Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing loss.This study aimed to assess the potential effect of the DNA methyltransferase(DNMT)inhibitor RG108 on ci...Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing loss.This study aimed to assess the potential effect of the DNA methyltransferase(DNMT)inhibitor RG108 on cisplatin-induced ototoxicity.Immunohistochemistry,apoptosis assay,and auditory brainstem response(ABR)were employed to determine the impacts of RG108 on cisplatin-induced injury in murine hair cells(HCs)and spiral ganglion neurons(SGNs).Rhodamine 123 and TMRM were utilized for mitochondrial membrane potential(MMP)assessment.Reactive oxygen species(ROS)amounts were evaluated by Cellrox green and Mitosox-red probes.Mitochondrial respiratory function evaluation was performed by determining oxygen consumption rates(OCRs).The results showed that RG108 can markedly reduce cisplatin induced damage in HCs and SGNs,and alleviate apoptotic rate by protecting mitochondrial function through preventing ROS accumulation.Furthermore,RG108 upregulated BCL-2 and downregulated APAF1,BAX,and BAD in HEI-OC1 cells,and triggered the PI3K/AKT pathway.Decreased expression of low-density lipoprotein receptor-related protein 1(LRP1)and high methylation of the LRP1 promoter were observed after cisplatin treatment.RG108 treatment can increase LRP1expression and decrease LRP1 promoter methylation.In conclusion,RG108 might represent a new potential agent for preventing hearing loss induced by cisplatin via activating the LRP1-PI3K/AKT pathway.展开更多
Polyhydroxyalkanoates are natural,biodegradable,thermoplastic and sustainable polymers with a huge potential in fabrication of bioresorbable implantable devices for tissue engineering.We describe a comparative evaluat...Polyhydroxyalkanoates are natural,biodegradable,thermoplastic and sustainable polymers with a huge potential in fabrication of bioresorbable implantable devices for tissue engineering.We describe a comparative evaluation of three medium chain length polyhydroxyalkanoates(mcl-PHAs),namely poly(3-hydroxyoctanoate),poly(3-hydroxyoctanoate-co-3-hydoxydecanoate)and poly(3-hydroxyoctanoate-co-3-hydroxydecanoate-co-3-hydroxydodecanoate),one short chain length polyhydroxyalkanoate,poly(3-hydroxybutyrate),P(3HB)and synthetic aliphatic polyesters(polycaprolactone and polylactide)with a specific focus on nerve regeneration,due to mechanical properties of mcl-PHAs closely matching nerve tissues.In vitro biological studies with NG108-15 neuronal cell and primary Schwann cells did not show a cytotoxic effect of the materials on both cell types.All mcl-PHAs supported cell adhesion and viability.Among the three mcl-PHAs,P(3HO-co-3HD)exhibited superior properties with regards to numbers of cells adhered and viable cells for both cell types,number of neurite extensions from NG108-15 cells,average length of neurite extensions and Schwann cells.Although,similar characteristics were observed for flat P(3HB)surfaces,high rigidity of this biomaterial,and FDA-approved polymers such as PLLA,limits their applications in peripheral nerve regeneration.Therefore,we have designed,synthesized and evaluated these materials for nerve tissue engineering and regenerative medicine,the interaction of mcl-PHAs with neuronal and Schwann cells,identifying mcl-PHAs as excellent materials to enhance nerve regeneration and potentially their clinical application in peripheral nerve repair.展开更多
基金was supported by grants from the National Key R&D Program of China(No.2017YFA0103900)the National Natural Science Foundation of China(Nos.82071045,81870728,81830029,and 81970875)Shanghai Rising-Star Program(19QA1401800)。
文摘Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing loss.This study aimed to assess the potential effect of the DNA methyltransferase(DNMT)inhibitor RG108 on cisplatin-induced ototoxicity.Immunohistochemistry,apoptosis assay,and auditory brainstem response(ABR)were employed to determine the impacts of RG108 on cisplatin-induced injury in murine hair cells(HCs)and spiral ganglion neurons(SGNs).Rhodamine 123 and TMRM were utilized for mitochondrial membrane potential(MMP)assessment.Reactive oxygen species(ROS)amounts were evaluated by Cellrox green and Mitosox-red probes.Mitochondrial respiratory function evaluation was performed by determining oxygen consumption rates(OCRs).The results showed that RG108 can markedly reduce cisplatin induced damage in HCs and SGNs,and alleviate apoptotic rate by protecting mitochondrial function through preventing ROS accumulation.Furthermore,RG108 upregulated BCL-2 and downregulated APAF1,BAX,and BAD in HEI-OC1 cells,and triggered the PI3K/AKT pathway.Decreased expression of low-density lipoprotein receptor-related protein 1(LRP1)and high methylation of the LRP1 promoter were observed after cisplatin treatment.RG108 treatment can increase LRP1expression and decrease LRP1 promoter methylation.In conclusion,RG108 might represent a new potential agent for preventing hearing loss induced by cisplatin via activating the LRP1-PI3K/AKT pathway.
基金funded by the European Community’s Seventh Framework Programme(FP7-NMP-2013-SME-7)for NEURIMP un-der grant agreement no.604450CST also acknowledges funding by the Department of Materials Science and Engineering,Faculty of Engineering,University of Sheffield.IR acknowledges funding from the British Council:Innovative and Collaborative Research Partnerships Grants under Pakistan UK Education Gateway(ICRG-2020)+1 种基金Project No:105:006326/DIISB/007/2021the Engineering and Physical Sciences Research Council(EPSRC)funding for the See More Make More(SM3)project,EP/V012126/1.
文摘Polyhydroxyalkanoates are natural,biodegradable,thermoplastic and sustainable polymers with a huge potential in fabrication of bioresorbable implantable devices for tissue engineering.We describe a comparative evaluation of three medium chain length polyhydroxyalkanoates(mcl-PHAs),namely poly(3-hydroxyoctanoate),poly(3-hydroxyoctanoate-co-3-hydoxydecanoate)and poly(3-hydroxyoctanoate-co-3-hydroxydecanoate-co-3-hydroxydodecanoate),one short chain length polyhydroxyalkanoate,poly(3-hydroxybutyrate),P(3HB)and synthetic aliphatic polyesters(polycaprolactone and polylactide)with a specific focus on nerve regeneration,due to mechanical properties of mcl-PHAs closely matching nerve tissues.In vitro biological studies with NG108-15 neuronal cell and primary Schwann cells did not show a cytotoxic effect of the materials on both cell types.All mcl-PHAs supported cell adhesion and viability.Among the three mcl-PHAs,P(3HO-co-3HD)exhibited superior properties with regards to numbers of cells adhered and viable cells for both cell types,number of neurite extensions from NG108-15 cells,average length of neurite extensions and Schwann cells.Although,similar characteristics were observed for flat P(3HB)surfaces,high rigidity of this biomaterial,and FDA-approved polymers such as PLLA,limits their applications in peripheral nerve regeneration.Therefore,we have designed,synthesized and evaluated these materials for nerve tissue engineering and regenerative medicine,the interaction of mcl-PHAs with neuronal and Schwann cells,identifying mcl-PHAs as excellent materials to enhance nerve regeneration and potentially their clinical application in peripheral nerve repair.
