Abnormal synaptic plasticity causes cognitive deficits.Hippocampal long-term potentiation(LTP)is a critical synaptic plasticity process[1].Rescuing impaired LTP is challenging;hence,novel agents are required for LTP f...Abnormal synaptic plasticity causes cognitive deficits.Hippocampal long-term potentiation(LTP)is a critical synaptic plasticity process[1].Rescuing impaired LTP is challenging;hence,novel agents are required for LTP facilitation.Chinese medicine Dengzhan Shengmai(DzSM)has shown notable clinical efficacy against cognitive deficits[2].However,it remains unclear how DzSM modulates cognition.Our previous study[3]revealed the influence of DZSM on glutamatergic and GABAergic synapses following chronic cerebral hypoperfusion(CCH),which motivated us to assess how DzSM affects synaptic functions.展开更多
The authors regret there was an unfortunate error in the reproduction of Fig.1I in the article.In the original figure,the fluorescence picture of the positive control drug-ifenprodil was misused.The authors have corre...The authors regret there was an unfortunate error in the reproduction of Fig.1I in the article.In the original figure,the fluorescence picture of the positive control drug-ifenprodil was misused.The authors have corrected Fig.1I and provided the original fluorescence pictures of all groups(seven groups,n=5 for each group)to the editorial office.Below,the corrected Fig.1I is shown below.The authors declare that this correction does not affect the description,interpretation,or the original conclusions of the article.展开更多
Neutrophil extracellular traps(NETs)formation(NETosis),is a crucial immune system mechanism mediated by neutrophils,measuring the capacity to induce NETosis is proposed as a clinical biomarker indicating the severity ...Neutrophil extracellular traps(NETs)formation(NETosis),is a crucial immune system mechanism mediated by neutrophils,measuring the capacity to induce NETosis is proposed as a clinical biomarker indicating the severity of COVID-19 and long COVID.Azvudine(FNC),has shown efficacy in treating SARS-CoV-2 infection and potential for alleviating inflammation.However,the molecular mechanism underlying its anti-inflammatory effects has not been extensively investigated.Therefore,a series of experiments were conducted on SARS-CoV-2 infected rhesus macaques(RMs)to investigate the anti-inflammatory effects of FNC.The experiments involved HE staining,mass spectrometry-based proteomics,validation experiments conducted in vivo using RMs tissues and in vitro differentiation of HL-60 cells.Additionally,interaction investigations were carried out utilizing LiP-MS,CETSA,Co-IP along with molecular docking.The results demonstrated that FNC treatment effectively alleviated neutrophil infiltration and attenuated inflammatory injury following infection.In addition to exhibiting antiviral effects,FNC treatment exhibited a reduction in inflammation-associated proteins and pathways such as myeloperoxidase(MPO)and the formation of NETs,respectively.Validation experiments confirmed the impact of FNC on regulating NETs formation,interaction experiments suggested that MPO may serves as a therapeutic target.The multifaceted properties of FNC,including its antiviral and anti-inflammatory characteristics,highlight the therapeutic potential in diseases associated with NETosis,particularly those involving concurrent SARS-CoV-2 infection,providing insights for drug development targeting MPO and NETosis-associated diseases.展开更多
There is an urgent need to elucidate the pathogenesis of myocardial ischemia(MI)and potential drug treatments.Here,the anti-MI mechanism and material basis of Ginkgo biloba L.extract(GBE)were studied from the perspect...There is an urgent need to elucidate the pathogenesis of myocardial ischemia(MI)and potential drug treatments.Here,the anti-MI mechanism and material basis of Ginkgo biloba L.extract(GBE)were studied from the perspective of energy metabolism flux regulation.Metabolic flux analysis(MFA)was performed to investigate energy metabolism flux disorder and the regulatory nodes of GBE components in isoproterenol(ISO)-induced ischemia-like cardiomyocytes.It showed that[U-13 C]glucose derived m+2 isotopologues from the upstream tricarboxylic acid(TCA)cycle metabolites were markedly accumulated in ISO-injured cardiomyocytes,but the opposite was seen for the downstream metabolites,while their