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
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
Coronavirus disease-2019(COVID-19)is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).The infection is spreading globally and poses a huge threat to human health.Besides common respiratory symptom...Coronavirus disease-2019(COVID-19)is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).The infection is spreading globally and poses a huge threat to human health.Besides common respiratory symptoms,some patients with COVID-19 experience gastrointestinal symptoms,such as diarrhea,nausea,vomiting,and loss of appetite.SARS-CoV-2 might infect the gastrointestinal tract through its viral receptor angiotensin-converting enzyme 2(ACE2)and there is increasing evidence of a possible fecal–oral transmission route.In addition,there exist multiple abnormalities in liver enzymes.COVID-19-related liver injury may be due to drug-induced liver injury,systemic inflammatory reaction,and hypoxia–ischemia reperfusion injury.The direct toxic attack of SARS-CoV-2 on the liver is still questionable.This review highlights the manifestations and potential mechanisms of gastrointestinal and hepatic injuries in COVID-19 to raise awareness of digestive system injury in COVID-19.展开更多
Currently,there is no effective drugs for treating clinically COVID-19 except dexamethasone.We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluron...Currently,there is no effective drugs for treating clinically COVID-19 except dexamethasone.We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluronic acid(HA).As the inhibitor of HA synthesis,hymecromone is an approved prescription drug used for treating biliary spasm.Here,we aimed to investigate the relation between HA and COVID-19,and evaluate the therapeutic effects of hymecromone on COVID-19.Firstly,HA was closely relevant to clinical parameters,including lymphocytes(n=158;r=−0.50;P<0.0001),C-reactive protein(n=156;r=0.55;P<0.0001),D-dimer(n=154;r=0.38;P<0.0001),and fibrinogen(n=152;r=0.37;P<0.0001),as well as the mass(n=78;r=0.43;P<0.0001)and volume(n=78;r=0.41;P=0.0002)of ground-glass opacity,the mass(n=78;r=0.48;P<0.0001)and volume(n=78;r=0.47;P<0.0001)of consolidation in patient with low level of hyaluronan(HA<48.43 ng/mL).Furthermore,hyaluronan could directly cause mouse pulmonary lesions.Besides,hymecromone remarkably reduced HA via downregulating HAS2/HAS3 expression.Moreover,89%patients with hymecromone treatment had pulmonary lesion absorption while only 42%patients in control group had pulmonary lesion absorption(P<0.0001).In addition,lymphocytes recovered more quickly in hymecromone-treated patients(n=8)than control group(n=5)(P<0.05).These findings suggest that hymecromone is a promising drug for COVID-19 and deserves our further efforts to determine its effect in a larger cohort.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
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).
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 State’s Key Project of Research and Development Plan in China(2017YFC1310602,2017YFC1310600)the National Natural Science Foundation of China(81701937).
文摘Coronavirus disease-2019(COVID-19)is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).The infection is spreading globally and poses a huge threat to human health.Besides common respiratory symptoms,some patients with COVID-19 experience gastrointestinal symptoms,such as diarrhea,nausea,vomiting,and loss of appetite.SARS-CoV-2 might infect the gastrointestinal tract through its viral receptor angiotensin-converting enzyme 2(ACE2)and there is increasing evidence of a possible fecal–oral transmission route.In addition,there exist multiple abnormalities in liver enzymes.COVID-19-related liver injury may be due to drug-induced liver injury,systemic inflammatory reaction,and hypoxia–ischemia reperfusion injury.The direct toxic attack of SARS-CoV-2 on the liver is still questionable.This review highlights the manifestations and potential mechanisms of gastrointestinal and hepatic injuries in COVID-19 to raise awareness of digestive system injury in COVID-19.
基金the National Key R&D Program of China(2018YFC1005004)Major Special Projects of Basic Research of Shanghai Science and Technology Commission(18JC1411101)+1 种基金National Natural Science Foundation of China(31872814,32000505)Shanghai Science and Technology Innovation Action Plan,Medical Innovation Research Special Project(20Z11900900).
文摘Currently,there is no effective drugs for treating clinically COVID-19 except dexamethasone.We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluronic acid(HA).As the inhibitor of HA synthesis,hymecromone is an approved prescription drug used for treating biliary spasm.Here,we aimed to investigate the relation between HA and COVID-19,and evaluate the therapeutic effects of hymecromone on COVID-19.Firstly,HA was closely relevant to clinical parameters,including lymphocytes(n=158;r=−0.50;P<0.0001),C-reactive protein(n=156;r=0.55;P<0.0001),D-dimer(n=154;r=0.38;P<0.0001),and fibrinogen(n=152;r=0.37;P<0.0001),as well as the mass(n=78;r=0.43;P<0.0001)and volume(n=78;r=0.41;P=0.0002)of ground-glass opacity,the mass(n=78;r=0.48;P<0.0001)and volume(n=78;r=0.47;P<0.0001)of consolidation in patient with low level of hyaluronan(HA<48.43 ng/mL).Furthermore,hyaluronan could directly cause mouse pulmonary lesions.Besides,hymecromone remarkably reduced HA via downregulating HAS2/HAS3 expression.Moreover,89%patients with hymecromone treatment had pulmonary lesion absorption while only 42%patients in control group had pulmonary lesion absorption(P<0.0001).In addition,lymphocytes recovered more quickly in hymecromone-treated patients(n=8)than control group(n=5)(P<0.05).These findings suggest that hymecromone is a promising drug for COVID-19 and deserves our further efforts to determine its effect in a larger cohort.
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.
