Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Na...Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity,but also exhibit remarkable anti-inflammatory properties.However,the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood.In this study,we developed perfluoropentane-based oxygen-loaded nanodroplets(PFP-OLNDs)and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo,and suppressed microglial activation in a mouse model of Parkinson’s disease.Microglial suppression led to a reduction in the inflammatory response,oxidative stress,and cell migration capacity in vitro.Consequently,the neurotoxic effects were mitigated,which alleviated neuronal degeneration.Additionally,ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming.We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1αpathway.Collectively,our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.展开更多
Objective Contrast-enhanced ultrasound(CEUS)is advantageous for evaluating microcirculation,and has been applied to assess arthritis in previous studies.However,CEUS examinations have not been studied for hemophilia a...Objective Contrast-enhanced ultrasound(CEUS)is advantageous for evaluating microcirculation,and has been applied to assess arthritis in previous studies.However,CEUS examinations have not been studied for hemophilia arthritis.Hemophilia arthritis is different from other arthritis,because it is induced by spontaneous joint bleeding.Hence,CEUS may have special value in evaluating hemophilia arthritis.The present study assessed the value of CEUS in evaluating synovial hypertrophy and predicting recurrent joint bleeding in severe hemophilia A patients.Methods From August 2016 to January 2017,81 severe hemophilia A patients,who were referred to our hospital for ultrasound joint assessment with conventional ultrasound,were enrolled.Among these 81 patients,46 patients consented for CEUS examinations on the same day.Results Compared to color Doppler flow imaging(CDFI),four more joints presented with a blood flow signal under CEUS mode.In addition,the synovial hypertrophy measured by CEUS was thicker than that measured by conventional ultrasound.The ultrasound scores(including the total grey-scale ultrasound score,joint effusion/hemarthrosis,synovial hypertrophy,CDFI semi-quantitative score,and CEUS semi-quantitative score)were significantly higher in the joint bleeding group than in the no joint bleeding group(P<0.05).Furthermore,these ultrasound scores were positively correlated with the joint bleeding frequency,and had the highest correlation with the CEUS score(r=0.620,P<0.05).Conclusion CEUS can more accurately assess the degree of synovial hypertrophy and vascularization,and diagnose synovitis,when compared to conventional ultrasound.In addition,CEUS appears to be essential for evaluating the possibility of recurrent joint bleeding,and providing more reliable evidence for individualized treatment.展开更多
Ferroptosis,as a newly discovered cell death form,has become an attractive target for precision cancer therapy.Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing int...Ferroptosis,as a newly discovered cell death form,has become an attractive target for precision cancer therapy.Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing intracellular iron levels or by inhibition of glutathione(GSH)-dependent lipid hydroperoxidase glutathione peroxidase 4(GPX4).However,the strategy by simultaneous iron delivery and GPX4 inhibition has rarely been reported.Herein,novel tumor microenvironments(TME)-activated metal-organic frameworks involving Fe&Cu ions bridged by disulfide bonds with PEGylation(FCSP MOFs)were developed,which would be degraded specifically under the redox TME,simultaneously achieving GSH-depletion induced GPX4 inactivation and releasing Fe ions to produce ROS via Fenton reaction,therefore causing ferroptosis.More ROS could be generated by the acceleration of Fenton reaction due to the released Cu ions and the intrinsic photothermal capability of FCSP MOFs.The overexpressed GSH and H2O2 in TME could ensure the specific TME self-activated therapy.Better tumor therapeutic efficiency could be achieved by doxorubicin(DOX)loading since it can not only cause apoptosis,but also indirectly produce H2O2 to amplify Fenton reaction.Remarkable anti-tumor effect of obtained FCSP@DOX MOFs was verified via both in vitro and in vivo assays.展开更多
基金supported by the National Natural Science Foundation of China,No.82101327(to YY)President Foundation of Nanfang Hospital,Southern Medical University,No.2020A001(to WL)+1 种基金Guangdong Basic and Applied Basic Research Foundation,Nos.2019A1515110150,2022A1515012362(both to YY)Guangzhou Science and Technology Project,No.202201020111(to YY).
