Acute lung injury/acute respiratory distress syndrome(ALI/ARDS)is characterized by diffuse alveolar injury primarily caused by an excessive inflammatory response.Regrettably,the lack of effective pharmacotherapy curre...Acute lung injury/acute respiratory distress syndrome(ALI/ARDS)is characterized by diffuse alveolar injury primarily caused by an excessive inflammatory response.Regrettably,the lack of effective pharmacotherapy currently available contributes to the high mortality rate in patients with this condition.Xuebijing(XBJ),a traditional Chinese medicine recognized for its potent anti-inflammatory properties,exhibits promise as a potential therapeutic agent for ALI/ARDS.This study aimed to explore the preventive effects of XBJ on ALI and its underlying mechanism.To this end,we established an LPS-induced ALI model and treated ALI mice with XBJ.Our results demonstrated that pre-treatment with XBJ significantly alleviated lung inflammation and increased the survival rate of ALI mice by 37.5%.Moreover,XBJ substantially suppressed the production of TNF-α,IL-6,and IL-1βin the lung tissue.Subsequently,we performed a network pharmacology analysis and identified identified 109 potential target genes of XBJ that were mainly involved in multiple signaling pathways related to programmed cell death and anti-inflammatory responses.Furthermore,we found that XBJ exerted its inhibitory effect on gasdermin-E-mediated pyroptosis of lung cells by suppressing TNF-αproduction.Therefore,this study not only establishes the preventive efficacy of XBJ in ALI but also reveals its role in protecting alveolar epithelial cells against gasdermin-E-mediated pyroptosis by reducing TNF-αrelease.展开更多
Acute lung injury(ALI)and acute respiratory distress syndrome(ARDS),which are characterized by excessive inflammation and accompanied by diffuse injury of alveoli,can result in severe respiratory failures.The morbidit...Acute lung injury(ALI)and acute respiratory distress syndrome(ARDS),which are characterized by excessive inflammation and accompanied by diffuse injury of alveoli,can result in severe respiratory failures.The morbidity and mortality of patients remain high because the major treatments for ALI/ARDS are mainly supportive due to the lack of effective therapies.Numerous studies have demonstrated that the aggravation of coronavirus disease 2019(COVID-19)leads to severe pneumonia and even ARDS.Pyroptosis,a biological process identified as a type of programed cell death,is mainly triggered by inflammatory caspase activation and is directly meditated by the gasdermin protein family,as well as being associated with the secretion and release of pro-inflammatory cytokines.Clinical and experimental evidence corroborates that pyroptosis of various cells in the lung,such as immune cells and structural cells,may play an important role in the pathogenesis of“cytokine storms”in ALI/ARDS,including those induced by COVID-19.Here,with a focus on ALI/ARDS and COVID-19,we summarized the recent advances in this field and proposed the theory of an inflammatory cascade in pyroptosis to identify new targets and pave the way for new approaches to treat these diseases.展开更多
Sepsis is a life-threatening syndrome resulting from a dysregulated host response to infection.It is the primary cause of death in the intensive care unit,posing a substantial challenge to human health and medical res...Sepsis is a life-threatening syndrome resulting from a dysregulated host response to infection.It is the primary cause of death in the intensive care unit,posing a substantial challenge to human health and medical resource allocation.The pathogenesis and pathophysiology of sepsis are complex.During its onset,pro-inflammatory and anti-inflammatory mechanisms engage in intricate interactions,possibly leading to hyperinflammation,immuno-suppression,and long-term immune disease.Of all critical outcomes,hyperinflammation is the main cause of early death among patients with sepsis.Therefore,early suppression of hyperinflammation may improve the progno-sis of these patients.Nafamostat mesilate is a serine protease inhibitor,which can inhibit the activation of the complement system,coagulation system,and contact system.In this review,we discuss the pathophysiological changes occurring in these systems during sepsis,and describe the possible targets of the serine protease inhibitor nafamostat mesilate in the treatment of this condition.展开更多
