Background:Radiotherapy(RT)is a key treatment modality in cancer therapy,utilizing high-energy radiation to directly kill tumor cells.Recent research has increasingly highlighted RT’s potential to indirectly enhance ...Background:Radiotherapy(RT)is a key treatment modality in cancer therapy,utilizing high-energy radiation to directly kill tumor cells.Recent research has increasingly highlighted RT’s potential to indirectly enhance antitumor immunity.However,this immune activation alone often fails to generate sustained systemic antitumor responses.In this study,we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7(TLR7)agonist liposomes,specifically 1V209-Cho-Lip,with RT.Methods:Mouse tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment.In vitro,primary mouse bone marrow-derived dendritic cells(BMDCs)were utilized to investigate changes in function and the activated pathways through RNA sequencing.Additionally,we explored the role of oxidized mitochondrial DNA(ox-mtDNA)released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses.The involvement of interleukin-1β(IL-1β)and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1β^(−/−)and cysteinyl aspartate specific proteinase 1 knockout(Casp1^(−/−))mouse models.Results:The combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models.This combination therapy enhanced maturation,antigen presentation and IL-1βsecretion of dendritic cells(DCs)in vitro.Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs.The antitumor effect of the combined therapy was significantly reduced in Il-1β^(−/−)and Casp1^(−/−)mice.Conclusions:This study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.展开更多
The emergence of XBB-and JN.1-lineages with remarkable immune evasion characteristics have led to rises in breakthrough infections within populations.In addition,the unfavorable impacts of immune imprinting,stemming f...The emergence of XBB-and JN.1-lineages with remarkable immune evasion characteristics have led to rises in breakthrough infections within populations.In addition,the unfavorable impacts of immune imprinting,stemming from continuous exposure to antigens from circulated viruses,have been observed to incline immune response against earlier lineages,thereby declining the neutralization to newly emerged Omicron subvariants.In response to this,the advancement of next-generation vaccines against COVID-19 targeting components from new subvariants such as XBB-lineage is imperative.In the current study,a self-assembled trimeric recombinant protein(RBDXBB.1.5-HR)was generated by concatenating the sequences of the receptor binding domain(RBD)derived from XBB.1.5 with heptad-repeat 1(HR1)and HR2 sequences from the spike S2 subunit.Adjuvanted-RBDXBB.1.5-HR induced robust humoral and cellular immune responses,characterized by elevated neutralization against JN.1-inculuded subvariants and a substantial population of antigen-specific T memory cells.Protective immunity conferred by RBDXBB.1.5-HR vaccine was preserved post-immunization,as evidenced by germinal center B(GC B)and T follicular helper(Tfh)responses,sustained neutralization potency,and an increase in memory B cells(MBCs)and long-lived plasma cells(LLPCs).The RBDXBB.1.5-HR vaccine showed a favorable boosting effect when administered heterologously after three doses of inactivated virus(IV)and mRNA vaccines.Significantly,it provided protection against live Omicron EG.5.1 viruses in vivo.The monovalent RBDXBB.1.5-HR vaccine showed favorable safety and immunogenicity,boosting neutralizing antibodies against JN.1-and XBB-lineage subvariants in individuals with prior COVID-19 vaccinations.These findings highlight its clinical potential in safeguarding against circulating Omicron subvariants.展开更多
The mucosal immune response plays a crucial role in the prevention of respiratory viruses.Given the risk of recurrent SARS-CoV-2 infections in the population,the rapid development of next-generation intranasal COVID-1...The mucosal immune response plays a crucial role in the prevention of respiratory viruses.Given the risk of recurrent SARS-CoV-2 infections in the population,the rapid development of next-generation intranasal COVID-19 vaccines with high safety and efficacy is paramount.In the current study,we developed a protein-based intranasal vaccine comprising the_(XBB.1.5)receptor binding domain(RBD)-derived trimeric recombinant protein(RBD_(XBB.1.5)-HR)and an MF59-like oil-in-water adjuvant.Intranasal administration of RBD_(XBB.1.5)-HR vaccine elicited robust and sustained humoral immune responses in mice and rats,resulting in high levels of neutralizing antibodies against XBB-lineage subvariants,with protection lasting for at least six months.The intranasal RBD_(XBB.1.5)-HR vaccine generated potent mucosal immune responses,characterized by the inductions of tissue-resident T(TRM)cells,local cellular immunity,germinal center,and memory B cell responses in the respiratory tract.The combination of intramuscular and intranasal delivery of the RBD_(XBB.1.5)-HR vaccine demonstrated exceptional systemic and mucosal protective immunity.Furthermore,intranasal delivery of RBD_(XBB.1.5)-HR vaccine as a heterologous booster shot showed more effective boosting effects after mRNA administration compared to homologous vaccination,as evidenced by the induction of superior systemic and extra mucosal immune response.Importantly,the intranasal RBD_(XBB.1.5)-HR vaccine conferred efficient protection against the challenge with authentic EG.5.1 viruses in vivo.These findings identify the intranasal RBD_(XBB.1.5)-HR vaccine as a potential mucosal vaccine candidate for the prevention of SARS-CoV-2 infection.展开更多
