Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response...Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response,and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFNstimulated genes(ISGs)through the Janus kinase-signal transducer and activator of transcription 1(JAK-STAT)pathway.However,the tremendous amount of IFNs produced during late infection could not restrain HTNV replication,and the mechanism remains unclear.Here,we demonstrated that receptor-interacting protein kinase 3(RIPK3),a crucial molecule that mediates necroptosis,was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation.RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection,with RIPK3 identified as a key modulator of viral replication.RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication,without affecting the expression of pattern recognition receptors(PRRs)or the production of type I IFNs.Conversely,exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication.RIPK3^(-/-)mice also maintained a robust ability to clear HTNV with enhanced innate immune responses.Mechanistically,we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain(PKD)of RIPK3 but not its kinase activity.Overall,these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.展开更多
Hantaan virus(HTNV),the prototype virus of hantavirus,could escape innate immunity by restraining type I interferon(IFN)responses.It is largely unknown whether there existed other efficient anti-hantaviral tactics in ...Hantaan virus(HTNV),the prototype virus of hantavirus,could escape innate immunity by restraining type I interferon(IFN)responses.It is largely unknown whether there existed other efficient anti-hantaviral tactics in host cells.Here,we demonstrate that the stimulator of interferon genes(STING)strengthens the host IFNindependent anti-hantaviral immunity.HTNV infection activates RIG-I through IRE1-XBP 1-mediated ER stress,which further facilitates the subcellular translocation and activation of STING.During this process,STING triggers cellular autophagy by interacting with Rab7A,thus restricting viral replication.To note,the anti-hantaviral effects of STING are independent of canonical IFN signaling.Additionally,neither application of the pharmacological antagonist nor the agonist targeting STING could improve the outcomes of nude mice post HTNV challenge in vivo.However,the administration of plasmids exogenously expressing the mutant C-terminal tail(ΔCTT)STING,which would not trigger the type I IFN responses,protected the nude mice from lethal HTNV infection.In summary,our research revealed a novel antiviral pathway through the RIG-I-STING-autophagy pathway,which offered novel therapeutic strategies against hantavirus infection.展开更多
Thrombolytic therapy has been the mainstay for patients with pulmonary embolism(PE).Despite being linked to a higher risk of significant bleeding,clinical trials demonstrate that thrombolytic therapy should be used in...Thrombolytic therapy has been the mainstay for patients with pulmonary embolism(PE).Despite being linked to a higher risk of significant bleeding,clinical trials demonstrate that thrombolytic therapy should be used in patients with moderate to high-risk PE,in addition to hemodynamic instability symptoms.This prevents the progression of right heart failure and impending hemodynamic collapse.Diagnosing PE can be challenging due to the variety of presentations;therefore,guidelines and scoring systems have been established to guide physicians to correctly identify and manage the condition.Traditionally,systemic thrombolysis has been utilized to lyse the emboli in PE.However,newer techniques for thrombolysis have been developed,such as endovascular ultrasound-assisted catheter-directed thrombolysis for massive and intermediatehigh submassive risk groups.Additional newer techniques explored are the use of extracorporeal membrane oxygenation,direct aspiration,or fragmentation with aspiration.Because of the constantly changing therapeutic options and the scarcity of randomized controlled trials,choosing the best course of treatment for a given patient may be difficult.To help,the Pulmonary Embolism Reaction Team is a multidisciplinary,rapid response team that has been developed and is used at many institutions.Hence to bridge the knowledge gap,our review highlights various indications of thrombolysis in addition to the recent advances and management guidelines.展开更多
Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin(DOX)-loaded silk fibroinbased nanoparticles(NPs) with...Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin(DOX)-loaded silk fibroinbased nanoparticles(NPs) with surface functionalization by photosensitizer(N770). The obtained nanotheranostics(N770-DOX@NPs) had desirable particle size(157 nm) and negative surface charge(-25 m V). These NPs presented excellent oxygen-generating capacity and responded to a quadruple of stimuli(acidic solution, reactive oxygen species, glutathione, and hyperthermia). Surface functionalization of DOX@NPs with N770 could endow them with active internalization by cancerous cell lines, but not by normal cells. Furthermore, the intracellular NPs were found to be preferentially retained in mitochondria, which were also efficient for near-infrared(NIR) fluorescence imaging, photothermal imaging,and photoacoustic imaging. Meanwhile, DOX could spontaneously accumulate in the nucleus. Importantly, a mouse test group treated with N770-DOX@NPs plus NIR irradiation achieved the best tumorretardation effect among all treatment groups based on tumor-bearing mouse models and a patientderived xenograft model, demonstrating the unprecedented therapeutic effects of trimodal imagingguided mitochondrial phototherapy(photothermal therapy and photodynamic therapy) and chemotherapy.Therefore, the present study brings new insight into the exploitation of an easy-to-use, versatile, and robust nanoplatform for programmable targeting, imaging, and applying synergistic therapy to tumors.展开更多