Neutrophil extracellular traps(NETs),extrusions of intracellular DNA with attached granular material that exert an antibacterial effect through entangling,isolating,and immobilizing microorganisms,have been extensivel...Neutrophil extracellular traps(NETs),extrusions of intracellular DNA with attached granular material that exert an antibacterial effect through entangling,isolating,and immobilizing microorganisms,have been extensively studied in recent decades.The primary role of NETs is to entrap and facilitate the killing of bacteria,fungi,viruses,and parasites,preventing bacterial and fungal dissemination.NET formation has been described in many pulmonary diseases,including both infectious and non-infectious.NETs are considered a double-edged sword.As innate immune cells,neutrophils release NETs to kill pathogens and remove cellular debris.However,the dele-terious effects of excessive NET release in lung disease are particularly important because NETs and by-products of NETosis can directly induce epithelial and endothelial cell death while simultaneously inducing inflammatory cytokine secretion and immune-mediated thrombosis.Thus,NET formation must be tightly regulated to preserve the anti-microbial capability of NETs while minimizing damage to the host.In this review,we summarized the recent updates on the mechanism of NETs formation and pathophysiology associated with excessive NETs,aiming to provide insights for research and treatment of pulmonary infectious diseases.展开更多
Advancements in high-throughput sequencing(HTS)of antibody repertoires(Ig-Seq)have unprecedentedly improved our ability to characterize the antibody repertoires on a large scale.However,currently,only a few studies ex...Advancements in high-throughput sequencing(HTS)of antibody repertoires(Ig-Seq)have unprecedentedly improved our ability to characterize the antibody repertoires on a large scale.However,currently,only a few studies explored the influence of chronic HIV-1 infection on human antibody repertoires and many of them reached contradictory conclusions,possibly limited by inadequate sequencing depth and throughput.To better understand how HIV-1 infection would impact humoral immune system,in this study,we systematically analyzed the differences between the IgM(HIV-IgM)and IgG(HIV-IgG)heavy chain repertoires of HIV-1 infected patients,as well as between antibody repertoires of HIV-1 patients and healthy donors(HH).Notably,the public unique clones accounted for only a negligible proportion between the HIV-IgM and HIV-IgG repertoires libraries,and the diversity of unique clones in HIV-IgG remarkably reduced.In aspect of somatic mutation rates of CDR1 and CDR2,the HIV-IgG repertoire was higher than HIV-IgM.Besides,the average length of CDR3 region in HIV-IgM was significant longer than that in the HH repertoire,presumably caused by the great number of novel VDJ rearrangement patterns,especially a massive use of IGHJ6.Moreover,some of the B cell clonotypes had numerous clones,and somatic variants were detected within the clonotype lineage in HIV-IgG,indicating HIV-1 neutralizing activities.The in-depth characterization of HIV-IgG and HIV-IgM repertoires enriches our knowledge in the profound effect of HIV-1 infection on human antibody repertoires and may have practical value for the discovery of therapeutic antibodies.展开更多
The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years.The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines an...The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years.The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants.Here we show that the bivalency of an affinity maturated fully human singledomain antibody(n3113.1-Fc)exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus,and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2(ACE2)humanized mice.The crystal structure of n3113 in complex with the receptor-binding domain(RBD)of SARS-CoV-2,combined with the cryo-EM structures of n3113 and spike ecto-domain,reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2.The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion,expanding our recognition of neutralization by antibodies against SARS-CoV-2.Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages,including Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),and Delta(B.1.617.2)for n3113.1-Fc with Y58L mutation,demonstrating the potential of n3113.1-Fc(Y58L)as a promising candidate for clinical development to treat COVID-19.展开更多
By the end of July 2022,the SARS-CoV-2 pandemic had caused more than 6 million deaths worldwide.This viral infection results in a series of atypical respiratory diseases termed COVID-19,from asymptomatic infection to ...By the end of July 2022,the SARS-CoV-2 pandemic had caused more than 6 million deaths worldwide.This viral infection results in a series of atypical respiratory diseases termed COVID-19,from asymptomatic infection to severe symptoms such as acute respiratory distress syndrome and pulmonary fibrosis.Development of vaccines and therapeutic measures that mitigate the sufferings caused by the pandemic has been achieved in a short period of time.Only 1 year after the emergence of the pandemic,COVID-19 vaccines have been approved in several countries.展开更多
