Objective:Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression.How neutrophils promote lung cancer progression,however,has not been...Objective:Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression.How neutrophils promote lung cancer progression,however,has not been established.Methods:Kaplan–Meier plotter online analysis and tissue immunohistochemistry were used to determine the relationship between neutrophils and overall survival in lung cancer patients.The effect of neutrophils on lung cancer was determined using the Transwell migration assay,a proliferation assay,and a murine tumor model.Gene knockdown was used to determine poly ADPribose polymerase(PARP)-1 function in lung cancer-educated neutrophils.Western blot analysis and gelatin zymography were used to demonstrate the correlation between PARP-1 and matrix metallopeptidase 9(MMP-9).Immunoprecipitation coupled to mass spectrometry(IP/MS)was used to identify the proteins interacting with PARP-1.Co-immunoprecipitation(Co-IP)was used to confirm that PARP-1 interacts with arachidonate 5-lipooxygenase(ALOX5).Neutrophil PARP-1 blockage by AG14361 rescued neutrophil-promoted lung cancer progression.Results:An increased number of infiltrating neutrophils was negatively associated with overall survival in lung cancer patients(P<0.001).Neutrophil activation promoted lung cancer cell invasion,migration,and proliferation in vitro,and murine lung cancer growth in vivo.Mechanistically,PARP-1 was shown to be involved in lung cancer cell-induced neutrophil activation to increase MMP-9 expression through interacting and stabilizing ALOX5 by post-translational protein modification(PARylation).Blocking PARP-1 by gene knockdown or AG14361 significantly decreased ALOX5 expression and MMP-9 production,and eliminated neutrophil-mediated lung cancer cell invasion and in vivo tumor growth.Conclusion:We identified a novel mechanism by which PARP-1 mediates lung cancer cell-induced neutrophil activation and PARylates ALOX5 to regulate MMP-9 expression,which exacerbates lung cancer progression.展开更多
This study investigated the effects of small interfering RNA （siRNA）-mediated silencing of chemokine receptor 4 （CXCR4） on the invasion capacity of human neuroblastoma cell line SH-SY5Y in vitro. Three siRNAs targ...This study investigated the effects of small interfering RNA （siRNA）-mediated silencing of chemokine receptor 4 （CXCR4） on the invasion capacity of human neuroblastoma cell line SH-SY5Y in vitro. Three siRNAs targeting CXCR4 were chemically synthesized and individually transfected into SH-SY5Y cells. Expression of CXCR4 mRNA and protein was signiifcantly sup-pressed in transfected cells by all three sequence-speciifc siRNAs compared with control groups. Furthermore, the invasion capacity of SH-SY5Y cells was signiifcantly decreased following trans-fection with CXCR4-speciifc siRNA compared with the control groups. These data demonstrate that down-regulation of CXCR4 can inhibit in vitro invasion of neuroblastoma.展开更多
For red-flowered cultivars of tree peony(Paeonia suffruticosa),anthocyanin content is a critical factor determining the different petal pigmentations.Glutathione S-transferases(GSTs)are ubiquitous and multifunctional ...For red-flowered cultivars of tree peony(Paeonia suffruticosa),anthocyanin content is a critical factor determining the different petal pigmentations.Glutathione S-transferases(GSTs)are ubiquitous and multifunctional conjugating proteins that may be responsible for the transport of anthocyanin pigments from the cytoplasm to vacuole.The underlying function of the GST family in tree peony,however,remains unclear.In this study,we systematically isolated and identified a total of 54 putative full-length Ps GST genes through a combination of bioinformatics approaches from transcriptome databases.Intraspecific phylogenetic analyses revealed extensive differentiation in their coding sequences and divided them into 10 of the 14 known classes of plant GSTs.The phylogenetic relationships,evolutionary characteristics,protein domain,and motif organization were clearly conserved among the different phylogenetic subclasses.The results of the RNA-seq and quantitative real-time polymerase chain reaction experiments exhibited extensive variation in gene expression profiles among different developmental stages and varieties.Furthermore,the phylogenetic relationships,expression profiles,protein interactions,weighted gene co-expression network analysis,and correlation analysis results suggested that PsGSTF3(Unigene 0064200)is a candidate participant in anthocyanin transport and the promotion of pigment accumulation,exhibiting a strong positive correlation with anthocyanin content among different tissues(r=0.908**)and an increasing rate of anthocyanin content during the flower developmental process(r=0.961*).These results furthered our understanding of the transport and accumulation functions of the GST family as well as the enhancement of tree peony breeding through molecular biology techniques.展开更多