The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants has decreased the efficacy of SARs-CoV-2 vaccines in containing coronavirus disease 2019(CoVID-19)over time,and booster vaccination ...The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants has decreased the efficacy of SARs-CoV-2 vaccines in containing coronavirus disease 2019(CoVID-19)over time,and booster vaccination strategies are urgently necessitated to achieve sufficient protection.Intranasal immunization can improvemucosal immunity,offer-ing protection against the infection and sustaining the spread of SARS-CoV-2.In this study,an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum,nasal lavage fluid,and bronchoal-veolar lavage fluid compared with only two doses of mRNA vaccine.After intranasal boosting with the RBD-HR vaccine,the levels of serum neutralizing antibodies against prototype and variant strains of SARS-Cov-2 pseudoviruses weremarkedly higher than those in mice receiving mRNA vaccine alone,and intranasal boosting with the RBD-HR vaccine also inhibited the bind-ing of RBD to hACE2 receptors.Furthermore,the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+dendritic cells in the respiratory mucosa,and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs,including mediastinal lymph nodes,inguinal lymph nodes,and spleen.Collectively,these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locallyandsystemically.展开更多
To the Editor:Current therapeutic strategies against breast cancer are limited by poor prognosis and unwanted side effects,especially in triple-negative breast cancer(TNBC).Ginkgetin(Gk),a natural,non-toxic bioflavono...To the Editor:Current therapeutic strategies against breast cancer are limited by poor prognosis and unwanted side effects,especially in triple-negative breast cancer(TNBC).Ginkgetin(Gk),a natural,non-toxic bioflavonoid extracted from Ginkgo biloba leaves,is a promising therapeutic candidate against breast cancer,[1]but the underlying mechanisms remain obscure.展开更多
Lysosome is a ubiquitous acidic organelle fundamental for the turnover of unwanted cellular molecules,particles,and organelles.Currently,the pivotal role of lysosome in regulating cell death is drawing great attention...Lysosome is a ubiquitous acidic organelle fundamental for the turnover of unwanted cellular molecules,particles,and organelles.Currently,the pivotal role of lysosome in regulating cell death is drawing great attention.Over the past decades,we largely focused on how lysosome influences apoptosis and autophagic cell death.However,extensive studies showed that lysosome is also prerequisite for the execution of regulated necrosis(RN).Different types of RN have been uncovered,among which,necroptosis,ferroptosis,and pyroptosis are under the most intensive investigation.It becomes a hot topic nowadays to target RN as a therapeutic intervention,since it is important in many patho/physiological settings and contributing to numerous diseases.It is promising to target lysosome to control the occurrence of RN thus altering the outcomes of diseases.Therefore,we aim to give an introduction about the common factors influencing lysosomal stability and then summarize the current knowledge on the role of lysosome in the execution of RN,especially in that of necroptosis,ferroptosis,and pyroptosis.展开更多
Head and neck cancer(HNC)is malignant,genetically complex and difficult to treat and is the sixth most frequent cancer,with tobacco,alcohol and human papillomavirus being major risk factors.Based on epigenetic data,HN...Head and neck cancer(HNC)is malignant,genetically complex and difficult to treat and is the sixth most frequent cancer,with tobacco,alcohol and human papillomavirus being major risk factors.Based on epigenetic data,HNC is remarkably heterogeneous,and treatment remains challenging.There is a lack of significant improvement in survival and quality of life in patients with HNC.Over half of HNC patients experience locoregional recurrence or distal metastasis despite the current multiple traditional therapeutic strategies and immunotherapy.In addition,resistance to chemotherapy,radiotherapy and some targeted therapies is common.Therefore,it is urgent to explore more effective and tolerable targeted therapies to improve the clinical outcomes of HNC patients.Recent targeted therapy studies have focused on identifying promising biomarkers and developing more effective targeted therapies.A well understanding of the pathogenesis of HNC contributes to learning more about its inner association,which provides novel insight into the development of small molecule inhibitors.In this review,we summarized the vital signaling pathways and discussed the current potential therapeutic targets against critical molecules in HNC,as well as presenting preclinical animal models and ongoing or completed clinical studies about targeted therapy,which may contribute to a more favorable prognosis of HNC.Targeted therapy in combination with other therapies and its limitations were also discussed.展开更多