Erythroleukemia belongs to acute myeloid leukemia(AML)type 6(M6),and treatment remains difficult due to the poor prognosis of the disease.Friend virus(FV)is a complex of two viruses:Friend murine leukemia virus(F-MuLV...Erythroleukemia belongs to acute myeloid leukemia(AML)type 6(M6),and treatment remains difficult due to the poor prognosis of the disease.Friend virus(FV)is a complex of two viruses:Friend murine leukemia virus(F-MuLV)strain along with a defective spleen focus-forming virus(SFFV),which can induce acute eryth-roleukemia in mice.We have previously reported that activation of vagalα7 nicotinic acetylcholine receptor(nAChR)signaling promotes HIV-1 transcription.Whether vagal muscarinic signaling mediates FV-induced erythroleukemia and the underlying mechanisms remain unclear.In this study,sham and vagotomized mice were intraperitoneally injected with FV.FV infection caused anemia in sham mice,and vagotomy reversed this change.FV infection increased erythroblasts ProE,EryA,and EryB cells in the spleen,and these changes were blocked by vagotomy.In bone marrow,FV infection reduced EryC cells in sham mice,an effect that was coun-teracted by vagotomy.FV infection increased choline acetyltransferase(ChAT)expression in splenic CD4^(+)and CD8þT cells,and this change was reversed by vagotomy.Furthermore,the increase of EryA and EryB cells in spleen of FV-infected wild-type mice was reversed after deletion of ChAT in CD4^(+)T cells.In bone marrow,FV infection reduced EryB and EryC cells in sham mice,whereas lack of ChAT in CD4^(+)T cells did not affect this change.Activation of muscarinic acetylcholine receptor 4(mAChR4)by clozapine N-oxide(CNO)significantly increased EryB in the spleen but decreased the EryC cell population in the bone marrow of FV-infected mice.Thus,vagal-mAChR4 signaling in the spleen and bone marrow synergistically promotes the pathogenesis of acute erythroleukemia.We uncover an unrecognized mechanism of neuromodulation in erythroleukemia.展开更多
Dear Editor,Identifying the host factors that are utilized for virus infection and mapping their cell-type expression profile can help to understand the viral tissue/organ tropism and pathogenesis.Much effort has been...Dear Editor,Identifying the host factors that are utilized for virus infection and mapping their cell-type expression profile can help to understand the viral tissue/organ tropism and pathogenesis.Much effort has been devoted to the identification of SARS-CoV-2 infection-dependent host factors.CRISPR-based activation(Konermann et al.,2015).展开更多
基金supported by the National Natural Science Foundation of China(Nos.82130001,82200089,8173000,81800077,and 82070045)Shanghai Sailing Program(No.22YF1406100)+3 种基金the National Key R&D Plan(No.2020YFC2003700)the Science and Technology Commission of Shanghai Municipality(Nos.20Z11901000,20DZ2261200,and 20XD1401200)Shanghai Municipal Science and Technology Major Project,Clinical Research Plan of SHDC(No.SHDC2020CR5010-002)Shanghai Municipal Key Clinical Specialty(No.shslczdzk02201).
文摘Acute lung injury/acute respiratory distress syndrome(ALI/ARDS)is characterized by diffuse alveolar injury primarily caused by an excessive inflammatory response.Regrettably,the lack of effective pharmacotherapy currently available contributes to the high mortality rate in patients with this condition.Xuebijing(XBJ),a traditional Chinese medicine recognized for its potent anti-inflammatory properties,exhibits promise as a potential therapeutic agent for ALI/ARDS.This study aimed to explore the preventive effects of XBJ on ALI and its underlying mechanism.To this end,we established an LPS-induced ALI model and treated ALI mice with XBJ.Our results demonstrated that pre-treatment with XBJ significantly alleviated lung inflammation and increased the survival rate of ALI mice by 37.5%.Moreover,XBJ substantially suppressed the production of TNF-α,IL-6,and IL-1βin the lung tissue.Subsequently,we performed a network pharmacology analysis and identified identified 109 potential target genes of XBJ that were mainly involved in multiple signaling pathways related to programmed cell death and anti-inflammatory responses.Furthermore,we found that XBJ exerted its inhibitory effect on gasdermin-E-mediated pyroptosis of lung cells by suppressing TNF-αproduction.Therefore,this study not only establishes the preventive efficacy of XBJ in ALI but also reveals its role in protecting alveolar epithelial cells against gasdermin-E-mediated pyroptosis by reducing TNF-αrelease.