GA20-oxidase (GA20ox) gene encodes a key enzyme in gibberellins (GAs) biosynthesis pathway. Previously, we have cloned a PlGA20ox gene (GeneBank accession number: KU886552) from Paeonia lactiflora. To further reveal i...GA20-oxidase (GA20ox) gene encodes a key enzyme in gibberellins (GAs) biosynthesis pathway. Previously, we have cloned a PlGA20ox gene (GeneBank accession number: KU886552) from Paeonia lactiflora. To further reveal its function, we constructed an expression vector in the present study and then transformed it into Arabidopsis thaliana plants by floral dip method. The transgenic plants exhibited an early bolting, increased height and improved vegetative growth. These results provided efficient vector tool and functional information of PlGA20ox for future gene engineering in peony.展开更多
This paper details the design and simulation of a novel low-loss four-bit reconfigurable bandpass filter that integrates microelectromechanical system(MEMS)switches and comb resonators.A T-shaped reconfigurable resona...This paper details the design and simulation of a novel low-loss four-bit reconfigurable bandpass filter that integrates microelectromechanical system(MEMS)switches and comb resonators.A T-shaped reconfigurable resonator is reconfigured in a'one resonator,multiple MEMS switches'configuration and used to gate the load capacitances of comb resonators so that a multiple-frequency filtering function is realized within the 7-16 GHz frequency range.In addition,the insertion loss of the filter is less than 1.99 dB,the out-of-band rejection is more than 18.30 dB,and the group delay is less than 0.25 ns.On the other hand,the size of this novel filter is only 4.4 mm×2.5 mm×0.4 mm.Our results indicate that this MEMS reconfigurable filter,which can switch 16 central frequency bands through eight switches,achieves a low insertion loss compared to those of traditional MEMS filters.In addition,the advantages of small size are obtained while achieving high integration.展开更多
Hyperhomocysteinemia(HHcy)is a risk factor for chronic kidney diseases(CKDs)that affects about 85%CKD patients.HHcy stimulates B cells to secrete pathological antibodies,although it is unknown whether this pathway med...Hyperhomocysteinemia(HHcy)is a risk factor for chronic kidney diseases(CKDs)that affects about 85%CKD patients.HHcy stimulates B cells to secrete pathological antibodies,although it is unknown whether this pathway mediates kidney injury.In HHcytreated 2-kidney,1-clip(2K1C)hypertensive murine model,HHcy-activated B cells secreted anti-beta 2 glycoprotein I(β2GPI)antibodies that deposited in glomerular endothelial cells(GECs),exacerbating glomerulosclerosis and reducing renal function.Mechanistically,HHcy 2K1C mice increased phosphatidylethanolamine(PE)(18:0/20:4,18:0/22:6,16:0/20:4)in kidney tissue,as determined by lipidomics.GECs oxidative lipidomics validated the increase of oxidized phospholipids upon Hcy-activated B cells culture medium(Hcy-B CM)treatment,including PE(18:0/20:4+3[O],PE(18:0a/22:4+1[O],PE(18:0/22:4+2[O]and PE(18:0/22:4+3[O]).PE synthases ethanolamine kinase 2(etnk2)and ethanolamine-phosphate cytidylyltransferase 2(pcyt2)were increased in the kidney GECs of HHcy 2K1C mice and facilitated polyunsaturated PE synthesis to act as lipid peroxidation substrates.In HHcy 2K1C mice and Hcy-B CM-treated GECs,the oxidative environment induced by iron accumulation and the insufficient clearance of lipid peroxides caused by transferrin receptor(TFR)elevation and down-regulation of SLC7A11/glutathione peroxidase 4(GPX4)contributed to GECs ferroptosis of the kidneys.In vivo,pharmacological depletion of B cells or inhibition of ferroptosis mitigated the HHcy-aggravated hypertensive renal injury.Consequently,our findings uncovered a novel mechanism by which B cell-derived pathogenic anti-β2GPI IgG generated by HHcy exacerbated hypertensive kidney damage by inducing GECs ferroptosis.Targeting B cells or ferroptosis may be viable therapeutic strategies for ameliorating lipid peroxidative renal injury in HHcy patients with hypertensive nephropathy.展开更多
