Influenza A viruses(IAVs)are single-stranded negative-sense RNA viruses that continually challenge animal and human health.In IAV-infected cells,host RNA-binding proteins play key roles in the life cycle of IAV by dir...Influenza A viruses(IAVs)are single-stranded negative-sense RNA viruses that continually challenge animal and human health.In IAV-infected cells,host RNA-binding proteins play key roles in the life cycle of IAV by directly binding to viral RNA.Here,we examined the role of the host RNA-binding protein nucleophosmin-1(NPM1)in IAV replication.We found that,as a nucleolar phosphoprotein,NPM1 directly binds to viral RNA(vRNA)and inhibits the replication of various subtypes of IAV.NPM1 binding to vRNA competitively reduces the assembly of the viral ribonucleoprotein complex and the viral polymerase activity,thereby reducing the generation of progeny viral RNA and virions.The RNA-binding activity of NPM1,with the key residues T199,T219,T234,and T237,is essential for its anti-influenza function.Taken together,our findings demonstrate that NPM1 acts as an RNA-binding protein and interacts with IAV vRNA to suppress viral replication.展开更多
CuInSe_(2) is an N-type diamond-like semiconductors thermoelectric candidate for power generation at medium temperature with its environmentally friendly and cost-effective properties.However,the intrinsic high therma...CuInSe_(2) is an N-type diamond-like semiconductors thermoelectric candidate for power generation at medium temperature with its environmentally friendly and cost-effective properties.However,the intrinsic high thermal conductivity of CuInSe_(2) limits the enhancement of its thermoelectric performance.Herein,we investigate the thermoelectric performance of N-type CuInSe_(2) materials by incorporating ZnSe through a solid solution strategy.A series of(CuInSe_(2))_(1-x)(ZnSe)_(x)(x=0.0,0.2,0.4,0.6,0.8,1.0)samples were synthesized,forming continuous solid solutions,while introducing minor porosity.ZnSe solid solution effectively reduces the lattice thermal conductivity of the CuInSe_(2) matrix at near-room temperatures,but has a weaker effect at higher temperatures.Due to the intrinsic low carrier concentration of the system,resulting in high resistivity,the maximum figure of merit(ZT)of(CuInSe_(2))0.8(ZnSe)0.2 reaches 0.08 at 773 K.Despite the relatively low ZT,the solid solution strategy proves effective in reducing the lattice thermal conductivity near-room temperature and offers potential for cost-effective thermoelectric materials.展开更多
Cellular senescence assumes pivotal roles in various diseases through the secretion of proinflammatory factors.Despite extensive investigations into vascular senescence associated with aging and degenerative diseases,...Cellular senescence assumes pivotal roles in various diseases through the secretion of proinflammatory factors.Despite extensive investigations into vascular senescence associated with aging and degenerative diseases,the molecular mechanisms governing microvascular endothelial cell senescence induced by traumatic stress,particularly its involvement in senescence-induced inflammation,remain insufficiently elucidated.In this study,we present a comprehensive demonstration and characterization of microvascular endothelial cell senescence induced by spinal cord injury(SCI).Lysine demethylase 6A(Kdm6a),commonly known as UTX,emerges as a crucial regulator of cell senescence in injured spinal cord microvascular endothelial cells(SCMECs).Upregulation of UTX induces senescence in SCMECs,leading to an amplified release of proinflammatory factors,specifically the senescenceassociated secretory phenotype(SASP)components,thereby modulating the inflammatory microenvironment.Conversely,the deletion of UTX in endothelial cells shields SCMECs against senescence,mitigates the release of proinflammatory SASP factors,and promotes neurological functional recovery after SCI.UTX forms an epigenetic regulatory axis by binding to calponin 1(CNN1),orchestrating trauma-induced SCMECs senescence and SASP secretion,thereby influencing neuroinflammation and neurological functional repair.Furthermore,local delivery of a senolytic drug reduces senescent SCMECs and suppresses proinflammatory SASP secretion,reinstating a local regenerative microenvironment and enhancing functional repair after SCI.In conclusion,targeting the UTX-CNN1 epigenetic axis to prevent trauma-induced SCMECs senescence holds the potential to inhibit SASP secretion,alleviate neuroinflammation,and provide a novel treatment strategy for SCI repair.展开更多
Effective methods for visualizing neurovascular morphology are essential for understanding the normal spinal cord and the morphological alterations associated with diseases.However,ideal techniques for simultaneously ...Effective methods for visualizing neurovascular morphology are essential for understanding the normal spinal cord and the morphological alterations associated with diseases.However,ideal techniques for simultaneously imaging neurovascular structure in a broad region of a specimen are still lacking.In this study,we combined Golgi staining with angiography and synchrotron radiation micro-computed tomography(SRμCT)to visualize the 3D neurovascular network in the mouse spinal cord.Using our method,the 3D neurons,nerve fibers,and vasculature in a broad region could be visualized in the same image at cellular resolution without destructive sectioning.Besides,we found that the 3D morphology of neurons,nerve fiber tracts,and vasculature visualized by SRjiCT were highly consistent with that visualized using the histological method.Moreover,the 3D neurovascular structure could be quantitatively evaluated by the combined methodology.The method shown here will be useful in fundamental neuroscience studies.展开更多
Hemocytes are pivotal in the immune response of insects against invasive pathogens.However,our knowledge of hemocyte types and their specific function in Tribolium castaneum,an increasingly important Coleoptera model ...Hemocytes are pivotal in the immune response of insects against invasive pathogens.However,our knowledge of hemocyte types and their specific function in Tribolium castaneum,an increasingly important Coleoptera model insect in various research fields,remains limited.Presently,a combination of morphological criteria and dye-staining properties were used to characterize hemocyte types from T.castaneum larvae,and 4 distinct types were identified:granulocytes,oenocytoids,plasmatocytes and prohemocytes.Following different immune challenges,the total hemocyte counts declined rapidly in the initial phase(at 2 h),then increased over time(at 4 and 6 h)and eventually returned to the naive state by 24 h post-injection.Notably,the morphology of granulocytes underwent dramatic changes,characterized by an expansion of the surface area and an increased production of pseudopods,and with the number of granulocytes rising significantly through mitotic division.Granulocytes and plasmatocytes,the main hemocyte types in T.castaneum larvae,can phagocytose bacteria or latex beads injected into the larval hemolymph in vivo.Furthermore,these hemocytes participate in the encapsulation and melanization processes in vitro,forming capsules to encapsulate and melanize nickel-nitrilotriacetic acid(Ni-NTA)beads.This study provides the first comprehensive characterization of circulating hemocytes in T.castaneum larvae,offering valuable insights into cell-mediated immunity in response to bacterial infection and the injection of latex beads.These results deepen our understanding of the cellular response mechanisms in T.castaneum larvae and lay a solid foundation for subsequent investigations of the involvement of T.castaneum hemocytes in combating pathogens.展开更多