文摘Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity,but also exhibit remarkable anti-inflammatory properties.However,the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood.In this study,we developed perfluoropentane-based oxygen-loaded nanodroplets(PFP-OLNDs)and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo,and suppressed microglial activation in a mouse model of Parkinson’s disease.Microglial suppression led to a reduction in the inflammatory response,oxidative stress,and cell migration capacity in vitro.Consequently,the neurotoxic effects were mitigated,which alleviated neuronal degeneration.Additionally,ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming.We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1αpathway.Collectively,our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.
基金The study was financially supported by the Project of New Technology and New Business of Nanfang Hospital,Southern Medical University(No.2016018).
文摘Objective Contrast-enhanced ultrasound(CEUS)is advantageous for evaluating microcirculation,and has been applied to assess arthritis in previous studies.However,CEUS examinations have not been studied for hemophilia arthritis.Hemophilia arthritis is different from other arthritis,because it is induced by spontaneous joint bleeding.Hence,CEUS may have special value in evaluating hemophilia arthritis.The present study assessed the value of CEUS in evaluating synovial hypertrophy and predicting recurrent joint bleeding in severe hemophilia A patients.Methods From August 2016 to January 2017,81 severe hemophilia A patients,who were referred to our hospital for ultrasound joint assessment with conventional ultrasound,were enrolled.Among these 81 patients,46 patients consented for CEUS examinations on the same day.Results Compared to color Doppler flow imaging(CDFI),four more joints presented with a blood flow signal under CEUS mode.In addition,the synovial hypertrophy measured by CEUS was thicker than that measured by conventional ultrasound.The ultrasound scores(including the total grey-scale ultrasound score,joint effusion/hemarthrosis,synovial hypertrophy,CDFI semi-quantitative score,and CEUS semi-quantitative score)were significantly higher in the joint bleeding group than in the no joint bleeding group(P<0.05).Furthermore,these ultrasound scores were positively correlated with the joint bleeding frequency,and had the highest correlation with the CEUS score(r=0.620,P<0.05).Conclusion CEUS can more accurately assess the degree of synovial hypertrophy and vascularization,and diagnose synovitis,when compared to conventional ultrasound.In addition,CEUS appears to be essential for evaluating the possibility of recurrent joint bleeding,and providing more reliable evidence for individualized treatment.
基金supported by the National Natural Science Foundation of China(Grant Nos.81371559,81671709,81601550,81871371,81701711,and 82072056)Guangzhou Municipal Science and Technology Project(No.201804010106,China)National College Students Innovation and Entrepreneurship Training Program(No.201812121007,China)。
文摘Ferroptosis,as a newly discovered cell death form,has become an attractive target for precision cancer therapy.Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing intracellular iron levels or by inhibition of glutathione(GSH)-dependent lipid hydroperoxidase glutathione peroxidase 4(GPX4).However,the strategy by simultaneous iron delivery and GPX4 inhibition has rarely been reported.Herein,novel tumor microenvironments(TME)-activated metal-organic frameworks involving Fe&Cu ions bridged by disulfide bonds with PEGylation(FCSP MOFs)were developed,which would be degraded specifically under the redox TME,simultaneously achieving GSH-depletion induced GPX4 inactivation and releasing Fe ions to produce ROS via Fenton reaction,therefore causing ferroptosis.More ROS could be generated by the acceleration of Fenton reaction due to the released Cu ions and the intrinsic photothermal capability of FCSP MOFs.The overexpressed GSH and H2O2 in TME could ensure the specific TME self-activated therapy.Better tumor therapeutic efficiency could be achieved by doxorubicin(DOX)loading since it can not only cause apoptosis,but also indirectly produce H2O2 to amplify Fenton reaction.Remarkable anti-tumor effect of obtained FCSP@DOX MOFs was verified via both in vitro and in vivo assays.