Biotherapy has recently become a hotspot research topic with encouraging prospects in various fields due to a wide range of treatments applications,as demonstrated in preclinical and clinical studies.However,the broad...Biotherapy has recently become a hotspot research topic with encouraging prospects in various fields due to a wide range of treatments applications,as demonstrated in preclinical and clinical studies.However,the broad applications of biotherapy have been limited by critical challenges,including the lack of safe and efficient de-livery systems and serious side effects.Due to the unique potentials of biomaterials,such as good biocompati-bility and bioactive properties,biomaterial-assisted biotherapy has been demonstrated to be an attractive strategy.The biomaterial-based delivery systems possess sufficient packaging capacity and versatile functions,enabling a sustained and localized release of drugs at the target sites.Furthermore,the biomaterials can provide a niche with specific extracellular conditions for the proliferation,differentiation,attachment,and migration of stem cells,leading to tissue regeneration.In this review,the state-of-the-art studies on the applications of bio-materials in biotherapy,including drug delivery,vaccine development,gene therapy,and stem cell therapy,have been summarized.The challenges and an outlook of biomaterial-assisted biotherapies have also been discussed.展开更多
The COVID-19 response strategies in Chinese mainland were recently adjusted due to the reduced pathogenicity and enhanced infectivity of Omicron subvariants.In Chengdu,China,an infection wave was predominantly induced...The COVID-19 response strategies in Chinese mainland were recently adjusted due to the reduced pathogenicity and enhanced infectivity of Omicron subvariants.In Chengdu,China,an infection wave was predominantly induced by the BA.5 subvariant.It is crucial to determine whether the hybrid anti-SARS-CoV-2 immunity following BA.5 infection.展开更多
The outbreak of coronavirus disease 2019(COVID-19)has posed great threats to global health and economy.Several effective vaccines are available now,but additional booster immunization is required to retain or increase...The outbreak of coronavirus disease 2019(COVID-19)has posed great threats to global health and economy.Several effective vaccines are available now,but additional booster immunization is required to retain or increase the immune responses owing to waning immunity and the emergency of new variant strains.The deficiency of intramuscularly delivered vaccines to induce mucosal immunity urged the development of mucosal vaccines.Here,we developed an adjuvanted intranasal RBD vaccine and monitored its long-term immunogenicity against both wild-type and mutant strains of severe acute respiratory syndrome coronavirus-2(SARSCoV-2),including Omicron variants,in mice.Three-dose intranasal immunization with this vaccine induced and maintained high levels of neutralizing IgG antibodies in the sera for at least 1 year.Strong mucosal immunity was also provoked,including mucosal secretory IgA and lung-resident memory T cells(TRM).We also demonstrated that the long-term persistence of lung TRM cells is a consequence of local T-cell proliferation,rather than T-cell migration from lymph nodes.Our data suggested that the adjuvanted intranasal RBD vaccine is a promising vaccine candidate to establish robust,long-lasting,and broad protective immunity against SARS-CoV-2 both systemically and locally.展开更多
Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expec...Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.展开更多