Relatively little is known about the effects of estrogen on postischemic cerebral vasomotor dynamics after ischemic injury. Emerging hypotheses suggest that the timing after menopause at which hormone replacement is i...Relatively little is known about the effects of estrogen on postischemic cerebral vasomotor dynamics after ischemic injury. Emerging hypotheses suggest that the timing after menopause at which hormone replacement is initiated might be important and might modulate the potential benefits of estrogen on brain rescue once a cerebral ischemic event occurs. Therefore, we sought to determine if protracted hypoestrogenicity modifies estrogen’s protective effects on postischemic pial artery dilatory dysfunction and if the arachidonic acid metabolite 20-hydroxyeicosatetraeonic (20-HETE) contributes to the dysfunction. Pial artery dilation to acetylcholine was examined before and 1 hour after 15 minutes forebrain ischemia. The rat study groups included: sexually mature males (M), naive (N), OVX (OV), estrogen-treated OVX females (E1;estrogen started 1 week post ovariectomy) and delayed estrogen-treated (E10;started 10 weeks post ovariectomy) females. Postischemic responses were assessed before and after superfusion of the 20-HETE synthesis inhibitor N-hydroxy-N’-(4-butyl-2-methylphenyl)-formamidine (HET0016). Postischemic acetylcholine dilation was depressed in M, OV and E10 compared to N and E1 rats. Compared to E1, delayed estrogen replacement worsened acetylcholine-induced dilation. Postischemic microvascular estrogen receptor alpha (ERα) density was similar in the OV, E1 and E10 rats. Postischemic application of HET0016 failed to improve acetylcholine dilation. Continuous infusion of HET0016 during and after ischemia did not reverse postischemic pial vasodilatory dysfunction. Timing of estrogen replacement may be critical for vascular health after cerebral ischemic injury. Postischemic loss of acetylcholine reactivity does not appear to involve mechanisms related to 20-HETE synthesis or microvascular ERα expression.展开更多
基金This work was supported in whole or in part by the National Natural Science Foundation of China(82172272,31970148 and 82222367)the Key Research and Development Program of Shaanxi(2021ZDLSF01-05 and 2021ZDLSF01-02).
文摘Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response,and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFNstimulated genes(ISGs)through the Janus kinase-signal transducer and activator of transcription 1(JAK-STAT)pathway.However,the tremendous amount of IFNs produced during late infection could not restrain HTNV replication,and the mechanism remains unclear.Here,we demonstrated that receptor-interacting protein kinase 3(RIPK3),a crucial molecule that mediates necroptosis,was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation.RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection,with RIPK3 identified as a key modulator of viral replication.RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication,without affecting the expression of pattern recognition receptors(PRRs)or the production of type I IFNs.Conversely,exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication.RIPK3^(-/-)mice also maintained a robust ability to clear HTNV with enhanced innate immune responses.Mechanistically,we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain(PKD)of RIPK3 but not its kinase activity.Overall,these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.
基金supported by grants from the National Natural Science Foundation of China (No.31970148,82172272 and 82202367)the Key Research and Development Program of Shaanxi (2021ZDLSF01-02 and 2021ZDLSF01-05).
文摘Hantaan virus(HTNV),the prototype virus of hantavirus,could escape innate immunity by restraining type I interferon(IFN)responses.It is largely unknown whether there existed other efficient anti-hantaviral tactics in host cells.Here,we demonstrate that the stimulator of interferon genes(STING)strengthens the host IFNindependent anti-hantaviral immunity.HTNV infection activates RIG-I through IRE1-XBP 1-mediated ER stress,which further facilitates the subcellular translocation and activation of STING.During this process,STING triggers cellular autophagy by interacting with Rab7A,thus restricting viral replication.To note,the anti-hantaviral effects of STING are independent of canonical IFN signaling.Additionally,neither application of the pharmacological antagonist nor the agonist targeting STING could improve the outcomes of nude mice post HTNV challenge in vivo.However,the administration of plasmids exogenously expressing the mutant C-terminal tail(ΔCTT)STING,which would not trigger the type I IFN responses,protected the nude mice from lethal HTNV infection.In summary,our research revealed a novel antiviral pathway through the RIG-I-STING-autophagy pathway,which offered novel therapeutic strategies against hantavirus infection.