Among various efficient electrocatalysts for water splitting,CoFe and NiFe-based oxides/hydroxides are typically promising candidates thanks to their extraordinary activities towards oxygen evolution reaction (OER).Ho...Among various efficient electrocatalysts for water splitting,CoFe and NiFe-based oxides/hydroxides are typically promising candidates thanks to their extraordinary activities towards oxygen evolution reaction (OER).However,the endeavor to advance their performance towards overall water splitting has been largely impeded by the limited activities for hydrogen evolution reaction (HER).Herein,we present a CoFeNi ternary metal-based oxide (CoFeNi-O) with impressive hierarchical bimodal channel nanostructures,which was synthesized via a facile one-step dealloying strategy.The oxide shows superior catalytic activities towards both HER and OER in alkaline solution due to the alloying effect and the intrinsic hierarchical porous structure.CoFeNi-O loaded on glass carbon electrodes only requires the overpotentials as low as 230 and 278 mV to achieve the OER current densities of 10 and 100 mA·cm-2,respectively.In particular,extremely low overpotentials of 200 and 57.9 mV are sufficient enough for Ni foam-supported CoFeNi-O to drive the current density of 10 mA·cm-2 towards OER and HER respectively,which is comparable with or even better than the already-developed state-of-the-art non-noble metal oxide based catalysts.Benefiting from the bifunctionalities of CoFeNi-O,an alkaline electrolyzer constructed by the Ni foam-supported CoFeNi-O electrodes as both the anode and the cathode can deliver a current density of 10 mA·cm-2 at a fairly low cell-voltage of 1.558 V.In view of its electrocatalytic merits together with the facile and cost-effective dealloying route,CoFeNi-O is envisioned as a promising catalyst for future production of sustainable energy resources.展开更多
Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is ...Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is the suppression of type I and III interferon(IFN)-mediated antiviral immunity.However,the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive.Here,we reported that the SARS-CoV-2 membrane(M)protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling.In addition,the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly(I:C)transfection.Mechanistically,the SARS-CoV-2 M protein interacts with RIG-I,MAVS,and TBK1,thus preventing the formation of the multiprotein complex containing RIG-I,MAVS,TRAF3,and TBK1 and subsequently impeding the phosphorylation,nuclear translocation,and activation of IRF3.Consequently,ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus.Taken together,these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling,which subsequently attenuates antiviral immunity and enhances viral replication.This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.展开更多
Dear Editor Cardiovascular disease(CVD)is the leading cause of death around the world(Truelsen,et al.,2015).Atherosclerosis,the dominant underlying cause of CVD,is a chronic inflam-matory disease characterized by lipi...Dear Editor Cardiovascular disease(CVD)is the leading cause of death around the world(Truelsen,et al.,2015).Atherosclerosis,the dominant underlying cause of CVD,is a chronic inflam-matory disease characterized by lipid accumulation and immune cell infiltration in plaques and vessels(Weber,et al.,1950).The immune microenvironment is critical for the development of atherosclerosis.Homocysteine(Hcy)is an intermediate product of methionine metabolism,and its ele-vation in plasma(>15μmol/L),known as hyperhomocys-teinemia(HHcy),is an independent risk factor for atherosclerosis.HHcy is more common in Asia because of genetic factors and dietary habits(Huo,et al.,2015).folic acid supplement is one of the most important way to treat HHcy in clinic.Although HHcy potentiates atherosclerosis mainly through endothelial injury and inflammatory activa-tion(Luo,et al.,2016),a comprehensive understanding of the immune microenvironment and potential mechanisms in HHcy-accelerated atherosclerotic aortas(HHcy-AA)is still lacking.展开更多
Cell migration plays a crucial role in a variety of physiological and pathological processes.In this study a method of capillary force lithography was used to treat poly(sodium 4-styrenesulfonate) (PSS)/poly(diallyldi...Cell migration plays a crucial role in a variety of physiological and pathological processes.In this study a method of capillary force lithography was used to treat poly(sodium 4-styrenesulfonate) (PSS)/poly(diallyldimethylammonium) chloride (PDADMAC) multilayers with a PDMS stamp before or after etching by NaC1 solution,yielding physical patterns with various features such as double thin lines,double strips,meniscus-shaped ridges,and high ridges.The ridge height is controllable in the range of 25 and 1100 nm.Migration of smooth muscle cells (SMCs) was restrained by the double-line patterns in a ridge height-dependent manner.By contrast,the mobility of SMCs was controlled by both the hydration ratio of the multilayers and the pattern features.展开更多