total cellular concentrations were increased.This indicates a blockage of carbon flow from glycolysis and enhanced anaplerosis from other carbon sources.A Seahorse test was used to screen for GBE components with regulatory effects on mitochondrial aerobic respiratory dysfunction.It showed that bilobalide protected against impaired mitochondrial aerobic respiration.MFA also showed that bilobalide significantly modulated the TCA cycle flux,reduced abnormal metabolite accumulation,and balanced the demand of different carbon sources.Western blotting and PCR analysis showed that bilobalide decreased the enhanced expression of key metabolic enzymes in injured cells.Bilobalide’s efficacy was verified by in vivo experiments in rats.This is the first report to show that bilobalide,the active ingredient of GBE,protects against MI by rescuing impaired TCA cycle flux.This provides a new mechanism and potential drug treatment for MI.It also shows the potential of MFA/Seahorse combination as a powerful strategy for pharmacological research on herbal medicine.展开更多
Azvudine(FNC)is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase(RdRp).Recently,we discovered FNC an agent against SARS-CoV-2,and have taken it into Phase III trial for COVID-19 patients.FNC monoph...Azvudine(FNC)is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase(RdRp).Recently,we discovered FNC an agent against SARS-CoV-2,and have taken it into Phase III trial for COVID-19 patients.FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC_(50) between 1.2 and 4.3 μM,depending on viruses or cells,and selective index(SI)in 15-83 range.Oral administration of FNC in rats revealed a substantial thymus-homing feature,with FNC triphosphate(the active form)concentrated in the thymus and peripheral blood mononuclear cells(PBMC).Treating SARS-CoV-2 infected rhesus macaques with FNC(0.07 mg/kg, qd,orally)reduced viral load,recuperated the thymus,improved lymphocyte profiles,alleviated in flammation and orga n damage,and lessened grou nd・glass opacities in chest X-ray.Sin gle-cell seque ncing suggested the promotion of thymus function by FNC.A randomized,single-arm clinical trial of FNC on compassionate use(n=31)showed that oral FNC(5 mg,qd)cured all COVID-19 patients,with 100%viral ribonucleic acid negative conversion in 3.29±2.22 days(range:1-9 days)and 100%hospital discharge rate in 9.00±4.93 days(range:2-25 days).The side-effect of FNC is minor and transient dizziness and nausea in 16.12%(5/31)patients.Thus,FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus,followed by promoted immunity.展开更多
Thymus is the important immune organ,responsible for T cell development and differentiation.The lower circulating T counts have been observed in patients who died from COVID-19 compared with survivors.Azvudine,also kn...Thymus is the important immune organ,responsible for T cell development and differentiation.The lower circulating T counts have been observed in patients who died from COVID-19 compared with survivors.Azvudine,also known as FNC,is a thymus-homing anti-SARS-CoV-2 drug in treating COVID-19 patients.In this study,single-cell transcriptome,proteomics,and parallel reaction monitoring(PRM)were applied to insight into the activation process of FNC in rat and SARS-CoV-2 rhesus monkey thymus.The results indicated that thymic immune cells possess a robust metabolic capacity for cytidine-analogue drugs such as FNC.Key enzymes involved in the FNC phosphorylation process,such as Dck,Cmpk1,and Nme2,were highly expressed in CD4+ T cells,CD8+ T cells,and DP(CD4+ CD8+)cells.Additionally,FNC could upregulate multiple phosphorylated kinases in various cell types while downregulating the phosphatases,phosphoribosyl transferases,and deaminases,respectively.The robust phosphorylation capacity of the thymus for cytidine analogue drug FNC,and the activation effect of FNC on the NAs metabolism system potentially contribute to its enrichment in the thymus and immune protection effect.This suggests that it is crucial to consider the expression level of phosphorylation kinases when evaluating NA drug properties,as an important factor during antiviral drug design.展开更多
基金the National Natural Science Foundation of China(Grant No.:82204341)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(Grant No.:2022-I2M-2-002)the National Key Research and Development Program of China(Grant No.:2019YFC1708901).
