Commensal microbiota is closely related to Hepatitis B virus(HBV)infection.Gut bacteria maturation accelerates HBV immune clearance in hydrodynamic injection(HDI)HBV mouse model.However,the effect of gut bacteria on H...Commensal microbiota is closely related to Hepatitis B virus(HBV)infection.Gut bacteria maturation accelerates HBV immune clearance in hydrodynamic injection(HDI)HBV mouse model.However,the effect of gut bacteria on HBV replication in recombinant adeno-associated virus(AAV)-HBV mouse model with immune tolerance remains obscure.We aim to investigate its role on HBV replication in AAV-HBV mouse model.C57BL/6 mice were administrated with broad-spectrum antibiotic mixtures(ABX)to deplete gut bacteria and intravenously injected with AAV-HBV to establish persistent HBV replication.Gut microbiota community was analyzed by fecal qPCR assay and 16S ribosomal RNA(rRNA)gene sequencing.HBV replication markers in blood and liver were determined by ELISA,qPCR assay and Western blot at indicated time points.Immune response in AAV-HBV mouse model was activated through HDI of HBV plasmid or poly(I:C)and then detected by quantifying the percentage of IFN-γ^(+)/CD8^(+)T cells in the spleen via flow cytometry as well as the splenic IFN-γmRNA level via qPCR assay.We found that antibiotic exposure remarkably decreased gut bacteria abundance and diversity.Antibiotic treatment failed to alter the levels of serological HBV antigens,intrahepatic HBV RNA transcripts and HBc protein in AAV-HBV mouse model,but contributed to HBsAg increase after breaking of immune tolerance.Overall,our data uncovered that antibiotic-induced gut bacteria depletion has no effect on HBV replication in immune tolerant AAV-HBV mouse model,providing new thoughts for elucidating the correlation between gut bacteria dysbiosis by antibiotic abuse and clinical chronic HBV infection.展开更多
Synthetic lethality is a proven effective antitumor strategy that has attracted great attention.Large-scale screening has revealed many synthetic lethal genetic phenotypes,and relevant smallmolecule drugs have also be...Synthetic lethality is a proven effective antitumor strategy that has attracted great attention.Large-scale screening has revealed many synthetic lethal genetic phenotypes,and relevant smallmolecule drugs have also been implemented in clinical practice.Increasing evidence suggests that CDKs,constituting a kinase family predominantly involved in cell cycle control,are synthetic lethal factors when combined with certain oncogenes,such as MFC,TP53,and RAS,which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality.In this review,we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.展开更多
HepatitisBvirus(HBV)infection causes acuteand chronic liver diseases,but is not directly cytopathic.Liver injury results fromrepeated attempts of the cellular immune response system to control the viral infection.Here...HepatitisBvirus(HBV)infection causes acuteand chronic liver diseases,but is not directly cytopathic.Liver injury results fromrepeated attempts of the cellular immune response system to control the viral infection.Here,we investigate the roles of cellular factors and signaling pathways involved in the regulation of HBV replication to reveal the mechanism underlying HBV infection and pathogenesis.Weshowthat collagen triple helix repeat containing 1(CTHRC1)expression is elevated in HBV-infected patients andin HBV-transfected cells through epigenetic modification and transcriptional regulation.CTHRC1 facilitates HBV replication in cultured cells and BALB/c mice by activating the PKCa/ERK/JNK/c-Jun cascade to repress the IFN/JAK/STAT pathway.HBV-activated CTHRC1 downregulates the activityof typeI interferon(IFN),theproductionof IFN-stimulatedgenes(ISGs),andthephosphorylationofsignal transducerandactivator of transcription 1/2(STAT1/2),whereas it upregulates the phosphorylation and ubiquitination of type I IFN receptors(IFNARa/b).Thus,our results showthat HBV uses a novelmechanismto hijack cellular factors and signal cascades in order to evade host antiviral immunity and maintain persistent infection.We also demonstrate that CTHRC1 has a novel role in viral infection.展开更多
Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)is a major pathological feature of Coronavirus Disease 2019(COVID-19)and a crucial determinant in COVID-19 prognosis.Understanding t...Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)is a major pathological feature of Coronavirus Disease 2019(COVID-19)and a crucial determinant in COVID-19 prognosis.Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control.Here,we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1α(HIF-1α)play key roles in the virus infection and pro-inflammatory responses.展开更多
基金the National Natural Science Foundation of China(project no.81971936)Hubei Province's Outstanding Medical Academic Leader Program,Foundation for Innovative Research Groups of the Natural Science Foundation of Hubei(project no.2020CFA015)the Funda-mental Research Funds for the Central Universities(project no.2042022kf1215 and 2042021gf0013)and Basic and Clinical Medical Research Joint Fund of Zhongnan Hospital,Wuhan University.