The global dissemination of H5 avian influenza viruses represents a significant threat to both human and animal health.In thisstudy,we conducted a genome-wide siRNA library screening against the highly pathogenic H5N1 i...The global dissemination of H5 avian influenza viruses represents a significant threat to both human and animal health.In thisstudy,we conducted a genome-wide siRNA library screening against the highly pathogenic H5N1 influenza virus,leading us tothe identification of 457 cellular cofactors(441 proviral factors and 16 antiviral factors)involved in the virus replication cycle.Gene Ontology term enrichment analysis revealed that the candidate gene data sets were enriched in gene categoriesassociated with mRNA splicing via spliceosome in the biological process,integral component of membrane in the cellularcomponent,and protein binding in the molecular function.Reactome pathway analysis showed that the immune system(up to63 genes)was the highest enriched pathway.Subsequent comparisons with four previous siRNA library screenings revealedthat the overlapping rates of the involved pathways were 8.53%-62.61%,which were significantly higher than those of thecommon genes(1.85%-6.24%).Together,our genome-wide siRNA library screening unveiled a panorama of host cellularnetworks engaged in the regulation of highly pathogenic H5N1 influenza virus replication,which may provide potential targetsand strategies for developing novel antiviral countermeasures.展开更多
With the development of 5G technology and increasing chip integration,traditional active cooling methods struggle to meet the growing thermal demands of chips.Thermoelectric coolers(TECs)have garnered great attention ...With the development of 5G technology and increasing chip integration,traditional active cooling methods struggle to meet the growing thermal demands of chips.Thermoelectric coolers(TECs)have garnered great attention due to their rapid response,significant cooling differentials,strong compatibility,high stability and controllable device dimensions.In this review,starting from the fundamental principles of thermoelectric cooling and device design,high-performance thermoelectric cooling materials are summarized,and the progress of advanced on-chip TECs is comprehensively reviewed.Finally,the paper outlines the challenges and opportunities in TEC design,performance and applications,laying great emphasis on the critical role of thermoelectric cooling in addressing the evolving thermal management requirements in the era of emerging chip technologies.展开更多
Influenza A virus(IAV) commandeers numerous host cellular factors for successful replication. However, very few host factors have been revealed to be involved in the fusion of viral envelope and late endosomal membran...Influenza A virus(IAV) commandeers numerous host cellular factors for successful replication. However, very few host factors have been revealed to be involved in the fusion of viral envelope and late endosomal membranes. In this study, we identified cation-dependent mannose-6-phosphate receptor(M6PR) as a crucial host factor for the replication of IAV. We found that siRNA knockdown of M6PR expression significantly reduced the growth titers of different subtypes of IAV, and that the inhibitory effect of M6PR siRNA treatment on IAV growth was overcome by the complement of exogenously expressed M6PR. When A549 cells were treated with siRNA targeting M6PR,the nuclear accumulation of viral nucleoprotein(NP) was dramatically inhibited at early timepoints post-infection, indicating that M6PR engages in the early stage of the IAV replication cycle. By investigating the role of M6PR in the individual entry and post-entry steps of IAV replication, we found that the downregulation of M6PR expression had no effect on attachment, internalization, early endosome trafficking,or late endosome acidification. However, we found that M6PR expression was critical for the fusion of viral envelope and late endosomal membranes. Of note, M6PR interacted with the hemagglutinin(HA) protein of IAV, and further studies showed that the lumenal domain of M6PR and the ectodomain of HA2 mediated the interaction and directly promoted the fusion of the viral and late endosomal membranes,thereby facilitating IAV replication. Together, our findings highlight the importance of the M6PR–HA interaction in the fusion of viral and late endosomal membranes during IAV replication.展开更多
Inflammation is a major adverse outcome induced by inhaled particulate matter with a diameter of≤2.5μm(PM_(2.5)),and a critical trigger ofmost PM_(2.5) exposure-associated diseases.However,the key molecular events r...Inflammation is a major adverse outcome induced by inhaled particulate matter with a diameter of≤2.5μm(PM_(2.5)),and a critical trigger ofmost PM_(2.5) exposure-associated diseases.However,the key molecular events regulating the PM_(2.5)-induced airway inflammation are yet to be elucidated.Considering the critical role of circular RNAs(circRNAs)in regulating inflammation,we predicted 11 circRNAs that may be involved in the PM_(2.5)-induced airway inflammation using three previously reportedmiRNAs through the starBasewebsite.A novel circRNA circ_0008553 was identified to be responsible for the PM_(2.5)-activated inflammatory response in human bronchial epithelial cells(16HBE)via inducing oxidative stress.Using a combinatorial model PM_(2.5) library,we found that the synergistic effect of the insoluble core and loaded Zn^(2+)ions at environmentally relevant concentrations was the major contributor to the upregulation of circ_0008553 and subsequent induction of oxidative stress and inflammation in response to PM2.5 exposures.Our findings provided new insight into the intervention of PM_(2.5)-induced adverse outcomes.展开更多
Colleges and universities are the educational institutions of training young students. The reform of the modem higher education system requires the personnel training in colleges and universities to lay a stress on th...Colleges and universities are the educational institutions of training young students. The reform of the modem higher education system requires the personnel training in colleges and universities to lay a stress on the diversified development, so that the traditional single professional course education can be changed. Mental health has a close tie with the personal development trend of each student in colleges and universities, and also developing mental health education is one of the most important parts in higher education. For a long time, colleges and universities always adhere to the personnel-based educational idea and attach high importance to the work of professional course education, but fail to provide enough importance for guiding the detailed mental health of students. Thus, the mental health education in colleges and universities is misunderstood in many aspects, and this is studied in this paper.展开更多