文摘Abnormal synaptic plasticity causes cognitive deficits.Hippocampal long-term potentiation(LTP)is a critical synaptic plasticity process[1].Rescuing impaired LTP is challenging;hence,novel agents are required for LTP facilitation.Chinese medicine Dengzhan Shengmai(DzSM)has shown notable clinical efficacy against cognitive deficits[2].However,it remains unclear how DzSM modulates cognition.Our previous study[3]revealed the influence of DZSM on glutamatergic and GABAergic synapses following chronic cerebral hypoperfusion(CCH),which motivated us to assess how DzSM affects synaptic functions.
文摘The authors regret there was an unfortunate error in the reproduction of Fig.1I in the article.In the original figure,the fluorescence picture of the positive control drug-ifenprodil was misused.The authors have corrected Fig.1I and provided the original fluorescence pictures of all groups(seven groups,n=5 for each group)to the editorial office.Below,the corrected Fig.1I is shown below.The authors declare that this correction does not affect the description,interpretation,or the original conclusions of the article.
基金supported by National Nature Science Foundation of China(No.82151525).
文摘Neutrophil extracellular traps(NETs)formation(NETosis),is a crucial immune system mechanism mediated by neutrophils,measuring the capacity to induce NETosis is proposed as a clinical biomarker indicating the severity of COVID-19 and long COVID.Azvudine(FNC),has shown efficacy in treating SARS-CoV-2 infection and potential for alleviating inflammation.However,the molecular mechanism underlying its anti-inflammatory effects has not been extensively investigated.Therefore,a series of experiments were conducted on SARS-CoV-2 infected rhesus macaques(RMs)to investigate the anti-inflammatory effects of FNC.The experiments involved HE staining,mass spectrometry-based proteomics,validation experiments conducted in vivo using RMs tissues and in vitro differentiation of HL-60 cells.Additionally,interaction investigations were carried out utilizing LiP-MS,CETSA,Co-IP along with molecular docking.The results demonstrated that FNC treatment effectively alleviated neutrophil infiltration and attenuated inflammatory injury following infection.In addition to exhibiting antiviral effects,FNC treatment exhibited a reduction in inflammation-associated proteins and pathways such as myeloperoxidase(MPO)and the formation of NETs,respectively.Validation experiments confirmed the impact of FNC on regulating NETs formation,interaction experiments suggested that MPO may serves as a therapeutic target.The multifaceted properties of FNC,including its antiviral and anti-inflammatory characteristics,highlight the therapeutic potential in diseases associated with NETosis,particularly those involving concurrent SARS-CoV-2 infection,providing insights for drug development targeting MPO and NETosis-associated diseases.
基金supported by grants from the National Natural Science Foundation of China(Grant No.:81803496)the CAMS Innovation Fund for Medical Sciences(Grant No.:2016-I2M-3-016)the Applications and Core Technology University Research(ACT-UR,Grant No.:4084)。
文摘There is an urgent need to elucidate the pathogenesis of myocardial ischemia(MI)and potential drug treatments.Here,the anti-MI mechanism and material basis of Ginkgo biloba L.extract(GBE)were studied from the perspective of energy metabolism flux regulation.Metabolic flux analysis(MFA)was performed to investigate energy metabolism flux disorder and the regulatory nodes of GBE components in isoproterenol(ISO)-induced ischemia-like cardiomyocytes.It showed that[U-13 C]glucose derived m+2 isotopologues from the upstream tricarboxylic acid(TCA)cycle metabolites were markedly accumulated in ISO-injured cardiomyocytes,but the opposite was seen for the downstream metabolites,while their total cellular concentrations were increased.This indicates a blockage of carbon flow from glycolysis and enhanced anaplerosis from other carbon sources.A Seahorse test was used to screen for GBE components with regulatory effects on mitochondrial aerobic respiratory dysfunction.It showed that bilobalide protected against impaired mitochondrial aerobic respiration.MFA also showed that bilobalide significantly modulated the TCA cycle flux,reduced abnormal metabolite accumulation,and balanced the demand of different carbon sources.Western blotting and PCR analysis showed that bilobalide decreased the enhanced expression of key metabolic enzymes in injured cells.Bilobalide’s efficacy was verified by in vivo experiments in rats.This is the first report to show that bilobalide,the active ingredient of GBE,protects against MI by rescuing impaired TCA cycle flux.This provides a new mechanism and potential drug treatment for MI.It also shows the potential of MFA/Seahorse combination as a powerful strategy for pharmacological research on herbal medicine.