文摘Acute lung injury(ALI)and acute respiratory distress syndrome(ARDS),which are characterized by excessive inflammation and accompanied by diffuse injury of alveoli,can result in severe respiratory failures.The morbidity and mortality of patients remain high because the major treatments for ALI/ARDS are mainly supportive due to the lack of effective therapies.Numerous studies have demonstrated that the aggravation of coronavirus disease 2019(COVID-19)leads to severe pneumonia and even ARDS.Pyroptosis,a biological process identified as a type of programed cell death,is mainly triggered by inflammatory caspase activation and is directly meditated by the gasdermin protein family,as well as being associated with the secretion and release of pro-inflammatory cytokines.Clinical and experimental evidence corroborates that pyroptosis of various cells in the lung,such as immune cells and structural cells,may play an important role in the pathogenesis of“cytokine storms”in ALI/ARDS,including those induced by COVID-19.Here,with a focus on ALI/ARDS and COVID-19,we summarized the recent advances in this field and proposed the theory of an inflammatory cascade in pyroptosis to identify new targets and pave the way for new approaches to treat these diseases.
基金supported by the National Natural Science Foundation of China(grant numbers 82102287)Key dis-cipline of Shanghai’s Three-year Action Plan to Strengthen the construction of public health system(2023-2025)(grant num-bers GWVI-11.1-14).
文摘Sepsis is a life-threatening syndrome resulting from a dysregulated host response to infection.It is the primary cause of death in the intensive care unit,posing a substantial challenge to human health and medical resource allocation.The pathogenesis and pathophysiology of sepsis are complex.During its onset,pro-inflammatory and anti-inflammatory mechanisms engage in intricate interactions,possibly leading to hyperinflammation,immuno-suppression,and long-term immune disease.Of all critical outcomes,hyperinflammation is the main cause of early death among patients with sepsis.Therefore,early suppression of hyperinflammation may improve the progno-sis of these patients.Nafamostat mesilate is a serine protease inhibitor,which can inhibit the activation of the complement system,coagulation system,and contact system.In this review,we discuss the pathophysiological changes occurring in these systems during sepsis,and describe the possible targets of the serine protease inhibitor nafamostat mesilate in the treatment of this condition.
基金supported by the National Natural Science Foundation of China(Nos.82130001,82070045)the National key Research&Development plan(No.2020YFC2003700).
文摘Neutrophil extracellular traps(NETs),extrusions of intracellular DNA with attached granular material that exert an antibacterial effect through entangling,isolating,and immobilizing microorganisms,have been extensively studied in recent decades.The primary role of NETs is to entrap and facilitate the killing of bacteria,fungi,viruses,and parasites,preventing bacterial and fungal dissemination.NET formation has been described in many pulmonary diseases,including both infectious and non-infectious.NETs are considered a double-edged sword.As innate immune cells,neutrophils release NETs to kill pathogens and remove cellular debris.However,the dele-terious effects of excessive NET release in lung disease are particularly important because NETs and by-products of NETosis can directly induce epithelial and endothelial cell death while simultaneously inducing inflammatory cytokine secretion and immune-mediated thrombosis.Thus,NET formation must be tightly regulated to preserve the anti-microbial capability of NETs while minimizing damage to the host.In this review,we summarized the recent updates on the mechanism of NETs formation and pathophysiology associated with excessive NETs,aiming to provide insights for research and treatment of pulmonary infectious diseases.
基金supported by grants from the National Key R&D Program of China(2019YFA0904400)National Natural Science Foundation of China(81822027,81630090,81902108)Science and Technology Commission of Shanghai Municipality(20DZ2254600,20DZ2261200)。
文摘Advancements in high-throughput sequencing(HTS)of antibody repertoires(Ig-Seq)have unprecedentedly improved our ability to characterize the antibody repertoires on a large scale.However,currently,only a few studies explored the influence of chronic HIV-1 infection on human antibody repertoires and many of them reached contradictory conclusions,possibly limited by inadequate sequencing depth and throughput.To better understand how HIV-1 infection would impact humoral immune system,in this study,we systematically analyzed the differences between the IgM(HIV-IgM)and IgG(HIV-IgG)heavy chain repertoires of HIV-1 infected patients,as well as between antibody repertoires of HIV-1 patients and healthy donors(HH).Notably,the public unique clones accounted for only a negligible proportion between the HIV-IgM and HIV-IgG repertoires libraries,and the diversity of unique clones in HIV-IgG remarkably reduced.In aspect of somatic mutation rates of CDR1 and CDR2,the HIV-IgG repertoire was higher than HIV-IgM.Besides,the average length of CDR3 region in HIV-IgM was significant longer than that in the HH repertoire,presumably caused by the great number of novel VDJ rearrangement patterns,especially a massive use of IGHJ6.Moreover,some of the B cell clonotypes had numerous clones,and somatic variants were detected within the clonotype lineage in HIV-IgG,indicating HIV-1 neutralizing activities.The in-depth characterization of HIV-IgG and HIV-IgM repertoires enriches our knowledge in the profound effect of HIV-1 infection on human antibody repertoires and may have practical value for the discovery of therapeutic antibodies.
