treatment in clinical, and the PDE4 inhibitors with antioxidant properties may be a good strategy to design bifunctional agents for COPD. Sappanone A was the first PDE4 inhibitor with antioxidant properties we identified from natural products in our previous study, which was used by us as a hit compound to design new bifunctional agents for COPD in this study. 27 derivatives of sappanone A including homoisoflavonoids , aurones and chalcones were designed and synthesized by innovatively fusing the antioxidant pharmacophore of catechol from polyphenols and the pharmacophore of catechol ether abstracted from the PDE4 inhibitors of the catechol ether class such as rolipram , roflumilast and apremilast respectively. All the compounds were assayed for the PDE4 inhibitory and radical scavenging against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) activities in vitro. Herein we obtained a series of bifunctional compounds with better PDE4 inhibitory activity than sappanone A, and their free radical scavenging activities were superior to edaravone in vitro. In addition, they can reduce tumour necrosis factor-alpha (TNF-α) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages and malondialdehyde (MDA) production induced by Fe 2+ in mouse lung homogenate . Meanwhile, it showed outstanding abilities in reducing Fe 3+ and complexing Fe 2+ . 6o , as the candidate anti-inflammatory and antioxidant bifunctional compound, exhibited good drug-likeness, ADME (Absorption, Distribution, Metabolism, Excretion) properties and human liver microsomal stability. In vivo, 6o (50 mg/kg and 100 mg/kg, i. p.) distinctly prevented LPS-induced serum levels of TNF-α in mice. In conclusion, the preliminary investigation provided a novel class of PDE4 inhibitors with antioxidant properties as bifunctional agents for the potential treatment of COPD, which can interrupt the vicious cycle of chronic inflammation and oxidative stress in COPD.
研究领域:
药理学
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药物化学
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呼吸医学
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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）