Metal ions trigger Fenton/Fenton-like reactions,generating highly toxic hydroxyl radicals(•OH)for chemodynamic therapy(CDT),which is crucial in inducing lethal oxidative DNA damage and subsequent cell apoptosis.Howeve...Metal ions trigger Fenton/Fenton-like reactions,generating highly toxic hydroxyl radicals(•OH)for chemodynamic therapy(CDT),which is crucial in inducing lethal oxidative DNA damage and subsequent cell apoptosis.However,tumor cells can counteract this damage through repair pathways,particularly MutT homolog 1(MTH1)protein attenuation of oxidative DNA damage.Suppression of MTH1 can enhance CDT efficacy,therefore,orderly integrating Fenton/Fenton-like agents with an MTH1 inhibitor is expected to significantly augment CDT effectiveness.Carrier-free CuTH@CD,self-assembled through the supramolecular orchestration ofγ-cyclodextrin(γ-CD)with Cu^(2+)and the MTH1 inhibitor TH588,effectively overcoming tumor resistance by greatly amplifying oxidative damage capability.Without additional carriers and mediated by multiple supramolecular regulatory effects,CuTH@CD enables high drug loading content,stability,and uniform size distribution.Upon internalization by tumor cells,CuTH@CD invalidates repair pathways through Cu^(2+)-mediated glutathione(GSH)depletion and TH588-mediated MTH1 inhibition.Meanwhile,both generated Cu^(+)ions and existing ones within the nanoassembly initiate a Fentonlike reaction,leading to the accumulation of•OH.This strategy enhances CDT efficiency with minimal side effects,improving oxidative damage potency and advancing self-delivery nanoplatforms for developing effective chemodynamic tumor therapies.展开更多
Hepatic encephalopathy(HE)is a neurological condition that occurs as a complication of liver dysfunction that involves sensorimotor symptoms in addition to cognitive and behavioral changes,particularly in cases of sev...Hepatic encephalopathy(HE)is a neurological condition that occurs as a complication of liver dysfunction that involves sensorimotor symptoms in addition to cognitive and behavioral changes,particularly in cases of severe liver disease or cirrhosis.Previous studies have reported spatially distributed structural and functional abnormalities related to HE,but the exact relationship between the structural and functional alterations with respect to disease progression remains unclear.In this study,we performed surface-based cortical thickness comparisons and functional connectivity(FC)analyses between three cross-sectional groups:healthy controls(HC,N¼51),patients with minimal hepatic en-cephalopathy(MHE,N¼50),patients with overt hepatic encephalopathy(OHE,N¼51).In addition to the distributed cortical thinning that is extensively thought to be associated with cognitive decline in HE,we found significant cortical thickening in the left para-hippocampal gyrus cortex in the OHE group(p<0.001,p¼0.009)as compared to the HC and MHE group respectively,which is further corroborated by the significant correlation between the cortical thickness and digit symbol test(DST)scores.Furthermore,the decreased FC between the right postcentral gyrus and several sensory regions(bilateral somatosensory and visual cortices)was found to be significant in MHE patients as compared to the HC group.Our results revealed cross-sectional structural and functional variations concerning disease progression across different subsystems(e.g.,visual,motor and sensory),providing evidence that can potentially explain the mechanisms underlying the sensorimotor and cognitive deficits related to HE.展开更多
基金funded by Tongzhou District Health Development Research Reserve Project Foundation(No.KJ2024CX024)Natural Science Foundation of Tianjin City(No.23JCQNJC01640)+1 种基金National Natural Science Foundation of China(Nos.82304393,22404122)Beijing Nova Program(No.Z211100002121127).
文摘Metal ions trigger Fenton/Fenton-like reactions,generating highly toxic hydroxyl radicals(•OH)for chemodynamic therapy(CDT),which is crucial in inducing lethal oxidative DNA damage and subsequent cell apoptosis.However,tumor cells can counteract this damage through repair pathways,particularly MutT homolog 1(MTH1)protein attenuation of oxidative DNA damage.Suppression of MTH1 can enhance CDT efficacy,therefore,orderly integrating Fenton/Fenton-like agents with an MTH1 inhibitor is expected to significantly augment CDT effectiveness.Carrier-free CuTH@CD,self-assembled through the supramolecular orchestration ofγ-cyclodextrin(γ-CD)with Cu^(2+)and the MTH1 inhibitor TH588,effectively overcoming tumor resistance by greatly amplifying oxidative damage capability.Without additional carriers and mediated by multiple supramolecular regulatory effects,CuTH@CD enables high drug loading content,stability,and uniform size distribution.Upon internalization by tumor cells,CuTH@CD invalidates repair pathways through Cu^(2+)-mediated glutathione(GSH)depletion and TH588-mediated MTH1 inhibition.Meanwhile,both generated Cu^(+)ions and existing ones within the nanoassembly initiate a Fentonlike reaction,leading to the accumulation of•OH.This strategy enhances CDT efficiency with minimal side effects,improving oxidative damage potency and advancing self-delivery nanoplatforms for developing effective chemodynamic tumor therapies.
基金the National Natural Scientific Foundation of China(82071994,82202249)Tianjin Health High Level Talent Selection and Training Project(TJSQNYXXR-D2-143)+4 种基金Natural Scientific Foundation of Tianjin(21CYBJC01580,21JCQNJC01480)Tianjin Health Research Project(TJWJ2023QN031,TJWJ2023XK012)Tianjin Health Science and technology project(Specific projects of key disciplines)(TJWJ2022XK019)Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-041A)Tianjin Natural Science Foundation(21JCYBJC01290).
文摘Hepatic encephalopathy(HE)is a neurological condition that occurs as a complication of liver dysfunction that involves sensorimotor symptoms in addition to cognitive and behavioral changes,particularly in cases of severe liver disease or cirrhosis.Previous studies have reported spatially distributed structural and functional abnormalities related to HE,but the exact relationship between the structural and functional alterations with respect to disease progression remains unclear.In this study,we performed surface-based cortical thickness comparisons and functional connectivity(FC)analyses between three cross-sectional groups:healthy controls(HC,N¼51),patients with minimal hepatic en-cephalopathy(MHE,N¼50),patients with overt hepatic encephalopathy(OHE,N¼51).In addition to the distributed cortical thinning that is extensively thought to be associated with cognitive decline in HE,we found significant cortical thickening in the left para-hippocampal gyrus cortex in the OHE group(p<0.001,p¼0.009)as compared to the HC and MHE group respectively,which is further corroborated by the significant correlation between the cortical thickness and digit symbol test(DST)scores.Furthermore,the decreased FC between the right postcentral gyrus and several sensory regions(bilateral somatosensory and visual cortices)was found to be significant in MHE patients as compared to the HC group.Our results revealed cross-sectional structural and functional variations concerning disease progression across different subsystems(e.g.,visual,motor and sensory),providing evidence that can potentially explain the mechanisms underlying the sensorimotor and cognitive deficits related to HE.
