The recently emerged severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is the causative agent of ongoing global pan demic of COVID-19,may trigger imm uno suppression in the early stage and overactive i...The recently emerged severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is the causative agent of ongoing global pan demic of COVID-19,may trigger imm uno suppression in the early stage and overactive immune resp onse in the late stage of infection;However,the un derlying mecha nisms are not well understood.Here we dem on strated that the SARS-CoV-2 nucleocapsid(N)protein dually regulated innate immune responses,i.e.,the low-dose N protein suppressed type I interferon(IFN-I)signaling and inflammatory cytokines,whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines.Mechanistically,the SARS-CoV-2 N protein dually regulated the phosphorylation and nuclear translocation of IRF3,STAT1,and STAT2.Additi on ally,low-dose N protein combined with TRIM25 could suppress the ubiquitination and activatio n of retinoic acidinducible gene I(RIG-I).Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein,which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses,and development of more effective strategies for controlling COVID-19.展开更多
β-Lapachone (β-Lap) is a promising orthonaphthoquinone drug for cancer treatment and has been inclinical trials. Its application is constrained by the low aqueoussolubility, and severe side effects. Even prodrug des...β-Lapachone (β-Lap) is a promising orthonaphthoquinone drug for cancer treatment and has been inclinical trials. Its application is constrained by the low aqueoussolubility, and severe side effects. Even prodrug designation isan effective approach to render it with tumor selectivity, it islimited by the lack of modifiable groups on β-Lap. Herein, anovel azo bond primary cleavage and carbon–carbon (C–C)bond secondary cleavage-based polymeric β-Lap prodrug(Azo-Lap NP) is designed, in which the self-immolated paraaminobenzyl linker is connected to poly(L-glutamic acid)(PGlu) via azo linkage and the responsive drug release of β-Lapagainst tumors can be achieved under high NAD(P)H:quinoneoxidoreductase 1 (NQO1) expression and low pH environmentin tumors. The effective covalent loading of β-Lap by Azo-LapNPs permitted a high administration dose of β-Lap and enabled significant tumor retention time. Moreover, Azo-LapNPs markedly reduced the side effects of β-Lap by avoidinghemolysis and the production of methemoglobin. The safety ofAzo-Lap NPs administration is validated in the antitumorexperiment of mice. In the 4T1 model, Azo-Lap NPs exhibiteda markedly higher tumor suppression rate than β-Lap. Thiswork provides an effective and safe polymeric prodrug fortumor selective delivery of β-Lap.展开更多
基金supported by grant from National Natural Science Foundation of China(81972873,81871699,82072330)the Pearl River Talent Plan in Guangdong Province of China(2019CX01N111)+2 种基金the Science and Technology Innovation Project in Foshan and Guangzhou,Guangdong Province,China(2020001000151,202103000008)the Foundation of Jilin Province Science and Technology Department(172408GHO10234983 and 20200301001RQ)the 68th batch of first-class funding from China Postdoctoral Science Foundation(2020M680044).
文摘The recently emerged severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is the causative agent of ongoing global pan demic of COVID-19,may trigger imm uno suppression in the early stage and overactive immune resp onse in the late stage of infection;However,the un derlying mecha nisms are not well understood.Here we dem on strated that the SARS-CoV-2 nucleocapsid(N)protein dually regulated innate immune responses,i.e.,the low-dose N protein suppressed type I interferon(IFN-I)signaling and inflammatory cytokines,whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines.Mechanistically,the SARS-CoV-2 N protein dually regulated the phosphorylation and nuclear translocation of IRF3,STAT1,and STAT2.Additi on ally,low-dose N protein combined with TRIM25 could suppress the ubiquitination and activatio n of retinoic acidinducible gene I(RIG-I).Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein,which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses,and development of more effective strategies for controlling COVID-19.
基金financially supported by the Ministry of Science and Technology of the People’s Republic of China (2022YFE0110200)the National Natural Science Foundation of China (52025035, 52273157, and 52073279)+1 种基金the Department of Science and Technology of Jilin Province (20240305041YY and 20230508102RC)the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2022224)。
文摘β-Lapachone (β-Lap) is a promising orthonaphthoquinone drug for cancer treatment and has been inclinical trials. Its application is constrained by the low aqueoussolubility, and severe side effects. Even prodrug designation isan effective approach to render it with tumor selectivity, it islimited by the lack of modifiable groups on β-Lap. Herein, anovel azo bond primary cleavage and carbon–carbon (C–C)bond secondary cleavage-based polymeric β-Lap prodrug(Azo-Lap NP) is designed, in which the self-immolated paraaminobenzyl linker is connected to poly(L-glutamic acid)(PGlu) via azo linkage and the responsive drug release of β-Lapagainst tumors can be achieved under high NAD(P)H:quinoneoxidoreductase 1 (NQO1) expression and low pH environmentin tumors. The effective covalent loading of β-Lap by Azo-LapNPs permitted a high administration dose of β-Lap and enabled significant tumor retention time. Moreover, Azo-LapNPs markedly reduced the side effects of β-Lap by avoidinghemolysis and the production of methemoglobin. The safety ofAzo-Lap NPs administration is validated in the antitumorexperiment of mice. In the 4T1 model, Azo-Lap NPs exhibiteda markedly higher tumor suppression rate than β-Lap. Thiswork provides an effective and safe polymeric prodrug fortumor selective delivery of β-Lap.