As a highly pathogenic human coronavirus,SARS-CoV-2 has to counteract an intricate network of antiviral host responses to establish infection and spread.The nucleic acid-induced stress response is an essential compone...As a highly pathogenic human coronavirus,SARS-CoV-2 has to counteract an intricate network of antiviral host responses to establish infection and spread.The nucleic acid-induced stress response is an essential component of antiviral defense and is closely related to antiviral innate immunity.However,whether SARS-CoV-2 regulates the stress response pathway to achieve immune evasion remains elusive.In this study,SARS-CoV-2 NSP5 and N protein were found to attenuate antiviral stress granule(avSG)formation.Moreover,NSP5 and N suppressed IFN expression induced by infection of Sendai virus or transfection of a synthetic mimic of dsRNA,poly(I:C),inhibiting TBK1 and IRF3 phosphorylation,and restraining the nuclear translocalization of IRF3.Furthermore,HEK293T cells with ectopic expression of NSP5 or N protein were less resistant to vesicular stomatitis virus infection.Mechanistically,NSP5 suppressed avSG formation and disrupted RIG-I–MAVS complex to attenuate the RIG-I–mediated antiviral immunity.In contrast to the multiple targets of NSP5,the N protein specifically targeted cofactors upstream of RIG-I.The N protein interacted with G3BP1 to prevent avSG formation and to keep the cofactors G3BP1 and PACT from activating RIG-I.Additionally,the N protein also affected the recognition of dsRNA by RIG-I.This study revealed the intimate correlation between SARS-CoV-2,the stress response,and innate antiviral immunity,shedding light on the pathogenic mechanism of COVID-19.展开更多
Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is ...Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is the suppression of type I and III interferon(IFN)-mediated antiviral immunity.However,the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive.Here,we reported that the SARS-CoV-2 membrane(M)protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling.In addition,the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly(I:C)transfection.Mechanistically,the SARS-CoV-2 M protein interacts with RIG-I,MAVS,and TBK1,thus preventing the formation of the multiprotein complex containing RIG-I,MAVS,TRAF3,and TBK1 and subsequently impeding the phosphorylation,nuclear translocation,and activation of IRF3.Consequently,ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus.Taken together,these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling,which subsequently attenuates antiviral immunity and enhances viral replication.This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.展开更多
基金supported by grants from the National Key R&D Program of China(Grant No.2018YFA0900900)the National Natural Science Foundation of China(Grant Nos.82273334,82203172,81871869,and 81400055)+3 种基金the Jiangsu Province Social Development Key Projects(Grant Nos.BE2020641 and BE2020640)the Xuzhou Medical University Excellent Talent Research Start-up Fund(Grant No.RC20552157)the Jiangsu Province Capability Improvement Project through Science,Technology and Education(Grant No.CXZX202234)funded by the China Postdoctoral Science Foundation(Grant No.2023M732970)。
文摘Objective:Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression.How neutrophils promote lung cancer progression,however,has not been established.Methods:Kaplan–Meier plotter online analysis and tissue immunohistochemistry were used to determine the relationship between neutrophils and overall survival in lung cancer patients.The effect of neutrophils on lung cancer was determined using the Transwell migration assay,a proliferation assay,and a murine tumor model.Gene knockdown was used to determine poly ADPribose polymerase(PARP)-1 function in lung cancer-educated neutrophils.Western blot analysis and gelatin zymography were used to demonstrate the correlation between PARP-1 and matrix metallopeptidase 9(MMP-9).Immunoprecipitation coupled to mass spectrometry(IP/MS)was used to identify the proteins interacting with PARP-1.Co-immunoprecipitation(Co-IP)was used to confirm that PARP-1 interacts with arachidonate 5-lipooxygenase(ALOX5).Neutrophil PARP-1 blockage by AG14361 rescued neutrophil-promoted lung cancer progression.Results:An increased number of infiltrating neutrophils was negatively associated with overall survival in lung cancer patients(P<0.001).Neutrophil activation promoted lung cancer cell invasion,migration,and proliferation in vitro,and murine lung cancer growth in vivo.Mechanistically,PARP-1 was shown to be involved in lung cancer cell-induced neutrophil activation to increase MMP-9 expression through interacting and stabilizing ALOX5 by post-translational protein modification(PARylation).Blocking PARP-1 by gene knockdown or AG14361 significantly decreased ALOX5 expression and MMP-9 production,and eliminated neutrophil-mediated lung cancer cell invasion and in vivo tumor growth.Conclusion:We identified a novel mechanism by which PARP-1 mediates lung cancer cell-induced neutrophil activation and PARylates ALOX5 to regulate MMP-9 expression,which exacerbates lung cancer progression.