Arsenic(As)is a naturally occurring chemical element widely distributed in the Earth's crust.Human activities have significantly altered As presence in the environment,posing significant threats to the biota as we...Arsenic(As)is a naturally occurring chemical element widely distributed in the Earth's crust.Human activities have significantly altered As presence in the environment,posing significant threats to the biota as well as human health.The environmental fates and adverse outcomes of As of various species have been extensively studied in the past few decades.It is imperative to summarize these advances as a whole to provide more profound insights into the As cycle for sustainable development.Embracing the One Health concept,we systematically reviewed previous studies in this work and explored the following three fundamental questions,i.e.,what the trends and associated changes are in As contamination,how living organisms interact and cope with As contamination,and most importantly what to do to achieve a sustainable future with As.By focusing on one critical question in each section,this review aims to provide a full picture of the complexity of environmental As.To tackle the significant research challenges and gaps in As pollution and mitigation,we further proposed a One Health framework with potential coping strategies,guiding a coordinated agenda on dealing with legacy As in the environment and ensuring a sustainable As future.展开更多
Spinal cord injury typically causes corticospinal tract disruption.Although the disrupted corticospinal tract can self-regenerate to a certain degree,the underlying mechanism of this process is still unclear.N6-methyl...Spinal cord injury typically causes corticospinal tract disruption.Although the disrupted corticospinal tract can self-regenerate to a certain degree,the underlying mechanism of this process is still unclear.N6-methyladenosine(m^(6)A)modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes.However,whether m^(6)A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown.We found that expression of methyltransferase 14 protein(METTL14)in the locomotor cortex was high after spinal cord injury and accompanied by elevated m^(6)A levels.Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury.Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction,we found that METTL14 regulated Trib2 expression in an m^(6)A-regulated manner,thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration.Finally,we administered syringin,a stabilizer of METTL14,using molecular docking.Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14.Findings from this study reveal that m^(6)A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.展开更多
The rational design of molecules with the desired functionality presents a significant challenge in chemistry.Moreover,it is worth noting that making chemicals safe and sustainable is crucial to bringing them to the m...The rational design of molecules with the desired functionality presents a significant challenge in chemistry.Moreover,it is worth noting that making chemicals safe and sustainable is crucial to bringing them to the market.To address this,we propose a novel deep learning framework developed explicitly for inverse design of molecules with both functionality and biocompatibility.This innovative approach comprises two predictive models and one generative model,facilitating the targeted screening of novel molecules from created virtual chemical space.Our method’s versatility is highlighted in the inverse design process,where it successfully generates molecules with specified motifs or composition,discovers synthetically accessible molecules,and jointly targets functional and safe properties beyond the training regime.The utility of this method is demonstrated in its ability to design ionic liquids(ILs)with enhanced antibacterial properties and reduced cytotoxicity,addressing the issue of balancing functionality and biocompatibility in molecular design.展开更多
The H7 N9 viruses that emerged in China in 2013 were nonpathogenic in chickens but mutated to a highly pathogenic form in early 2017 and caused severe disease outbreaks in chickens. The H7 N9 influenza viruses have ca...The H7 N9 viruses that emerged in China in 2013 were nonpathogenic in chickens but mutated to a highly pathogenic form in early 2017 and caused severe disease outbreaks in chickens. The H7 N9 influenza viruses have caused five waves of human infection, with almost half of the total number of human cases(766 of 1,567) being reported in the fifth wave, raising concerns that even more human infections could occur in the sixth wave. In September 2017, an H5/H7 bivalent inactivated vaccine for chickens was introduced, and the H7 N9 virus isolation rate in poultry dropped by 93.3% after vaccination. More importantly,only three H7 N9 human cases were reported between October 1, 2017 and September 30, 2018, indicating that vaccination of poultry successfully eliminated human infection with H7 N9 virus. These facts emphasize that active control of animal disease is extremely important for zoonosis control and human health protection.展开更多
Identification of host factors that play a key role in viral replication is of great importance for antiviral development.Metabotropic glutamate receptor subtype 2(mGluR2)is the receptor to trigger clathrin-mediated e...Identification of host factors that play a key role in viral replication is of great importance for antiviral development.Metabotropic glutamate receptor subtype 2(mGluR2)is the receptor to trigger clathrin-mediated endocytosis(CME),the major pathway by which influenza virus enters cells.However,other host factors almost certainly involved in the influenza virus CME are largely unknown.Here,we found that the four-transmembrane protein claudin-11 plays an integral part in influenza virus CME.Claudin-11 promotes the dissociation of KCa1.1(potassium calcium-activated channel subfamily M alpha 1)from mGluR2 and,together with mGluR2,is internalized in viruscontaining clathrin-coated pits(CCPs),where it regulates the depolymerization of polymerized F-actin,allowing the CCPs to mature.Importantly,over 60%of claudin-11-silenced mice survived infection with a lethal influenza virus.Our findings advance the understanding of influenza virus infection and provide a promising strategy for the development of host-based antiviral drugs.展开更多
As a major component of the viral ribonucleoprotein(vRNP)complex in influenza A virus(IAV),nucleoprotein(NP)interacts with isoforms of importinαfamily members,leading to the import of itself and vRNP complex into the...As a major component of the viral ribonucleoprotein(vRNP)complex in influenza A virus(IAV),nucleoprotein(NP)interacts with isoforms of importinαfamily members,leading to the import of itself and vRNP complex into the nucleus,a process pivotal in the replication cycle of IAV.In this study,we found that BinCARD1,an isoform of Bcl10-interacting protein with CARD(BinCARD),was leveraged by IAV for efficient viral replication.BinCARD1 promoted the nuclear import of the vRNP complex and newly synthesized NP and thus enhanced vRNP complex activity.Moreover,we found that BinCARD1 interacted with NP to promote NP binding to importinα7,an adaptor in the host nuclear import pathway.However,we also found that BinCARD1 promoted RIG-I-mediated innate immune signaling by mediating Lys63-linked polyubiquitination of TRAF3,and that TBK1 appeared to degrade BinCARD1.We showed that BinCARD1 was polyubiquitinated at residue K103 through a Lys63 linkage,which was recognized by the TBK1-p62 axis for autophagic degradation.Overall,our data demonstrate that IAV leverages BinCARD1 as an important host factor that promotes viral replication,and two mechanisms in the host defense system are triggered—innate immune signaling and autophagic degradation—to mitigate the promoting effect of BinCARD1 on the life cycle of IAV.展开更多