文摘Thrombolytic therapy has been the mainstay for patients with pulmonary embolism(PE).Despite being linked to a higher risk of significant bleeding,clinical trials demonstrate that thrombolytic therapy should be used in patients with moderate to high-risk PE,in addition to hemodynamic instability symptoms.This prevents the progression of right heart failure and impending hemodynamic collapse.Diagnosing PE can be challenging due to the variety of presentations;therefore,guidelines and scoring systems have been established to guide physicians to correctly identify and manage the condition.Traditionally,systemic thrombolysis has been utilized to lyse the emboli in PE.However,newer techniques for thrombolysis have been developed,such as endovascular ultrasound-assisted catheter-directed thrombolysis for massive and intermediatehigh submassive risk groups.Additional newer techniques explored are the use of extracorporeal membrane oxygenation,direct aspiration,or fragmentation with aspiration.Because of the constantly changing therapeutic options and the scarcity of randomized controlled trials,choosing the best course of treatment for a given patient may be difficult.To help,the Pulmonary Embolism Reaction Team is a multidisciplinary,rapid response team that has been developed and is used at many institutions.Hence to bridge the knowledge gap,our review highlights various indications of thrombolysis in addition to the recent advances and management guidelines.
基金supported by the National Natural Science Foundation of China(82072060,81773685,and 81571807)the Fundamental Research Funds for the Central Universities(XDJK2019TY002,China)+3 种基金the Chengdu Science and Technology Program(2018-CY02-00042-GX,China)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYYC21002,ZYJC18032 and ZY2016101,China)the Natural Scienceof Chongqing(cstc2020jcyj-msxm X0292,China)the Venture&Innovation Support Program for Chongqing Overseas Returnees(cx2018029,China)。
文摘Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin(DOX)-loaded silk fibroinbased nanoparticles(NPs) with surface functionalization by photosensitizer(N770). The obtained nanotheranostics(N770-DOX@NPs) had desirable particle size(157 nm) and negative surface charge(-25 m V). These NPs presented excellent oxygen-generating capacity and responded to a quadruple of stimuli(acidic solution, reactive oxygen species, glutathione, and hyperthermia). Surface functionalization of DOX@NPs with N770 could endow them with active internalization by cancerous cell lines, but not by normal cells. Furthermore, the intracellular NPs were found to be preferentially retained in mitochondria, which were also efficient for near-infrared(NIR) fluorescence imaging, photothermal imaging,and photoacoustic imaging. Meanwhile, DOX could spontaneously accumulate in the nucleus. Importantly, a mouse test group treated with N770-DOX@NPs plus NIR irradiation achieved the best tumorretardation effect among all treatment groups based on tumor-bearing mouse models and a patientderived xenograft model, demonstrating the unprecedented therapeutic effects of trimodal imagingguided mitochondrial phototherapy(photothermal therapy and photodynamic therapy) and chemotherapy.Therefore, the present study brings new insight into the exploitation of an easy-to-use, versatile, and robust nanoplatform for programmable targeting, imaging, and applying synergistic therapy to tumors.
文摘Relatively little is known about the effects of estrogen on postischemic cerebral vasomotor dynamics after ischemic injury. Emerging hypotheses suggest that the timing after menopause at which hormone replacement is initiated might be important and might modulate the potential benefits of estrogen on brain rescue once a cerebral ischemic event occurs. Therefore, we sought to determine if protracted hypoestrogenicity modifies estrogen’s protective effects on postischemic pial artery dilatory dysfunction and if the arachidonic acid metabolite 20-hydroxyeicosatetraeonic (20-HETE) contributes to the dysfunction. Pial artery dilation to acetylcholine was examined before and 1 hour after 15 minutes forebrain ischemia. The rat study groups included: sexually mature males (M), naive (N), OVX (OV), estrogen-treated OVX females (E1;estrogen started 1 week post ovariectomy) and delayed estrogen-treated (E10;started 10 weeks post ovariectomy) females. Postischemic responses were assessed before and after superfusion of the 20-HETE synthesis inhibitor N-hydroxy-N’-(4-butyl-2-methylphenyl)-formamidine (HET0016). Postischemic acetylcholine dilation was depressed in M, OV and E10 compared to N and E1 rats. Compared to E1, delayed estrogen replacement worsened acetylcholine-induced dilation. Postischemic microvascular estrogen receptor alpha (ERα) density was similar in the OV, E1 and E10 rats. Postischemic application of HET0016 failed to improve acetylcholine dilation. Continuous infusion of HET0016 during and after ischemia did not reverse postischemic pial vasodilatory dysfunction. Timing of estrogen replacement may be critical for vascular health after cerebral ischemic injury. Postischemic loss of acetylcholine reactivity does not appear to involve mechanisms related to 20-HETE synthesis or microvascular ERα expression.