基金supported by the National Natural Science Foundation of China,No.81272986the Natural Science Foundation of Shandong Province,No.ZR2011HZ002
文摘This study investigated the effects of small interfering RNA （siRNA）-mediated silencing of chemokine receptor 4 （CXCR4） on the invasion capacity of human neuroblastoma cell line SH-SY5Y in vitro. Three siRNAs targeting CXCR4 were chemically synthesized and individually transfected into SH-SY5Y cells. Expression of CXCR4 mRNA and protein was signiifcantly sup-pressed in transfected cells by all three sequence-speciifc siRNAs compared with control groups. Furthermore, the invasion capacity of SH-SY5Y cells was signiifcantly decreased following trans-fection with CXCR4-speciifc siRNA compared with the control groups. These data demonstrate that down-regulation of CXCR4 can inhibit in vitro invasion of neuroblastoma.
基金supported by grants from the National Key Research and Development Program (Grant No.2018YFD1000405)。
文摘For red-flowered cultivars of tree peony(Paeonia suffruticosa),anthocyanin content is a critical factor determining the different petal pigmentations.Glutathione S-transferases(GSTs)are ubiquitous and multifunctional conjugating proteins that may be responsible for the transport of anthocyanin pigments from the cytoplasm to vacuole.The underlying function of the GST family in tree peony,however,remains unclear.In this study,we systematically isolated and identified a total of 54 putative full-length Ps GST genes through a combination of bioinformatics approaches from transcriptome databases.Intraspecific phylogenetic analyses revealed extensive differentiation in their coding sequences and divided them into 10 of the 14 known classes of plant GSTs.The phylogenetic relationships,evolutionary characteristics,protein domain,and motif organization were clearly conserved among the different phylogenetic subclasses.The results of the RNA-seq and quantitative real-time polymerase chain reaction experiments exhibited extensive variation in gene expression profiles among different developmental stages and varieties.Furthermore,the phylogenetic relationships,expression profiles,protein interactions,weighted gene co-expression network analysis,and correlation analysis results suggested that PsGSTF3(Unigene 0064200)is a candidate participant in anthocyanin transport and the promotion of pigment accumulation,exhibiting a strong positive correlation with anthocyanin content among different tissues(r=0.908**)and an increasing rate of anthocyanin content during the flower developmental process(r=0.961*).These results furthered our understanding of the transport and accumulation functions of the GST family as well as the enhancement of tree peony breeding through molecular biology techniques.
文摘GA20-oxidase (GA20ox) gene encodes a key enzyme in gibberellins (GAs) biosynthesis pathway. Previously, we have cloned a PlGA20ox gene (GeneBank accession number: KU886552) from Paeonia lactiflora. To further reveal its function, we constructed an expression vector in the present study and then transformed it into Arabidopsis thaliana plants by floral dip method. The transgenic plants exhibited an early bolting, increased height and improved vegetative growth. These results provided efficient vector tool and functional information of PlGA20ox for future gene engineering in peony.