Animal influenza viruses continue to pose a threat to human public health. The Eurasian avian-like H1N1(EA H1N1) viruses are widespread in pigs throughout Europe and China and have caused human infections in several c...Animal influenza viruses continue to pose a threat to human public health. The Eurasian avian-like H1N1(EA H1N1) viruses are widespread in pigs throughout Europe and China and have caused human infections in several countries, indicating their pandemic potential. To carefully monitor the evolution of the EA H1N1 viruses in nature, we collected nasal swabs from 103,110pigs in 22 provinces in China between October 2013 and December 2019, and isolated 855 EA H1N1 viruses. Genomic analysis of 319 representative viruses revealed that these EA H1N1 viruses formed eight different genotypes through reassortment with viruses of other lineages circulating in humans and pigs, and two of these genotypes(G4 and G5) were widely distributed in pigs.Animal studies indicated that some strains have become highly pathogenic in mice and highly transmissible in ferrets via respiratory droplets. Moreover, two-thirds of the EA H1N1 viruses reacted poorly with ferret serum antibodies induced by the currently used H1N1 human influenza vaccine, suggesting that existing immunity may not prevent the transmission of the EA H1N1 viruses in humans. Our study reveals the evolution and pandemic potential of EA H1N1 viruses and provides important insights for future pandemic preparedness.展开更多
The generation and application of replication-competent influenza A virus （IAV） expressing a reporter gene represent a valuable tool to elucidate the mechanism of viral pathogenesis and establish new coun- termeasur...The generation and application of replication-competent influenza A virus （IAV） expressing a reporter gene represent a valuable tool to elucidate the mechanism of viral pathogenesis and establish new coun- termeasures to combat the threat of influenza. Here, replication-competent 1AVs with a neuraminidase （NA） segment harboring a fluorescent reporter protein, Venus, were generated in the background of H5N1, H7N9, and H9N2 influenza viruses, the three subtypes of viruses with imminent pandemic poten- tial. All three reporter viruses maintained virion morphology, replicated with similar or slightly reduced titers relative to their parental viruses, and stably expressed the fluorescent signal for at least two pas- sages in embryonated chicken eggs. As a proof of concept, we demonstrated that these reporter viruses, used in combination with a high-content imaging system, can serve as a convenient and rapid tool for the screening of antivirals and host factors involved in the virus life cycle. Moreover. the reporter viruses demonstrated similar growth properties and tissue tropism as their parental viruses in mice, among which the HTN9 NA-Venus virus could potentially be used in ex vivo studies to better understand H7N9 pathogenesis or to develop novel therapeutics.展开更多
The zona pellucida domain protein Dusky(Dy)plays a vital role in wing morphogenesis in insects,but little information on its function has been reported.In this study,we found that dy regulated wing cell size,larval an...The zona pellucida domain protein Dusky(Dy)plays a vital role in wing morphogenesis in insects,but little information on its function has been reported.In this study,we found that dy regulated wing cell size,larval and pupal duration,and the metabolism of amino acid and 20-hydroxyecdysone in Tribolium castaneum.Using RNA-seq,413 differentially expressed genes were identified between physiological buffer-injected and dy-double-stranded RNA-treated larvae,including 88 downregulated genes and 325 upregulated genes.Among these genes,dy knockdown increased CYP18A1 expression to elevate the 26-hydroxylation of 20-hydroxyecdysone,which ultimately led to growth defects in wing cells.Silencing of dy upregulated the transcription of genes encoding tyrosine aminotransferase,4-hydroxyphenylpyruvate dioxygenase,homogentisate 1,2-dioxygenase,and Pale to promote the catabolism of tyrosine and phenylalanine,which eventually reduced amino acid content.Furthermore,dy knockdown upregulated 4E-BP expression,and 4E-BP silencing partially phenocopied dy RNA interference-mediated wing morphogenesis.These results suggest that Dy controls 20-hydroxyecdysone and amino acid metabolism to regulate wing morphogenesis in the insect.展开更多
Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma.However,its clinical applications have been hindered due to low efficacy and bioavailability,and particularly frequent emergence of reactive...Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma.However,its clinical applications have been hindered due to low efficacy and bioavailability,and particularly frequent emergence of reactive oxygen species(ROS)-decrease induced drug resistance.The transcription factor NF-E2-related factor 2(Nrf2)is increased in cancer patients and induces poor outcome in osteosarcoma treatment,making it a novel target to improve the efficacy of chemotherapy.Herein,a hyaluronidase-responsive multi-layer liposome(HLCN)for co-delivery of cisplatin and Nrf2 siRNA(siNrf2)is developed.It is composed of Vpr52-96 modified liposome covered with hyaluronic acid(HA).HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44,and can be degraded by endosomal hyaluronidase to generate cationic liposome,which promotes the endosomal escape of Vpr52-96,cisplatin and siNrf2.HLCN can effectively decrease Nrf2 level,promote ROS generation,activate itochondrial apoptotic pathway,and consequently enhance anticancer efficacy of cisplatin.Particularly,HLCN shows high cytotoxicity to osteosarcoma cells with an IC50 value of about 1µM,which is four-fold lower than liposomal cisplatin(IC504µM),indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells.Importantly,HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects.Therefore,this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma.展开更多
基金supported by funding from the National Natural Science Foundation of China(U23A20243 and 32272972 to QZ,32172820 to SX)the Major Science and Technology Project of Gansu Province(22ZD6NA001 to SX)+1 种基金the Youth Innovation Program(Y2023QC30)the Agricultural Science and Technology Innovation Program(CAAS-ASTIP-JBGS-20210102 to SX)of the Chinese Academy of Agricultural Sciences.
文摘Influenza A viruses(IAVs)are single-stranded negative-sense RNA viruses that continually challenge animal and human health.In IAV-infected cells,host RNA-binding proteins play key roles in the life cycle of IAV by directly binding to viral RNA.Here,we examined the role of the host RNA-binding protein nucleophosmin-1(NPM1)in IAV replication.We found that,as a nucleolar phosphoprotein,NPM1 directly binds to viral RNA(vRNA)and inhibits the replication of various subtypes of IAV.NPM1 binding to vRNA competitively reduces the assembly of the viral ribonucleoprotein complex and the viral polymerase activity,thereby reducing the generation of progeny viral RNA and virions.The RNA-binding activity of NPM1,with the key residues T199,T219,T234,and T237,is essential for its anti-influenza function.Taken together,our findings demonstrate that NPM1 acts as an RNA-binding protein and interacts with IAV vRNA to suppress viral replication.
