Tripartite motif 21(TRIM21)is an E3 ubiquitin ligase that shows great promise for protein degradation through ubiquitination.Here,ultrasmall chiral gold nanoparticles(D-or L-NPs)modified by D-or L-glutathione ligands ...Tripartite motif 21(TRIM21)is an E3 ubiquitin ligase that shows great promise for protein degradation through ubiquitination.Here,ultrasmall chiral gold nanoparticles(D-or L-NPs)modified by D-or L-glutathione ligands were fabricated.After conjugated with an NLR family pyrin domain-containing protein 3(NLRP3)antibody(D-NP-a NLRP3 or L-NP-a NLRP3),DNP-a NLRP3 showed effective delivery efficiency of the antibody into microglia and prevented Aβ-mediated microglia senescence,and p16^(ink4a),a marker of senescence,in the microglia was reduced by 90.3%±7.8% while L-NP-a NLRP3 decreased by 48.01%±3.1%.Mechanistic investigations revealed that the D-NP-a NLRP3((1.5±0.3)×10^(7)M^(-1))exhibited sixteen-fold larger binding affinity to transmembrane glycoprotein SLC3A2 than L-type((9.5±2.7)×10^(5)M^(-1)),which led to a high efficiency of antibody delivery and TRIM21-dependent NLRP3 degradation.Notably,the blood-brain barrier(BBB)-crossing ability of chiral NP-a NLRP3 as well as NLRP3 degradation was demonstrated in vivo.The APP/PS1 Alzheimer's disease(AD)model mice experiments exhibited a reduction of 89.7%±6.8% for the NLRP3 protein and 84.2±7.5% for p16^(ink4a)following the intravenous administration of D-NP-a NLRP3 once a week for 60 days.Furthermore,the levels of the AD markers Aβ and phosphorylatedTau in the brains were reduced by 86.2%±8.2% and 81.6%±9.1%;these were 2.1-fold and 1.9-fold higher than those treated with L-NP-a NLRP3,respectively.The studies provide a method to rescue AD-like pathologies and prevent senescence.展开更多
The widespread precatalyst (prepared in-situ or ex-situ) (arene) RuTsDPEN advocated for highly effectual asymmetric transfer hydrogenation (ATH) reactions with 2-propanol as hydrogen donor at ambient conditions, is pr...The widespread precatalyst (prepared in-situ or ex-situ) (arene) RuTsDPEN advocated for highly effectual asymmetric transfer hydrogenation (ATH) reactions with 2-propanol as hydrogen donor at ambient conditions, is proven to be unstable under the strong reducing conditions prevailing in the reaction mixtures (blend of alcohol and a base such as KOH). We assert that the true catalysts are the ruthenium metal nanoclusters formed swiftly under the reducing conditions of these systems. The TsDPEN ligand plays a critical role in the generation and formatting of the active catalyst including wreaking chiral properties to the so formed catalytic nanoparticles. Kinetic measurements, NMR, UV-visible spectroscopy, circular dichroism (CD) and TEM analyses corroborate this argument.展开更多
Sensitive differentiation of an enantiomer from its mirror image(ie,enantiodifferentiation),a perennial challenge for pharmaceutical production and disease diagnosis,is technically limited by the weak optical activity...Sensitive differentiation of an enantiomer from its mirror image(ie,enantiodifferentiation),a perennial challenge for pharmaceutical production and disease diagnosis,is technically limited by the weak optical activity(OA)of enantiomers,mainly due to their dimensional mismatch with light wavelengths in the ultraviolet(UV)-visible region.Here we use silver chiral nanoparticles(Ag CNPs)with nominally sub-5 nm helical pitch(P)to amplify the OA of(20R,30R,40S)-riboflavin-50-phosphate sodium salts(RP),which have been found to indirectly affect metabolic processes,through the formation of an RP thin film(TF)covering a close-packed array of Ag CNPs.The OA of the RP in the deep-UV region can be amplified up to 80-fold,ascribed to the aggregation of RP in the TFs and the interactions between RP and the atomically chiral lattices at the CNPs'surfaces.The former contribution,not associated with the chiral Ag topographies,plays a dominant role by thickening the RP TFs,so that the observed amplification has no enantioselective dependence on the chirality of the Ag CNPs.This study extends progress in the sensitive detection of bio-enantiomers,which is highly desired for advanced bio-detection in disease diagnosis and production of single-enantiomer pharmaceuticals.展开更多