基金Project supported by the National Defense Technology Industry Strong Foundation Project of China (Grant No. JCKY2018* * **06)the Information System New items Project (Grant Nos. 2018****26 and 2019****10)the Key Laboratory of Instrumentation Science and Dynamic Measurement for their support
文摘This paper details the design and simulation of a novel low-loss four-bit reconfigurable bandpass filter that integrates microelectromechanical system(MEMS)switches and comb resonators.A T-shaped reconfigurable resonator is reconfigured in a'one resonator,multiple MEMS switches'configuration and used to gate the load capacitances of comb resonators so that a multiple-frequency filtering function is realized within the 7-16 GHz frequency range.In addition,the insertion loss of the filter is less than 1.99 dB,the out-of-band rejection is more than 18.30 dB,and the group delay is less than 0.25 ns.On the other hand,the size of this novel filter is only 4.4 mm×2.5 mm×0.4 mm.Our results indicate that this MEMS reconfigurable filter,which can switch 16 central frequency bands through eight switches,achieves a low insertion loss compared to those of traditional MEMS filters.In addition,the advantages of small size are obtained while achieving high integration.
基金the National Natural Science Foundation of China(No.31872787,82070462,81921001,91939105,and 82170476)the Natural Science Foundation of Beijing Municipality,China(No.M21008).
文摘Hyperhomocysteinemia(HHcy)is a risk factor for chronic kidney diseases(CKDs)that affects about 85%CKD patients.HHcy stimulates B cells to secrete pathological antibodies,although it is unknown whether this pathway mediates kidney injury.In HHcytreated 2-kidney,1-clip(2K1C)hypertensive murine model,HHcy-activated B cells secreted anti-beta 2 glycoprotein I(β2GPI)antibodies that deposited in glomerular endothelial cells(GECs),exacerbating glomerulosclerosis and reducing renal function.Mechanistically,HHcy 2K1C mice increased phosphatidylethanolamine(PE)(18:0/20:4,18:0/22:6,16:0/20:4)in kidney tissue,as determined by lipidomics.GECs oxidative lipidomics validated the increase of oxidized phospholipids upon Hcy-activated B cells culture medium(Hcy-B CM)treatment,including PE(18:0/20:4+3[O],PE(18:0a/22:4+1[O],PE(18:0/22:4+2[O]and PE(18:0/22:4+3[O]).PE synthases ethanolamine kinase 2(etnk2)and ethanolamine-phosphate cytidylyltransferase 2(pcyt2)were increased in the kidney GECs of HHcy 2K1C mice and facilitated polyunsaturated PE synthesis to act as lipid peroxidation substrates.In HHcy 2K1C mice and Hcy-B CM-treated GECs,the oxidative environment induced by iron accumulation and the insufficient clearance of lipid peroxides caused by transferrin receptor(TFR)elevation and down-regulation of SLC7A11/glutathione peroxidase 4(GPX4)contributed to GECs ferroptosis of the kidneys.In vivo,pharmacological depletion of B cells or inhibition of ferroptosis mitigated the HHcy-aggravated hypertensive renal injury.Consequently,our findings uncovered a novel mechanism by which B cell-derived pathogenic anti-β2GPI IgG generated by HHcy exacerbated hypertensive kidney damage by inducing GECs ferroptosis.Targeting B cells or ferroptosis may be viable therapeutic strategies for ameliorating lipid peroxidative renal injury in HHcy patients with hypertensive nephropathy.
基金The authors gratefully acknowledge financial support from the National Natural Science Foundation of China(Nos.51871133 and 51671115)Department of Education of Jilin Province(No.JJKH20190767KJ)Department of Science and Technology of Shandong Province for Young Tip-top Talent Support Project.