基金supported by the Fundamental Research Funds for the Central Universities under Grant No.2024BRB010。
文摘CuInSe_(2) is an N-type diamond-like semiconductors thermoelectric candidate for power generation at medium temperature with its environmentally friendly and cost-effective properties.However,the intrinsic high thermal conductivity of CuInSe_(2) limits the enhancement of its thermoelectric performance.Herein,we investigate the thermoelectric performance of N-type CuInSe_(2) materials by incorporating ZnSe through a solid solution strategy.A series of(CuInSe_(2))_(1-x)(ZnSe)_(x)(x=0.0,0.2,0.4,0.6,0.8,1.0)samples were synthesized,forming continuous solid solutions,while introducing minor porosity.ZnSe solid solution effectively reduces the lattice thermal conductivity of the CuInSe_(2) matrix at near-room temperatures,but has a weaker effect at higher temperatures.Due to the intrinsic low carrier concentration of the system,resulting in high resistivity,the maximum figure of merit(ZT)of(CuInSe_(2))0.8(ZnSe)0.2 reaches 0.08 at 773 K.Despite the relatively low ZT,the solid solution strategy proves effective in reducing the lattice thermal conductivity near-room temperature and offers potential for cost-effective thermoelectric materials.
基金funded by National Natural Science Foundation of China(grant 82030071 and 82272495)Natural Science Foundation of Hunan Province(grant 2020JJ5930 and 2020JJ4874)the Science and Technology Major Project of Changsha(No.kh2103008).
文摘Cellular senescence assumes pivotal roles in various diseases through the secretion of proinflammatory factors.Despite extensive investigations into vascular senescence associated with aging and degenerative diseases,the molecular mechanisms governing microvascular endothelial cell senescence induced by traumatic stress,particularly its involvement in senescence-induced inflammation,remain insufficiently elucidated.In this study,we present a comprehensive demonstration and characterization of microvascular endothelial cell senescence induced by spinal cord injury(SCI).Lysine demethylase 6A(Kdm6a),commonly known as UTX,emerges as a crucial regulator of cell senescence in injured spinal cord microvascular endothelial cells(SCMECs).Upregulation of UTX induces senescence in SCMECs,leading to an amplified release of proinflammatory factors,specifically the senescenceassociated secretory phenotype(SASP)components,thereby modulating the inflammatory microenvironment.Conversely,the deletion of UTX in endothelial cells shields SCMECs against senescence,mitigates the release of proinflammatory SASP factors,and promotes neurological functional recovery after SCI.UTX forms an epigenetic regulatory axis by binding to calponin 1(CNN1),orchestrating trauma-induced SCMECs senescence and SASP secretion,thereby influencing neuroinflammation and neurological functional repair.Furthermore,local delivery of a senolytic drug reduces senescent SCMECs and suppresses proinflammatory SASP secretion,reinstating a local regenerative microenvironment and enhancing functional repair after SCI.In conclusion,targeting the UTX-CNN1 epigenetic axis to prevent trauma-induced SCMECs senescence holds the potential to inhibit SASP secretion,alleviate neuroinflammation,and provide a novel treatment strategy for SCI repair.
基金by the National Natural Science Foundation of China(82030071,81874004,and 81672174)the Key R&D Program of the Hunan Provincial Science&Technology Department(2017SK2061)+1 种基金Hunan Provincial Department of Finance[(2018)2]by the Fundamental Research Funds for the Central Universities of Central South University(2018zzts254).
文摘Effective methods for visualizing neurovascular morphology are essential for understanding the normal spinal cord and the morphological alterations associated with diseases.However,ideal techniques for simultaneously imaging neurovascular structure in a broad region of a specimen are still lacking.In this study,we combined Golgi staining with angiography and synchrotron radiation micro-computed tomography(SRμCT)to visualize the 3D neurovascular network in the mouse spinal cord.Using our method,the 3D neurons,nerve fibers,and vasculature in a broad region could be visualized in the same image at cellular resolution without destructive sectioning.Besides,we found that the 3D morphology of neurons,nerve fiber tracts,and vasculature visualized by SRjiCT were highly consistent with that visualized using the histological method.Moreover,the 3D neurovascular structure could be quantitatively evaluated by the combined methodology.The method shown here will be useful in fundamental neuroscience studies.
基金supported by grants from the National Natural Science Foundation of China(32170521)Jiangsu Province Higher Education Basic Science(Natural Science)Research Project(23KJD210002)。
文摘Hemocytes are pivotal in the immune response of insects against invasive pathogens.However,our knowledge of hemocyte types and their specific function in Tribolium castaneum,an increasingly important Coleoptera model insect in various research fields,remains limited.Presently,a combination of morphological criteria and dye-staining properties were used to characterize hemocyte types from T.castaneum larvae,and 4 distinct types were identified:granulocytes,oenocytoids,plasmatocytes and prohemocytes.Following different immune challenges,the total hemocyte counts declined rapidly in the initial phase(at 2 h),then increased over time(at 4 and 6 h)and eventually returned to the naive state by 24 h post-injection.Notably,the morphology of granulocytes underwent dramatic changes,characterized by an expansion of the surface area and an increased production of pseudopods,and with the number of granulocytes rising significantly through mitotic division.Granulocytes and plasmatocytes,the main hemocyte types in T.castaneum larvae,can phagocytose bacteria or latex beads injected into the larval hemolymph in vivo.Furthermore,these hemocytes participate in the encapsulation and melanization processes in vitro,forming capsules to encapsulate and melanize nickel-nitrilotriacetic acid(Ni-NTA)beads.This study provides the first comprehensive characterization of circulating hemocytes in T.castaneum larvae,offering valuable insights into cell-mediated immunity in response to bacterial infection and the injection of latex beads.These results deepen our understanding of the cellular response mechanisms in T.castaneum larvae and lay a solid foundation for subsequent investigations of the involvement of T.castaneum hemocytes in combating pathogens.