Dear Editor,The worldwide outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has urged the investigation of preventive vaccines.Recently,our team has developed a recombinant protein vacci...Dear Editor,The worldwide outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has urged the investigation of preventive vaccines.Recently,our team has developed a recombinant protein vaccine,targeting receptor binding domain(RBD)of the spike protein(S-RBD)of SARS-CoV-2,which could induce a potent antibody response and protect non-human primates from SARS-CoV-2 challenge.1 The recombinant RBD protein is proved as a potent antigen and a novel adjuvant is in demand for the effective stimulation of adaptive immunity.Therefore,to improve the efficacy of the vaccine and seek a novel adjuvant that can stimulate both humoral and cellular immunity,we investigated the potential of series of cationic nanocarriers as adjuvants of the recombinant S-RBD vaccine for SARS-CoV-2.As the surface charge of a nanocarrier might dramatically affect the immunogenicity of a vaccine and enhance and/or shape antigen-specific immune responses,we also used anionic nanocarriers and neutral nanocarriers as controls(Supplementary Table S1).S-RBD vaccines with adjuvant candidates were administered intranasally or intramuscularly in the present study.展开更多
Dear Editor,The worldwide outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has urged the investigation of preventive vaccines.Recently,our team has developed a recombinant protein vacci...Dear Editor,The worldwide outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has urged the investigation of preventive vaccines.Recently,our team has developed a recombinant protein vaccine,targeting receptor binding domain(RBD)of the spike protein(S-RBD)of SARS-CoV-2,which could induce a potent antibody response and protect non-human primates from SARS-CoV-2 challenge.1 The recombinant RBD protein is proved as a potent antigen and a novel adjuvant is in demand for the effective stimulation of adaptive immunity.展开更多
Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age.Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by e...Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age.Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells.Chronic inflammation contributes to a variety of age-related diseases,such as neurodegenerative disease,cancer,infectious disease,and autoimmune diseases.Although not fully understood,recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellular levels.Immunosenescence is associated with dysregulated signaling pathways(e.g.,overactivation of the NF-κB signaling pathway and downregulation of the melatonin signaling pathway)and abnormal immune cell responses with functional alterations and phenotypic shifts.These advances remarkably promote the development of countermeasures against immunosenescence for the treatment of age-related diseases.Some anti-immunosenescence treatments have already shown promising results in clinical trials.In this review,we discuss the molecular and cellular mechanisms of immunosenescence and summarize the critical role of immunosenescence in the pathogenesis of age-related diseases.Potential interventions to mitigate immunosenescence,including reshaping immune organs,targeting different immune cells or signaling pathways,and nutritional and lifestyle interventions,are summarized.Some treatment strategies have already launched into clinical trials.This study aims to provide a systematic and comprehensive introduction to the basic and clinical research progress of immunosenescence,thus accelerating research on immunosenescence in related diseases and promoting the development of targeted therapy.展开更多
基金supported by the National Science Foundation for Excellent Young Scholars(32122052)National Natural Science Foundation Regional Innovation and Development(No.U19A2003)+3 种基金National Natural Science Foundation of China(82102896)China Postdoctoral Science Foundation(2024M762248)Natural Science Foundation of Sichuan Province(2024NSFSC1883)Postdoctor Research Fund of West China Hospital,Sichuan University(2024HXBH055).
文摘Background:Radiotherapy(RT)is a key treatment modality in cancer therapy,utilizing high-energy radiation to directly kill tumor cells.Recent research has increasingly highlighted RT’s potential to indirectly enhance antitumor immunity.However,this immune activation alone often fails to generate sustained systemic antitumor responses.In this study,we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7(TLR7)agonist liposomes,specifically 1V209-Cho-Lip,with RT.Methods:Mouse tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment.In vitro,primary mouse bone marrow-derived dendritic cells(BMDCs)were utilized to investigate changes in function and the activated pathways through RNA sequencing.Additionally,we explored the role of oxidized mitochondrial DNA(ox-mtDNA)released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses.The involvement of interleukin-1β(IL-1β)and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1β^(−/−)and cysteinyl aspartate specific proteinase 1 knockout(Casp1^(−/−))mouse models.Results:The combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models.This combination therapy enhanced maturation,antigen presentation and IL-1βsecretion of dendritic cells(DCs)in vitro.Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs.The antitumor effect of the combined therapy was significantly reduced in Il-1β^(−/−)and Casp1^(−/−)mice.Conclusions:This study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.
