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Cell-derived nanovesicles from mesenchymal stem cells as extracellular vesicle-mimetics in wound healing
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作者 Yub Raj Neupane Harish K.Handral +11 位作者 Syed Abdullah Alkaff Wei Heng Chng gopalakrishnan venkatesan Chenyuan Huang Choon Keong Lee Jiong-Wei Wang Gopu Sriram Rhonnie Austria Dienzo Wen Feng Lu Yusuf Ali Bertrand Czarny Giorgia Pastorin 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2023年第5期1887-1902,共16页
Wound healing is a dynamic process that involves a series of molecular and cellular events aimed at replacing devitalized and missing cellular components and/or tissue layers.Recently,extracellular vesicles(EVs),natur... Wound healing is a dynamic process that involves a series of molecular and cellular events aimed at replacing devitalized and missing cellular components and/or tissue layers.Recently,extracellular vesicles(EVs),naturally cell-secreted lipid membrane-bound vesicles laden with biological cargos including proteins,lipids,and nucleic acids,have drawn wide attention due to their ability to promote wound healing and tissue regeneration.However,current exploitation of EVs as therapeutic agents is limited by their low isolation yields and tedious isolation processes.To circumvent these challenges,bioinspired cell-derived nanovesicles(CDNs)that mimic EVs were obtained by shearing mesenchymal stem cells(MSCs)through membranes with different pore sizes.Physical characterisations and highthroughput proteomics confirmed that MSC-CDNs mimicked MSC-EVs.Moreover,these MSC-CDNs were efficiently uptaken by human dermal fibroblasts and demonstrated a dose-dependent activation of MAPK signalling pathway,resulting in enhancement of cell proliferation,cell migration,secretion of growth factors and extracellular matrix proteins,which all promoted tissue regeneration.Of note,MSC-CDNs enhanced angiogenesis in human dermal microvascular endothelial cells in a 3D PEGfibrin scaffold and animal model,accelerating wound healing in vitro and in vivo.These findings suggest that MSC-CDNs could replace both whole cells and EVs in promoting wound healing and tissue regeneration. 展开更多
关键词 Extracellular vesicles Cell-derived nanovesicles BIONANOTECHNOLOGY Mesenchymal stem cells Fibroblasts Cell proliferation Cell migration ECM Wound healing
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Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts 被引量:1
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作者 Aneesh V.Karkhanis gopalakrishnan venkatesan +9 位作者 Ryuichi Kambayashi Jacqueline Wen Hui Leow Marcus Qingrui Han Hiroko Izumi-Nakaseko Ai Goto Jeremy Kah Sheng Pang Boon Seng Soh Pipin Kojodjojo Atsushi Sugiyama Eric Chun Yong Chan 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2022年第10期3905-3923,共19页
Cytochrome P4502J2(CYP2J2)metabolizes arachidonic acid(AA)to cardioprotective epoxyeicosatrienoic acids(EETs).Dronedarone,an antiarrhythmic drug prescribed for treatment of atrial fibrillation(AF)induces cardiac adver... Cytochrome P4502J2(CYP2J2)metabolizes arachidonic acid(AA)to cardioprotective epoxyeicosatrienoic acids(EETs).Dronedarone,an antiarrhythmic drug prescribed for treatment of atrial fibrillation(AF)induces cardiac adverse effects(AEs)with poorly understood mechanisms.We previously demonstrated that dronedarone inactivates CYP2J2 potently and irreversibly,disrupts AA-EET pathway leading to cardiac mitochondrial toxicity rescuable via EET enrichment.In this study,we investigated if mitigation of CYP2J2 inhibition prevents dronedarone-induced cardiac AEs.We first synthesized a deuterated analogue of dronedarone(termed poyendarone)and demonstrated that it neither inactivates CYP2J2,disrupts AA-EETs metabolism nor causes cardiac mitochondrial toxicity in vitro.Our patch-clamp experiments demonstrated that pharmacoelectrophysiology of dronedarone is unaffected by deuteration.Next,we show that dronedarone treatment or CYP2J2 knockdown in spontaneously beating cardiomyocytes indicative of depleted CYP2J2 activity exacerbates beat-to-beat(BTB)variability reflective of proarrhythmic phenotype.In contrast,poyendarone treatment yields significantly lower BTB variability compared to dronedarone in cardiomyocytes indicative of preserved CYP2J2 activity.Importantly,poyendarone and dronedarone display similar antiarrhythmic properties in the canine model of persistent AF,while poyendarone substantially reduces beat-to-beat variability of repolarization duration suggestive of diminished proarrhythmic risk.Our findings prove that deuteration of dronedarone prevents CYP2J2 inactivation and mitigates dronedarone-induced cardiac AEs. 展开更多
关键词 Arachidonic acid Atrial fibrillation CYP2J2 Drug-induced proarrhythmia Epoxyeicosatrienoic acids Mechanism-based inactivation DRONEDARONE
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