基金supported by the National Key Research and DevelopmentProgram of China(2021YFD1800203 and 2021YFD1800204)the National Natural Science Foundation of China(NSFC)(32192453,32272979,and 32172847)+2 种基金the China PostdoctoralScience Foundation(2019M660897)the Innovation Program ofChinese Academy of Agricultural Sciences(CAAS-CSLPDCP-202401)the Earmarked Fund for China Agriculture Re-search System(CARS-41-G12)。
文摘The global dissemination of H5 avian influenza viruses represents a significant threat to both human and animal health.In thisstudy,we conducted a genome-wide siRNA library screening against the highly pathogenic H5N1 influenza virus,leading us tothe identification of 457 cellular cofactors(441 proviral factors and 16 antiviral factors)involved in the virus replication cycle.Gene Ontology term enrichment analysis revealed that the candidate gene data sets were enriched in gene categoriesassociated with mRNA splicing via spliceosome in the biological process,integral component of membrane in the cellularcomponent,and protein binding in the molecular function.Reactome pathway analysis showed that the immune system(up to63 genes)was the highest enriched pathway.Subsequent comparisons with four previous siRNA library screenings revealedthat the overlapping rates of the involved pathways were 8.53%-62.61%,which were significantly higher than those of thecommon genes(1.85%-6.24%).Together,our genome-wide siRNA library screening unveiled a panorama of host cellularnetworks engaged in the regulation of highly pathogenic H5N1 influenza virus replication,which may provide potential targetsand strategies for developing novel antiviral countermeasures.
基金supported by the National Natural Science Foundation of China(Grant No.92163211 and 52002137)the Fundamental Research Funds for the Central Universities(Grant No.2021XXJS008).
文摘With the development of 5G technology and increasing chip integration,traditional active cooling methods struggle to meet the growing thermal demands of chips.Thermoelectric coolers(TECs)have garnered great attention due to their rapid response,significant cooling differentials,strong compatibility,high stability and controllable device dimensions.In this review,starting from the fundamental principles of thermoelectric cooling and device design,high-performance thermoelectric cooling materials are summarized,and the progress of advanced on-chip TECs is comprehensively reviewed.Finally,the paper outlines the challenges and opportunities in TEC design,performance and applications,laying great emphasis on the critical role of thermoelectric cooling in addressing the evolving thermal management requirements in the era of emerging chip technologies.
基金supported by the National Natural Science Foundation of China(32192453,32172847)the National Key Research and Development Program of China(2021YFD1800204)+1 种基金the Laboratory of Lingnan Modern Agriculture Project(NT2021007)the earmarked fund for CARS-41。
文摘Influenza A virus(IAV) commandeers numerous host cellular factors for successful replication. However, very few host factors have been revealed to be involved in the fusion of viral envelope and late endosomal membranes. In this study, we identified cation-dependent mannose-6-phosphate receptor(M6PR) as a crucial host factor for the replication of IAV. We found that siRNA knockdown of M6PR expression significantly reduced the growth titers of different subtypes of IAV, and that the inhibitory effect of M6PR siRNA treatment on IAV growth was overcome by the complement of exogenously expressed M6PR. When A549 cells were treated with siRNA targeting M6PR,the nuclear accumulation of viral nucleoprotein(NP) was dramatically inhibited at early timepoints post-infection, indicating that M6PR engages in the early stage of the IAV replication cycle. By investigating the role of M6PR in the individual entry and post-entry steps of IAV replication, we found that the downregulation of M6PR expression had no effect on attachment, internalization, early endosome trafficking,or late endosome acidification. However, we found that M6PR expression was critical for the fusion of viral envelope and late endosomal membranes. Of note, M6PR interacted with the hemagglutinin(HA) protein of IAV, and further studies showed that the lumenal domain of M6PR and the ectodomain of HA2 mediated the interaction and directly promoted the fusion of the viral and late endosomal membranes,thereby facilitating IAV replication. Together, our findings highlight the importance of the M6PR–HA interaction in the fusion of viral and late endosomal membranes during IAV replication.
基金supported by the National Natural Science Foundation of China (Nos.22036002,21906035 and 91643204)the National Key Research&Development Program of China(No.2016YFA0203103)the introduced innovative R&D team project under the“The Pearl River Talent Recruitment Program”of Guangdong Province (No.2019ZT08L387)
文摘Inflammation is a major adverse outcome induced by inhaled particulate matter with a diameter of≤2.5μm(PM_(2.5)),and a critical trigger ofmost PM_(2.5) exposure-associated diseases.However,the key molecular events regulating the PM_(2.5)-induced airway inflammation are yet to be elucidated.Considering the critical role of circular RNAs(circRNAs)in regulating inflammation,we predicted 11 circRNAs that may be involved in the PM_(2.5)-induced airway inflammation using three previously reportedmiRNAs through the starBasewebsite.A novel circRNA circ_0008553 was identified to be responsible for the PM_(2.5)-activated inflammatory response in human bronchial epithelial cells(16HBE)via inducing oxidative stress.Using a combinatorial model PM_(2.5) library,we found that the synergistic effect of the insoluble core and loaded Zn^(2+)ions at environmentally relevant concentrations was the major contributor to the upregulation of circ_0008553 and subsequent induction of oxidative stress and inflammation in response to PM2.5 exposures.Our findings provided new insight into the intervention of PM_(2.5)-induced adverse outcomes.
文摘Colleges and universities are the educational institutions of training young students. The reform of the modem higher education system requires the personnel training in colleges and universities to lay a stress on the diversified development, so that the traditional single professional course education can be changed. Mental health has a close tie with the personal development trend of each student in colleges and universities, and also developing mental health education is one of the most important parts in higher education. For a long time, colleges and universities always adhere to the personnel-based educational idea and attach high importance to the work of professional course education, but fail to provide enough importance for guiding the detailed mental health of students. Thus, the mental health education in colleges and universities is misunderstood in many aspects, and this is studied in this paper.
基金supported by the National Natural Science Foundation of China(22006025,22276042,and 22106025)the Guangdong Basic and Applied Basic Research Foundation(202201010541 and 2023A1515012978)the introduced innovative R&D team project under the“The Pearl River Talent Recruitment Program”of Guangdong Province(2019ZT08L387).