文摘Commensal microbiota is closely related to Hepatitis B virus(HBV)infection.Gut bacteria maturation accelerates HBV immune clearance in hydrodynamic injection(HDI)HBV mouse model.However,the effect of gut bacteria on HBV replication in recombinant adeno-associated virus(AAV)-HBV mouse model with immune tolerance remains obscure.We aim to investigate its role on HBV replication in AAV-HBV mouse model.C57BL/6 mice were administrated with broad-spectrum antibiotic mixtures(ABX)to deplete gut bacteria and intravenously injected with AAV-HBV to establish persistent HBV replication.Gut microbiota community was analyzed by fecal qPCR assay and 16S ribosomal RNA(rRNA)gene sequencing.HBV replication markers in blood and liver were determined by ELISA,qPCR assay and Western blot at indicated time points.Immune response in AAV-HBV mouse model was activated through HDI of HBV plasmid or poly(I:C)and then detected by quantifying the percentage of IFN-γ^(+)/CD8^(+)T cells in the spleen via flow cytometry as well as the splenic IFN-γmRNA level via qPCR assay.We found that antibiotic exposure remarkably decreased gut bacteria abundance and diversity.Antibiotic treatment failed to alter the levels of serological HBV antigens,intrahepatic HBV RNA transcripts and HBc protein in AAV-HBV mouse model,but contributed to HBsAg increase after breaking of immune tolerance.Overall,our data uncovered that antibiotic-induced gut bacteria depletion has no effect on HBV replication in immune tolerant AAV-HBV mouse model,providing new thoughts for elucidating the correlation between gut bacteria dysbiosis by antibiotic abuse and clinical chronic HBV infection.
基金supported by grants from the National Natural Science Foundation of China(No.81872885 to Ji Cao)the Zhejiang Provincial Natural Science Foundation of China(No.LY15H160009 to Wen Meng)
文摘Synthetic lethality is a proven effective antitumor strategy that has attracted great attention.Large-scale screening has revealed many synthetic lethal genetic phenotypes,and relevant smallmolecule drugs have also been implemented in clinical practice.Increasing evidence suggests that CDKs,constituting a kinase family predominantly involved in cell cycle control,are synthetic lethal factors when combined with certain oncogenes,such as MFC,TP53,and RAS,which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality.In this review,we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.
基金supported by research grants from theMajor State Basic ResearchDevelopment Program(973 Program)(grant number 2012CB518900)the National Natural Science Foundation of China(grant numbers 31230005,31270206,31200134,and 81171525)+1 种基金the National Mega Project on Major Infectious Disease Prevention(grant numbers 2012ZX10002006-003 and 2012ZX10004-207)the Chinese Foundation for Hepatitis Prevention and Control(grant number CFHPC20132153).
文摘HepatitisBvirus(HBV)infection causes acuteand chronic liver diseases,but is not directly cytopathic.Liver injury results fromrepeated attempts of the cellular immune response system to control the viral infection.Here,we investigate the roles of cellular factors and signaling pathways involved in the regulation of HBV replication to reveal the mechanism underlying HBV infection and pathogenesis.Weshowthat collagen triple helix repeat containing 1(CTHRC1)expression is elevated in HBV-infected patients andin HBV-transfected cells through epigenetic modification and transcriptional regulation.CTHRC1 facilitates HBV replication in cultured cells and BALB/c mice by activating the PKCa/ERK/JNK/c-Jun cascade to repress the IFN/JAK/STAT pathway.HBV-activated CTHRC1 downregulates the activityof typeI interferon(IFN),theproductionof IFN-stimulatedgenes(ISGs),andthephosphorylationofsignal transducerandactivator of transcription 1/2(STAT1/2),whereas it upregulates the phosphorylation and ubiquitination of type I IFN receptors(IFNARa/b).Thus,our results showthat HBV uses a novelmechanismto hijack cellular factors and signal cascades in order to evade host antiviral immunity and maintain persistent infection.We also demonstrate that CTHRC1 has a novel role in viral infection.
基金This work was supported by the National Natural Science Foundation of China(81730061,81471942,and 32070148)Guangdong Province"Pearl River Talent Plan"Innovation and Entrepreneurship Team Project(2017ZT07Y580).
文摘Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)is a major pathological feature of Coronavirus Disease 2019(COVID-19)and a crucial determinant in COVID-19 prognosis.Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control.Here,we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1α(HIF-1α)play key roles in the virus infection and pro-inflammatory responses.