文摘Among various efficient electrocatalysts for water splitting,CoFe and NiFe-based oxides/hydroxides are typically promising candidates thanks to their extraordinary activities towards oxygen evolution reaction (OER).However,the endeavor to advance their performance towards overall water splitting has been largely impeded by the limited activities for hydrogen evolution reaction (HER).Herein,we present a CoFeNi ternary metal-based oxide (CoFeNi-O) with impressive hierarchical bimodal channel nanostructures,which was synthesized via a facile one-step dealloying strategy.The oxide shows superior catalytic activities towards both HER and OER in alkaline solution due to the alloying effect and the intrinsic hierarchical porous structure.CoFeNi-O loaded on glass carbon electrodes only requires the overpotentials as low as 230 and 278 mV to achieve the OER current densities of 10 and 100 mA·cm-2,respectively.In particular,extremely low overpotentials of 200 and 57.9 mV are sufficient enough for Ni foam-supported CoFeNi-O to drive the current density of 10 mA·cm-2 towards OER and HER respectively,which is comparable with or even better than the already-developed state-of-the-art non-noble metal oxide based catalysts.Benefiting from the bifunctionalities of CoFeNi-O,an alkaline electrolyzer constructed by the Ni foam-supported CoFeNi-O electrodes as both the anode and the cathode can deliver a current density of 10 mA·cm-2 at a fairly low cell-voltage of 1.558 V.In view of its electrocatalytic merits together with the facile and cost-effective dealloying route,CoFeNi-O is envisioned as a promising catalyst for future production of sustainable energy resources.
基金supported by grants from the COVID-19 emergency tackling research project of Shandong University(Grant No.2020XGB03 to P.-H.W)grants from the Natural Science Foundation of Jiangsu Province(SBK2020042706 to P.-H.W)+3 种基金grants from the Natural Science Foundation of China(81930039,31730026,81525012)awarded to C.G.,and the Fundamental Research Funds of Shandong University(21510078614099)the Fundamental Research Funds of Cheeloo College of Medicine(21510089393109)China Postdoctoral Science Foundation(2018M642662)the Natural Science Foundation of China(81901604)awarded to Y.Z.,and grants from the Key Research and Development Project of Shandong Province(2020SFXGFY08).
文摘Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is the suppression of type I and III interferon(IFN)-mediated antiviral immunity.However,the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive.Here,we reported that the SARS-CoV-2 membrane(M)protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling.In addition,the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly(I:C)transfection.Mechanistically,the SARS-CoV-2 M protein interacts with RIG-I,MAVS,and TBK1,thus preventing the formation of the multiprotein complex containing RIG-I,MAVS,TRAF3,and TBK1 and subsequently impeding the phosphorylation,nuclear translocation,and activation of IRF3.Consequently,ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus.Taken together,these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling,which subsequently attenuates antiviral immunity and enhances viral replication.This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.
基金This work was supported by grants from National Natural Science Foundation of China(31872787,91739303,91939105,81770445,81921001,and 82170476)Natural Science Foundation of Beijing,China(No.M21008).
文摘Dear Editor Cardiovascular disease(CVD)is the leading cause of death around the world(Truelsen,et al.,2015).Atherosclerosis,the dominant underlying cause of CVD,is a chronic inflam-matory disease characterized by lipid accumulation and immune cell infiltration in plaques and vessels(Weber,et al.,1950).The immune microenvironment is critical for the development of atherosclerosis.Homocysteine(Hcy)is an intermediate product of methionine metabolism,and its ele-vation in plasma(>15μmol/L),known as hyperhomocys-teinemia(HHcy),is an independent risk factor for atherosclerosis.HHcy is more common in Asia because of genetic factors and dietary habits(Huo,et al.,2015).folic acid supplement is one of the most important way to treat HHcy in clinic.Although HHcy potentiates atherosclerosis mainly through endothelial injury and inflammatory activa-tion(Luo,et al.,2016),a comprehensive understanding of the immune microenvironment and potential mechanisms in HHcy-accelerated atherosclerotic aortas(HHcy-AA)is still lacking.
基金This study is financially supported by the National Natural Science Foundation of China (Nos.20934003and 51003094),and the National Basic Research Program of China (No.2011CB606203).Z.W.Mao thanks Young Teacher Programs Foundation of Ministry of Education of China (No.20100101120034),'Qianjiang'outstanding researcher funding of Zhejiang Province (No.J20110541) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars,State Education Ministry.