The misfolding and aggregation ofα-synuclein(α-syn)is closely associated with Parkinson’s disease(PD).Here,chiral dimanganese trioxide(Mn_(2)O_(3))nanoparticles(NPs)were prepared for PD treatment enhanced by a noni...The misfolding and aggregation ofα-synuclein(α-syn)is closely associated with Parkinson’s disease(PD).Here,chiral dimanganese trioxide(Mn_(2)O_(3))nanoparticles(NPs)were prepared for PD treatment enhanced by a noninvasive electromagnetic field(MF).The affinity constants of D-NPs towardα-syn monomer(mono)orα-syn fibril were 3.5 times or 5.2 times higher,respectively,than those of L-NPs,and the mechanical force generated by NPs under a MF further promoted the interaction between NPs andα-syn to amplify the difference between L-NPs and D-NPs.As the synergy effect of the preferentially affinity ability and MF-induced mechanical forces,D-NPs exhibited a better inhibitory efficiency onα-syn fibrillization than L-NPs.Furthermore,after differentially cellular uptake of L-/D-NPs via the caveolin-mediated pathway,as reactive oxygen species(ROS)-scavengers,D-NPs possess higher efficiency in decreasing intracellular ROS level than L-NPs to provide higher cytoprotective efficiency to neuron cells.In vivo data showed that after treatment with D-NPs under a MF for 60 days,α-syn concentration in the cerebrospinal fluid of PD mice decreased 81%,while dopamine level in the brain of PD mice increased 2.3-fold.These findings indicated the potential of utilizing the synergic interplay of chiral NPs and MF for treating disease and opened a new path to explore the nanoscale chirality for regulating the biological effect.展开更多
基金supported by the National Natural Science Foundation of China(22274067,82071187)the Natural Science Foundation of Jiangsu Province(BK20230043)the Fundamental Research Funds for the Central Universities(JUSRP622009)。
文摘Tripartite motif 21(TRIM21)is an E3 ubiquitin ligase that shows great promise for protein degradation through ubiquitination.Here,ultrasmall chiral gold nanoparticles(D-or L-NPs)modified by D-or L-glutathione ligands were fabricated.After conjugated with an NLR family pyrin domain-containing protein 3(NLRP3)antibody(D-NP-a NLRP3 or L-NP-a NLRP3),DNP-a NLRP3 showed effective delivery efficiency of the antibody into microglia and prevented Aβ-mediated microglia senescence,and p16^(ink4a),a marker of senescence,in the microglia was reduced by 90.3%±7.8% while L-NP-a NLRP3 decreased by 48.01%±3.1%.Mechanistic investigations revealed that the D-NP-a NLRP3((1.5±0.3)×10^(7)M^(-1))exhibited sixteen-fold larger binding affinity to transmembrane glycoprotein SLC3A2 than L-type((9.5±2.7)×10^(5)M^(-1)),which led to a high efficiency of antibody delivery and TRIM21-dependent NLRP3 degradation.Notably,the blood-brain barrier(BBB)-crossing ability of chiral NP-a NLRP3 as well as NLRP3 degradation was demonstrated in vivo.The APP/PS1 Alzheimer's disease(AD)model mice experiments exhibited a reduction of 89.7%±6.8% for the NLRP3 protein and 84.2±7.5% for p16^(ink4a)following the intravenous administration of D-NP-a NLRP3 once a week for 60 days.Furthermore,the levels of the AD markers Aβ and phosphorylatedTau in the brains were reduced by 86.2%±8.2% and 81.6%±9.1%;these were 2.1-fold and 1.9-fold higher than those treated with L-NP-a NLRP3,respectively.The studies provide a method to rescue AD-like pathologies and prevent senescence.
