This experiment has been carried out to observe the potential thrombolytic activity of naturally occuring phytochemicals in Ginger (Zingiber officinale) and to analyze their drug likeness property and ADME/T profile. ...This experiment has been carried out to observe the potential thrombolytic activity of naturally occuring phytochemicals in Ginger (Zingiber officinale) and to analyze their drug likeness property and ADME/T profile. Thrombolytic activity of Ginger has already been confirmed in laboratory experiment and this study focuses on the molecular interactions among four phytocompounds (Isovanillin, Gingerol, Beta-sitosterol and 2,6-Dimethyl-2-octene-1,8-diol) found in Ginger and Tissue Plasminogen Activator (tPA). Present experiment is largely based on computer-aided drug design protocol where the strength of interaction is described as binding energy function. Isovanillin exhibited better docking score, and so this compound might have greater thrombolytic activity than others. Moreover, Isovanillin also suggested sound drug likeness property and ADME/T profile which predicts its safeness for consumption in human body. But Beta-sitosterol violated Lipinski’s rule of five and 2, 6-Dimethyl-2-octene-1,8-diol showed the lowest affinity of binding with tPA. However, further in vivo or in vitro study may be required to confirm the thrombolytic activity of Isovanillin.展开更多
Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its pathogenesis.This study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S...Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its pathogenesis.This study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)mice.Besides,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production.Due to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed cells.The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly.By encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,respectively.The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated biotransformation.In summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.展开更多
纳米颗粒因其独特的物理化学特性在工业、农业和医疗等领域得到了广泛应用,然而其环境暴露及对生物体的毒性效应也引起了广泛的忧虑。纳米颗粒可通过多种途径进入生物体并可能导致健康风险,因此准确预测其生物分布和毒代动力学过程至关...纳米颗粒因其独特的物理化学特性在工业、农业和医疗等领域得到了广泛应用,然而其环境暴露及对生物体的毒性效应也引起了广泛的忧虑。纳米颗粒可通过多种途径进入生物体并可能导致健康风险,因此准确预测其生物分布和毒代动力学过程至关重要。生理毒代动力学(physiologically based toxicokinetic,PBTK)模型为评估纳米颗粒在生物体内的吸收(absorption)、分布(distribution)、代谢(metabolism)和排泄(excretion)(统称ADME)以及毒性效应等过程提供了系统性的描述。本文综述了纳米颗粒PBTK模型的最新研究进展,探讨了模型构建中ADME特性的定量描述、模型框架、参数确定及验证方法,分析了当前面临的重要挑战:研究对象的局限性、纳米颗粒的理化特性纳入有限、缺乏环境因子相关参数、通用性模型处于起步阶段。最后,对纳米颗粒PBTK模型的发展提出展望。展开更多
文摘This experiment has been carried out to observe the potential thrombolytic activity of naturally occuring phytochemicals in Ginger (Zingiber officinale) and to analyze their drug likeness property and ADME/T profile. Thrombolytic activity of Ginger has already been confirmed in laboratory experiment and this study focuses on the molecular interactions among four phytocompounds (Isovanillin, Gingerol, Beta-sitosterol and 2,6-Dimethyl-2-octene-1,8-diol) found in Ginger and Tissue Plasminogen Activator (tPA). Present experiment is largely based on computer-aided drug design protocol where the strength of interaction is described as binding energy function. Isovanillin exhibited better docking score, and so this compound might have greater thrombolytic activity than others. Moreover, Isovanillin also suggested sound drug likeness property and ADME/T profile which predicts its safeness for consumption in human body. But Beta-sitosterol violated Lipinski’s rule of five and 2, 6-Dimethyl-2-octene-1,8-diol showed the lowest affinity of binding with tPA. However, further in vivo or in vitro study may be required to confirm the thrombolytic activity of Isovanillin.
基金supported by the Guangdong Local Innovation Team Program(2019BT02Y262,China)National Natural Science Foundation of China(U20A20101,82274002,22175083)+2 种基金Key-Area Research and Development Program of Guangdong Province(2023B1111050008,China)National Key Research and Development Program of China(2022YFA1206900,2023YFA0914200)Science and Technology Innovation Project of Guangdong Medical Products Administration(S2021ZDZ042,2023ZDZ06,2024ZDZ08,China).
文摘Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its pathogenesis.This study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)mice.Besides,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production.Due to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed cells.The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly.By encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,respectively.The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated biotransformation.In summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.
文摘纳米颗粒因其独特的物理化学特性在工业、农业和医疗等领域得到了广泛应用,然而其环境暴露及对生物体的毒性效应也引起了广泛的忧虑。纳米颗粒可通过多种途径进入生物体并可能导致健康风险,因此准确预测其生物分布和毒代动力学过程至关重要。生理毒代动力学(physiologically based toxicokinetic,PBTK)模型为评估纳米颗粒在生物体内的吸收(absorption)、分布(distribution)、代谢(metabolism)和排泄(excretion)(统称ADME)以及毒性效应等过程提供了系统性的描述。本文综述了纳米颗粒PBTK模型的最新研究进展,探讨了模型构建中ADME特性的定量描述、模型框架、参数确定及验证方法,分析了当前面临的重要挑战:研究对象的局限性、纳米颗粒的理化特性纳入有限、缺乏环境因子相关参数、通用性模型处于起步阶段。最后,对纳米颗粒PBTK模型的发展提出展望。