基金supported by the National Key Research and Development Program of China(2024YFC2310700,X.W.)1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University(ZYGD23038,X.W)+3 种基金National Natural Science Foundation Regional Innovation and Development(No.U19A2003)National Natural Science Foundation of China(82200018,Jingyun Yang)China Postdoctoral Science Foundation(No.2023T160458,Jingyun Yang)National Natural Science Foundation of China Young Student Basic Research Program(323B2050,W.H).
文摘The emergence of XBB-and JN.1-lineages with remarkable immune evasion characteristics have led to rises in breakthrough infections within populations.In addition,the unfavorable impacts of immune imprinting,stemming from continuous exposure to antigens from circulated viruses,have been observed to incline immune response against earlier lineages,thereby declining the neutralization to newly emerged Omicron subvariants.In response to this,the advancement of next-generation vaccines against COVID-19 targeting components from new subvariants such as XBB-lineage is imperative.In the current study,a self-assembled trimeric recombinant protein(RBDXBB.1.5-HR)was generated by concatenating the sequences of the receptor binding domain(RBD)derived from XBB.1.5 with heptad-repeat 1(HR1)and HR2 sequences from the spike S2 subunit.Adjuvanted-RBDXBB.1.5-HR induced robust humoral and cellular immune responses,characterized by elevated neutralization against JN.1-inculuded subvariants and a substantial population of antigen-specific T memory cells.Protective immunity conferred by RBDXBB.1.5-HR vaccine was preserved post-immunization,as evidenced by germinal center B(GC B)and T follicular helper(Tfh)responses,sustained neutralization potency,and an increase in memory B cells(MBCs)and long-lived plasma cells(LLPCs).The RBDXBB.1.5-HR vaccine showed a favorable boosting effect when administered heterologously after three doses of inactivated virus(IV)and mRNA vaccines.Significantly,it provided protection against live Omicron EG.5.1 viruses in vivo.The monovalent RBDXBB.1.5-HR vaccine showed favorable safety and immunogenicity,boosting neutralizing antibodies against JN.1-and XBB-lineage subvariants in individuals with prior COVID-19 vaccinations.These findings highlight its clinical potential in safeguarding against circulating Omicron subvariants.
基金supported by the National Science Foundation for Excellent Young Scholars(32122052,X.W.)National Natural Science Foundation Regional Innovation and Development(No.U19A2003,X.W.)+2 种基金National Natural Science Foundation of China(32300743,H.L.)the Project of the Science and Technology Department of Sichuan Province(NO.2024NSFSC1757,H.L.)National Natural Science Foundation of China Young Student Basic Research Program(323B2050,W.H.)。
文摘The mucosal immune response plays a crucial role in the prevention of respiratory viruses.Given the risk of recurrent SARS-CoV-2 infections in the population,the rapid development of next-generation intranasal COVID-19 vaccines with high safety and efficacy is paramount.In the current study,we developed a protein-based intranasal vaccine comprising the_(XBB.1.5)receptor binding domain(RBD)-derived trimeric recombinant protein(RBD_(XBB.1.5)-HR)and an MF59-like oil-in-water adjuvant.Intranasal administration of RBD_(XBB.1.5)-HR vaccine elicited robust and sustained humoral immune responses in mice and rats,resulting in high levels of neutralizing antibodies against XBB-lineage subvariants,with protection lasting for at least six months.The intranasal RBD_(XBB.1.5)-HR vaccine generated potent mucosal immune responses,characterized by the inductions of tissue-resident T(TRM)cells,local cellular immunity,germinal center,and memory B cell responses in the respiratory tract.The combination of intramuscular and intranasal delivery of the RBD_(XBB.1.5)-HR vaccine demonstrated exceptional systemic and mucosal protective immunity.Furthermore,intranasal delivery of RBD_(XBB.1.5)-HR vaccine as a heterologous booster shot showed more effective boosting effects after mRNA administration compared to homologous vaccination,as evidenced by the induction of superior systemic and extra mucosal immune response.Importantly,the intranasal RBD_(XBB.1.5)-HR vaccine conferred efficient protection against the challenge with authentic EG.5.1 viruses in vivo.These findings identify the intranasal RBD_(XBB.1.5)-HR vaccine as a potential mucosal vaccine candidate for the prevention of SARS-CoV-2 infection.