文摘Cell migration plays a crucial role in a variety of physiological and pathological processes.In this study a method of capillary force lithography was used to treat poly(sodium 4-styrenesulfonate) (PSS)/poly(diallyldimethylammonium) chloride (PDADMAC) multilayers with a PDMS stamp before or after etching by NaC1 solution,yielding physical patterns with various features such as double thin lines,double strips,meniscus-shaped ridges,and high ridges.The ridge height is controllable in the range of 25 and 1100 nm.Migration of smooth muscle cells (SMCs) was restrained by the double-line patterns in a ridge height-dependent manner.By contrast,the mobility of SMCs was controlled by both the hydration ratio of the multilayers and the pattern features.
基金This work was supported by grants from the Key Research and Development Program of Shandong Province(2020CXGC011305 to P.-H.W)grants from the Natural Science Foundation of Shandong Province(ZR2020QC085 to P.-H.W)+7 种基金grants from the Natural Science Foundation of Jiangsu Province(BK20200225 to P.-H.W)grants from the Natural Science Foundation of China(82101856 to P.-H.W)grants from the National Key R&D Program of China(2021YFC2701203 to P.-H.W)grants from the Natural Science Foundation of China(81930039,31730026,81525012)awarded to C.G,the Fundamental Research Funds of Shandong University(21510078614099)the Fundamental Research Funds of Cheeloo College of Medicine(21510089393109)China Postdoctoral Science Foundation(2018M642662)Future Scholar Program of Shandong University,and the Natural Science Foundation of China(81901604)awarded to Y.Zgrants from the Key Research and Development Project of Shandong Province(2020SFXGFY08).
文摘As a highly pathogenic human coronavirus,SARS-CoV-2 has to counteract an intricate network of antiviral host responses to establish infection and spread.The nucleic acid-induced stress response is an essential component of antiviral defense and is closely related to antiviral innate immunity.However,whether SARS-CoV-2 regulates the stress response pathway to achieve immune evasion remains elusive.In this study,SARS-CoV-2 NSP5 and N protein were found to attenuate antiviral stress granule(avSG)formation.Moreover,NSP5 and N suppressed IFN expression induced by infection of Sendai virus or transfection of a synthetic mimic of dsRNA,poly(I:C),inhibiting TBK1 and IRF3 phosphorylation,and restraining the nuclear translocalization of IRF3.Furthermore,HEK293T cells with ectopic expression of NSP5 or N protein were less resistant to vesicular stomatitis virus infection.Mechanistically,NSP5 suppressed avSG formation and disrupted RIG-I–MAVS complex to attenuate the RIG-I–mediated antiviral immunity.In contrast to the multiple targets of NSP5,the N protein specifically targeted cofactors upstream of RIG-I.The N protein interacted with G3BP1 to prevent avSG formation and to keep the cofactors G3BP1 and PACT from activating RIG-I.Additionally,the N protein also affected the recognition of dsRNA by RIG-I.This study revealed the intimate correlation between SARS-CoV-2,the stress response,and innate antiviral immunity,shedding light on the pathogenic mechanism of COVID-19.
基金This work was supported by grants from the COVID-19 emergency tackling research project of Shandong University(Grant No.2020XGB03 to P.-H.W)grants from the Natural Science Foundation of Jiangsu Province(SBK2020042706 to P.-H.W)+5 种基金grants from the Natural Science Foundation of China(81930039,31730026,81525012)awarded to C.G.the Fundamental Research Funds of Shandong University(21510078614099)the Fundamental Research Funds of Cheeloo College of Medicine(21510089393109)China Postdoctoral Science Foundation(2018M642662)the Natural Science Foundation of China(81901604)awarded to Y.Z.grants from the Key Research and Development Project of Shandong Province(2020SFXGFY08).
文摘Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is the suppression of type I and III interferon(IFN)-mediated antiviral immunity.However,the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive.Here,we reported that the SARS-CoV-2 membrane(M)protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling.In addition,the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly(I:C)transfection.Mechanistically,the SARS-CoV-2 M protein interacts with RIG-I,MAVS,and TBK1,thus preventing the formation of the multiprotein complex containing RIG-I,MAVS,TRAF3,and TBK1 and subsequently impeding the phosphorylation,nuclear translocation,and activation of IRF3.Consequently,ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus.Taken together,these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling,which subsequently attenuates antiviral immunity and enhances viral replication.This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.