文摘The widespread precatalyst (prepared in-situ or ex-situ) (arene) RuTsDPEN advocated for highly effectual asymmetric transfer hydrogenation (ATH) reactions with 2-propanol as hydrogen donor at ambient conditions, is proven to be unstable under the strong reducing conditions prevailing in the reaction mixtures (blend of alcohol and a base such as KOH). We assert that the true catalysts are the ruthenium metal nanoclusters formed swiftly under the reducing conditions of these systems. The TsDPEN ligand plays a critical role in the generation and formatting of the active catalyst including wreaking chiral properties to the so formed catalytic nanoparticles. Kinetic measurements, NMR, UV-visible spectroscopy, circular dichroism (CD) and TEM analyses corroborate this argument.
基金GRF,Grant/Award Number:12200118National Natural Science Foundation of China,Grant/Award Number:91856127SKLP,Grant/Award Number:1920_P06。
文摘Sensitive differentiation of an enantiomer from its mirror image(ie,enantiodifferentiation),a perennial challenge for pharmaceutical production and disease diagnosis,is technically limited by the weak optical activity(OA)of enantiomers,mainly due to their dimensional mismatch with light wavelengths in the ultraviolet(UV)-visible region.Here we use silver chiral nanoparticles(Ag CNPs)with nominally sub-5 nm helical pitch(P)to amplify the OA of(20R,30R,40S)-riboflavin-50-phosphate sodium salts(RP),which have been found to indirectly affect metabolic processes,through the formation of an RP thin film(TF)covering a close-packed array of Ag CNPs.The OA of the RP in the deep-UV region can be amplified up to 80-fold,ascribed to the aggregation of RP in the TFs and the interactions between RP and the atomically chiral lattices at the CNPs'surfaces.The former contribution,not associated with the chiral Ag topographies,plays a dominant role by thickening the RP TFs,so that the observed amplification has no enantioselective dependence on the chirality of the Ag CNPs.This study extends progress in the sensitive detection of bio-enantiomers,which is highly desired for advanced bio-detection in disease diagnosis and production of single-enantiomer pharmaceuticals.
基金supported by the National Natural Science Foundation of China (32071400,51902136)
文摘The misfolding and aggregation ofα-synuclein(α-syn)is closely associated with Parkinson’s disease(PD).Here,chiral dimanganese trioxide(Mn_(2)O_(3))nanoparticles(NPs)were prepared for PD treatment enhanced by a noninvasive electromagnetic field(MF).The affinity constants of D-NPs towardα-syn monomer(mono)orα-syn fibril were 3.5 times or 5.2 times higher,respectively,than those of L-NPs,and the mechanical force generated by NPs under a MF further promoted the interaction between NPs andα-syn to amplify the difference between L-NPs and D-NPs.As the synergy effect of the preferentially affinity ability and MF-induced mechanical forces,D-NPs exhibited a better inhibitory efficiency onα-syn fibrillization than L-NPs.Furthermore,after differentially cellular uptake of L-/D-NPs via the caveolin-mediated pathway,as reactive oxygen species(ROS)-scavengers,D-NPs possess higher efficiency in decreasing intracellular ROS level than L-NPs to provide higher cytoprotective efficiency to neuron cells.In vivo data showed that after treatment with D-NPs under a MF for 60 days,α-syn concentration in the cerebrospinal fluid of PD mice decreased 81%,while dopamine level in the brain of PD mice increased 2.3-fold.These findings indicated the potential of utilizing the synergic interplay of chiral NPs and MF for treating disease and opened a new path to explore the nanoscale chirality for regulating the biological effect.