文摘Arsenic(As)is a naturally occurring chemical element widely distributed in the Earth's crust.Human activities have significantly altered As presence in the environment,posing significant threats to the biota as well as human health.The environmental fates and adverse outcomes of As of various species have been extensively studied in the past few decades.It is imperative to summarize these advances as a whole to provide more profound insights into the As cycle for sustainable development.Embracing the One Health concept,we systematically reviewed previous studies in this work and explored the following three fundamental questions,i.e.,what the trends and associated changes are in As contamination,how living organisms interact and cope with As contamination,and most importantly what to do to achieve a sustainable future with As.By focusing on one critical question in each section,this review aims to provide a full picture of the complexity of environmental As.To tackle the significant research challenges and gaps in As pollution and mitigation,we further proposed a One Health framework with potential coping strategies,guiding a coordinated agenda on dealing with legacy As in the environment and ensuring a sustainable As future.
基金supported by the National Natural Science Foundation of China,Nos.82030071(to JH),82272495(to YC)Science and Technology Major Project of Changsha,No.kh2103008(to JH)Graduate Students’Independent Innovative Projects of Hunan Province,No.CX20230311(to YJ)。
文摘Spinal cord injury typically causes corticospinal tract disruption.Although the disrupted corticospinal tract can self-regenerate to a certain degree,the underlying mechanism of this process is still unclear.N6-methyladenosine(m^(6)A)modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes.However,whether m^(6)A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown.We found that expression of methyltransferase 14 protein(METTL14)in the locomotor cortex was high after spinal cord injury and accompanied by elevated m^(6)A levels.Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury.Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction,we found that METTL14 regulated Trib2 expression in an m^(6)A-regulated manner,thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration.Finally,we administered syringin,a stabilizer of METTL14,using molecular docking.Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14.Findings from this study reveal that m^(6)A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.
基金supported by the National Natural Science Foundation of China(22106025,22036002)the Introduced Innovative R&D Team Project under the“The Pearl River Talent Recruitment Program”of Guangdong Province(2019ZT08L387)+1 种基金the Basic and Applied Basic Research Foundation of Guangzhou,China(202201010541)the Guangdong Basic and Applied Basic Research Foundation(2022A1515111082).
文摘The rational design of molecules with the desired functionality presents a significant challenge in chemistry.Moreover,it is worth noting that making chemicals safe and sustainable is crucial to bringing them to the market.To address this,we propose a novel deep learning framework developed explicitly for inverse design of molecules with both functionality and biocompatibility.This innovative approach comprises two predictive models and one generative model,facilitating the targeted screening of novel molecules from created virtual chemical space.Our method’s versatility is highlighted in the inverse design process,where it successfully generates molecules with specified motifs or composition,discovers synthetically accessible molecules,and jointly targets functional and safe properties beyond the training regime.The utility of this method is demonstrated in its ability to design ionic liquids(ILs)with enhanced antibacterial properties and reduced cytotoxicity,addressing the issue of balancing functionality and biocompatibility in molecular design.
基金supported by the National Key R&D Program of China (2016YFD0500201, 2016YFD0500203)the National Natural Science Foundation of China (31521005)+1 种基金the China Agriculture Research System (CARS-41-G12)the US NIH CEIRS contract HHSN272201400004C
文摘The H7 N9 viruses that emerged in China in 2013 were nonpathogenic in chickens but mutated to a highly pathogenic form in early 2017 and caused severe disease outbreaks in chickens. The H7 N9 influenza viruses have caused five waves of human infection, with almost half of the total number of human cases(766 of 1,567) being reported in the fifth wave, raising concerns that even more human infections could occur in the sixth wave. In September 2017, an H5/H7 bivalent inactivated vaccine for chickens was introduced, and the H7 N9 virus isolation rate in poultry dropped by 93.3% after vaccination. More importantly,only three H7 N9 human cases were reported between October 1, 2017 and September 30, 2018, indicating that vaccination of poultry successfully eliminated human infection with H7 N9 virus. These facts emphasize that active control of animal disease is extremely important for zoonosis control and human health protection.
基金supported by the National Key R&D Program of China(2021YFD1800200,2021YFC2301700)the National Natural Science Foundation of China(32422087,32202773,32192451)+2 种基金the Innovation Program of Chinese Academy of Agricultural Sciences(CAASCSLPDCP-202301,CAAS-CSLPDCP-202401)the earmarked fund for CARS-41the Japan Initiative for Global Research Network on Infectious Diseases from the Japan Agency for Medical Research and Development.
文摘Identification of host factors that play a key role in viral replication is of great importance for antiviral development.Metabotropic glutamate receptor subtype 2(mGluR2)is the receptor to trigger clathrin-mediated endocytosis(CME),the major pathway by which influenza virus enters cells.However,other host factors almost certainly involved in the influenza virus CME are largely unknown.Here,we found that the four-transmembrane protein claudin-11 plays an integral part in influenza virus CME.Claudin-11 promotes the dissociation of KCa1.1(potassium calcium-activated channel subfamily M alpha 1)from mGluR2 and,together with mGluR2,is internalized in viruscontaining clathrin-coated pits(CCPs),where it regulates the depolymerization of polymerized F-actin,allowing the CCPs to mature.Importantly,over 60%of claudin-11-silenced mice survived infection with a lethal influenza virus.Our findings advance the understanding of influenza virus infection and provide a promising strategy for the development of host-based antiviral drugs.
基金This investigation was funded by a grant from the Laboratory of Lingnan Modern Agriculture Project(NT2021007 to HC and CL)the National Natural Science Foundation of China(NSFC)(32192453 to CL,32172847 to LJ)+2 种基金the National Key Research and Development Program of China(2021YFD1800203 to HC,2021YFD1800204 to CL)the Natural Science Foundation of Heilongjiang Province(JQ2019C005 to CL)the Central Public-Interest Scientific Institution Basal Research Fund(Y2017JC35 to GT).