基金This work was supported by the CAMS Innovation Fund for Medical Sciences(No.2020-I2M-1-003,2020-I2M-2-010,2020HY320001,China)The Drug Innovation Major Project(No.2018ZX09711001-003-002,China)+2 种基金National Natural Science Foundation(No.81621064,China)National key R&D project(No.2019YFC170890,China)CAMS Innovation Fund for Medical Sciences(No.2021-1-I2M-009,2021-1-I2M-030).
文摘Azvudine(FNC)is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase(RdRp).Recently,we discovered FNC an agent against SARS-CoV-2,and have taken it into Phase III trial for COVID-19 patients.FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC_(50) between 1.2 and 4.3 μM,depending on viruses or cells,and selective index(SI)in 15-83 range.Oral administration of FNC in rats revealed a substantial thymus-homing feature,with FNC triphosphate(the active form)concentrated in the thymus and peripheral blood mononuclear cells(PBMC).Treating SARS-CoV-2 infected rhesus macaques with FNC(0.07 mg/kg, qd,orally)reduced viral load,recuperated the thymus,improved lymphocyte profiles,alleviated in flammation and orga n damage,and lessened grou nd・glass opacities in chest X-ray.Sin gle-cell seque ncing suggested the promotion of thymus function by FNC.A randomized,single-arm clinical trial of FNC on compassionate use(n=31)showed that oral FNC(5 mg,qd)cured all COVID-19 patients,with 100%viral ribonucleic acid negative conversion in 3.29±2.22 days(range:1-9 days)and 100%hospital discharge rate in 9.00±4.93 days(range:2-25 days).The side-effect of FNC is minor and transient dizziness and nausea in 16.12%(5/31)patients.Thus,FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus,followed by promoted immunity.
基金the National Natural Science Foundation of China(No.82151525No.82394460)the National Key Research and Development Program of China(No.2021YFC0864600).
文摘Thymus is the important immune organ,responsible for T cell development and differentiation.The lower circulating T counts have been observed in patients who died from COVID-19 compared with survivors.Azvudine,also known as FNC,is a thymus-homing anti-SARS-CoV-2 drug in treating COVID-19 patients.In this study,single-cell transcriptome,proteomics,and parallel reaction monitoring(PRM)were applied to insight into the activation process of FNC in rat and SARS-CoV-2 rhesus monkey thymus.The results indicated that thymic immune cells possess a robust metabolic capacity for cytidine-analogue drugs such as FNC.Key enzymes involved in the FNC phosphorylation process,such as Dck,Cmpk1,and Nme2,were highly expressed in CD4+ T cells,CD8+ T cells,and DP(CD4+ CD8+)cells.Additionally,FNC could upregulate multiple phosphorylated kinases in various cell types while downregulating the phosphatases,phosphoribosyl transferases,and deaminases,respectively.The robust phosphorylation capacity of the thymus for cytidine analogue drug FNC,and the activation effect of FNC on the NAs metabolism system potentially contribute to its enrichment in the thymus and immune protection effect.This suggests that it is crucial to consider the expression level of phosphorylation kinases when evaluating NA drug properties,as an important factor during antiviral drug design.