基金This work was supported by grants from the National Key R&D Program of China(2019YFA0904400)National Natural Science Foundation of China(32070938,82041003,81822027,81630090,81902108)+2 种基金Chinese Academy of Medical Sciences(2019PT350002)Shanghai Municipal Health Commission(GWV-10.2-YQ06,GWV-10.2-XD01)Science and Technology Commission of Shanghai Municipality(20411950402,20XD1401200,18DZ2210200,20DZ2254600,20DZ2261200).
文摘The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years.The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants.Here we show that the bivalency of an affinity maturated fully human singledomain antibody(n3113.1-Fc)exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus,and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2(ACE2)humanized mice.The crystal structure of n3113 in complex with the receptor-binding domain(RBD)of SARS-CoV-2,combined with the cryo-EM structures of n3113 and spike ecto-domain,reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2.The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion,expanding our recognition of neutralization by antibodies against SARS-CoV-2.Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages,including Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),and Delta(B.1.617.2)for n3113.1-Fc with Y58L mutation,demonstrating the potential of n3113.1-Fc(Y58L)as a promising candidate for clinical development to treat COVID-19.
基金supported by grants from National Natural Science Foundation of China(32070938 an 32270984)Science and Technology Commission of ShanghaiMunicipality(20DZ2254600 and 20DZ2261200).
文摘By the end of July 2022,the SARS-CoV-2 pandemic had caused more than 6 million deaths worldwide.This viral infection results in a series of atypical respiratory diseases termed COVID-19,from asymptomatic infection to severe symptoms such as acute respiratory distress syndrome and pulmonary fibrosis.Development of vaccines and therapeutic measures that mitigate the sufferings caused by the pandemic has been achieved in a short period of time.Only 1 year after the emergence of the pandemic,COVID-19 vaccines have been approved in several countries.
基金from National Natural Science Foundation of China(82241042,81970075,81730001,91942305)National Key Research and Development Program of China(2022YFC2304700)+1 种基金Science and Technology Commission of Shanghai Municipality(20DZ2261200)Innovative research team of high-level local universities in Shanghai(SHSMU-ZDCX20210602).
文摘Erythroleukemia belongs to acute myeloid leukemia(AML)type 6(M6),and treatment remains difficult due to the poor prognosis of the disease.Friend virus(FV)is a complex of two viruses:Friend murine leukemia virus(F-MuLV)strain along with a defective spleen focus-forming virus(SFFV),which can induce acute eryth-roleukemia in mice.We have previously reported that activation of vagalα7 nicotinic acetylcholine receptor(nAChR)signaling promotes HIV-1 transcription.Whether vagal muscarinic signaling mediates FV-induced erythroleukemia and the underlying mechanisms remain unclear.In this study,sham and vagotomized mice were intraperitoneally injected with FV.FV infection caused anemia in sham mice,and vagotomy reversed this change.FV infection increased erythroblasts ProE,EryA,and EryB cells in the spleen,and these changes were blocked by vagotomy.In bone marrow,FV infection reduced EryC cells in sham mice,an effect that was coun-teracted by vagotomy.FV infection increased choline acetyltransferase(ChAT)expression in splenic CD4^(+)and CD8þT cells,and this change was reversed by vagotomy.Furthermore,the increase of EryA and EryB cells in spleen of FV-infected wild-type mice was reversed after deletion of ChAT in CD4^(+)T cells.In bone marrow,FV infection reduced EryB and EryC cells in sham mice,whereas lack of ChAT in CD4^(+)T cells did not affect this change.Activation of muscarinic acetylcholine receptor 4(mAChR4)by clozapine N-oxide(CNO)significantly increased EryB in the spleen but decreased the EryC cell population in the bone marrow of FV-infected mice.Thus,vagal-mAChR4 signaling in the spleen and bone marrow synergistically promotes the pathogenesis of acute erythroleukemia.We uncover an unrecognized mechanism of neuromodulation in erythroleukemia.
文摘Dear Editor,Identifying the host factors that are utilized for virus infection and mapping their cell-type expression profile can help to understand the viral tissue/organ tropism and pathogenesis.Much effort has been devoted to the identification of SARS-CoV-2 infection-dependent host factors.CRISPR-based activation(Konermann et al.,2015).