文摘As a major component of the viral ribonucleoprotein(vRNP)complex in influenza A virus(IAV),nucleoprotein(NP)interacts with isoforms of importinαfamily members,leading to the import of itself and vRNP complex into the nucleus,a process pivotal in the replication cycle of IAV.In this study,we found that BinCARD1,an isoform of Bcl10-interacting protein with CARD(BinCARD),was leveraged by IAV for efficient viral replication.BinCARD1 promoted the nuclear import of the vRNP complex and newly synthesized NP and thus enhanced vRNP complex activity.Moreover,we found that BinCARD1 interacted with NP to promote NP binding to importinα7,an adaptor in the host nuclear import pathway.However,we also found that BinCARD1 promoted RIG-I-mediated innate immune signaling by mediating Lys63-linked polyubiquitination of TRAF3,and that TBK1 appeared to degrade BinCARD1.We showed that BinCARD1 was polyubiquitinated at residue K103 through a Lys63 linkage,which was recognized by the TBK1-p62 axis for autophagic degradation.Overall,our data demonstrate that IAV leverages BinCARD1 as an important host factor that promotes viral replication,and two mechanisms in the host defense system are triggered—innate immune signaling and autophagic degradation—to mitigate the promoting effect of BinCARD1 on the life cycle of IAV.
基金supported by the National Key Research and Development Program of China(2021YFD1800200,2021YFC2301700)。
文摘Animal influenza viruses continue to pose a threat to human public health. The Eurasian avian-like H1N1(EA H1N1) viruses are widespread in pigs throughout Europe and China and have caused human infections in several countries, indicating their pandemic potential. To carefully monitor the evolution of the EA H1N1 viruses in nature, we collected nasal swabs from 103,110pigs in 22 provinces in China between October 2013 and December 2019, and isolated 855 EA H1N1 viruses. Genomic analysis of 319 representative viruses revealed that these EA H1N1 viruses formed eight different genotypes through reassortment with viruses of other lineages circulating in humans and pigs, and two of these genotypes(G4 and G5) were widely distributed in pigs.Animal studies indicated that some strains have become highly pathogenic in mice and highly transmissible in ferrets via respiratory droplets. Moreover, two-thirds of the EA H1N1 viruses reacted poorly with ferret serum antibodies induced by the currently used H1N1 human influenza vaccine, suggesting that existing immunity may not prevent the transmission of the EA H1N1 viruses in humans. Our study reveals the evolution and pandemic potential of EA H1N1 viruses and provides important insights for future pandemic preparedness.
基金supported by the National Natural Science Foundation of China(31472215,31521005,31422054,31402206)the National Key R&D Program of China(2016YFD0500205)
文摘The generation and application of replication-competent influenza A virus （IAV） expressing a reporter gene represent a valuable tool to elucidate the mechanism of viral pathogenesis and establish new coun- termeasures to combat the threat of influenza. Here, replication-competent 1AVs with a neuraminidase （NA） segment harboring a fluorescent reporter protein, Venus, were generated in the background of H5N1, H7N9, and H9N2 influenza viruses, the three subtypes of viruses with imminent pandemic poten- tial. All three reporter viruses maintained virion morphology, replicated with similar or slightly reduced titers relative to their parental viruses, and stably expressed the fluorescent signal for at least two pas- sages in embryonated chicken eggs. As a proof of concept, we demonstrated that these reporter viruses, used in combination with a high-content imaging system, can serve as a convenient and rapid tool for the screening of antivirals and host factors involved in the virus life cycle. Moreover. the reporter viruses demonstrated similar growth properties and tissue tropism as their parental viruses in mice, among which the HTN9 NA-Venus virus could potentially be used in ex vivo studies to better understand H7N9 pathogenesis or to develop novel therapeutics.
基金supported by the National Natural Science Foundation of China(Nos.32070501 and 31601893)General Project of the Natural Science Foundation of the Jiangsu Higher Education Institu・tions(No.16KJB180004)Young Talents Training Pto・gram of Jiangsu University,and Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX19_1576).
文摘The zona pellucida domain protein Dusky(Dy)plays a vital role in wing morphogenesis in insects,but little information on its function has been reported.In this study,we found that dy regulated wing cell size,larval and pupal duration,and the metabolism of amino acid and 20-hydroxyecdysone in Tribolium castaneum.Using RNA-seq,413 differentially expressed genes were identified between physiological buffer-injected and dy-double-stranded RNA-treated larvae,including 88 downregulated genes and 325 upregulated genes.Among these genes,dy knockdown increased CYP18A1 expression to elevate the 26-hydroxylation of 20-hydroxyecdysone,which ultimately led to growth defects in wing cells.Silencing of dy upregulated the transcription of genes encoding tyrosine aminotransferase,4-hydroxyphenylpyruvate dioxygenase,homogentisate 1,2-dioxygenase,and Pale to promote the catabolism of tyrosine and phenylalanine,which eventually reduced amino acid content.Furthermore,dy knockdown upregulated 4E-BP expression,and 4E-BP silencing partially phenocopied dy RNA interference-mediated wing morphogenesis.These results suggest that Dy controls 20-hydroxyecdysone and amino acid metabolism to regulate wing morphogenesis in the insect.
基金This work was supported by the National Key Research and Development Program of China(No.2019YFA0802800)the Key Research and Development Program of Jiangsu Provincial Department of Science and Technology of China(No.BE2019002)+5 种基金the Medical Key Young Talents Programs of Jiangsu Province(No.QNRC2016915)the“The Six Top Talents”of Jiangsu Province(No.WSW-112)the Fundamental Research Funds for the Central Universities(No.021314380120)the National Key Research and Development Program of China(No.2018YFB1105400)National Natural Science Foundation of China(No.21708019)Natural Science Foundation of Jiangsu(No.BK20170987).
文摘Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma.However,its clinical applications have been hindered due to low efficacy and bioavailability,and particularly frequent emergence of reactive oxygen species(ROS)-decrease induced drug resistance.The transcription factor NF-E2-related factor 2(Nrf2)is increased in cancer patients and induces poor outcome in osteosarcoma treatment,making it a novel target to improve the efficacy of chemotherapy.Herein,a hyaluronidase-responsive multi-layer liposome(HLCN)for co-delivery of cisplatin and Nrf2 siRNA(siNrf2)is developed.It is composed of Vpr52-96 modified liposome covered with hyaluronic acid(HA).HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44,and can be degraded by endosomal hyaluronidase to generate cationic liposome,which promotes the endosomal escape of Vpr52-96,cisplatin and siNrf2.HLCN can effectively decrease Nrf2 level,promote ROS generation,activate itochondrial apoptotic pathway,and consequently enhance anticancer efficacy of cisplatin.Particularly,HLCN shows high cytotoxicity to osteosarcoma cells with an IC50 value of about 1µM,which is four-fold lower than liposomal cisplatin(IC504µM),indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells.Importantly,HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects.Therefore,this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma.