基金funded by the National Science Foundation for Excellent Young Scholars of China(No.32122052)the National Natural Science Foundation Regional Innovation and Development of China(No.U19A2003).
文摘The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants has decreased the efficacy of SARs-CoV-2 vaccines in containing coronavirus disease 2019(CoVID-19)over time,and booster vaccination strategies are urgently necessitated to achieve sufficient protection.Intranasal immunization can improvemucosal immunity,offer-ing protection against the infection and sustaining the spread of SARS-CoV-2.In this study,an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum,nasal lavage fluid,and bronchoal-veolar lavage fluid compared with only two doses of mRNA vaccine.After intranasal boosting with the RBD-HR vaccine,the levels of serum neutralizing antibodies against prototype and variant strains of SARS-Cov-2 pseudoviruses weremarkedly higher than those in mice receiving mRNA vaccine alone,and intranasal boosting with the RBD-HR vaccine also inhibited the bind-ing of RBD to hACE2 receptors.Furthermore,the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+dendritic cells in the respiratory mucosa,and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs,including mediastinal lymph nodes,inguinal lymph nodes,and spleen.Collectively,these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locallyandsystemically.
基金supported by the Natural Science Foundation of Sichuan Province(No.2022NSFSC0774)the National Natural Science Foundation of China(No.82102896).
文摘To the Editor:Current therapeutic strategies against breast cancer are limited by poor prognosis and unwanted side effects,especially in triple-negative breast cancer(TNBC).Ginkgetin(Gk),a natural,non-toxic bioflavonoid extracted from Ginkgo biloba leaves,is a promising therapeutic candidate against breast cancer,[1]but the underlying mechanisms remain obscure.
基金supported by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09733001,China)the Development Program of China(No.2016YFA0201402)the Excellent Youth Foundation of Sichuan Scientific Committee Grant in China(No.2019JDJQ008)
文摘Lysosome is a ubiquitous acidic organelle fundamental for the turnover of unwanted cellular molecules,particles,and organelles.Currently,the pivotal role of lysosome in regulating cell death is drawing great attention.Over the past decades,we largely focused on how lysosome influences apoptosis and autophagic cell death.However,extensive studies showed that lysosome is also prerequisite for the execution of regulated necrosis(RN).Different types of RN have been uncovered,among which,necroptosis,ferroptosis,and pyroptosis are under the most intensive investigation.It becomes a hot topic nowadays to target RN as a therapeutic intervention,since it is important in many patho/physiological settings and contributing to numerous diseases.It is promising to target lysosome to control the occurrence of RN thus altering the outcomes of diseases.Therefore,we aim to give an introduction about the common factors influencing lysosomal stability and then summarize the current knowledge on the role of lysosome in the execution of RN,especially in that of necroptosis,ferroptosis,and pyroptosis.
基金The figures in the article were created by Biorender.
文摘Head and neck cancer(HNC)is malignant,genetically complex and difficult to treat and is the sixth most frequent cancer,with tobacco,alcohol and human papillomavirus being major risk factors.Based on epigenetic data,HNC is remarkably heterogeneous,and treatment remains challenging.There is a lack of significant improvement in survival and quality of life in patients with HNC.Over half of HNC patients experience locoregional recurrence or distal metastasis despite the current multiple traditional therapeutic strategies and immunotherapy.In addition,resistance to chemotherapy,radiotherapy and some targeted therapies is common.Therefore,it is urgent to explore more effective and tolerable targeted therapies to improve the clinical outcomes of HNC patients.Recent targeted therapy studies have focused on identifying promising biomarkers and developing more effective targeted therapies.A well understanding of the pathogenesis of HNC contributes to learning more about its inner association,which provides novel insight into the development of small molecule inhibitors.In this review,we summarized the vital signaling pathways and discussed the current potential therapeutic targets against critical molecules in HNC,as well as presenting preclinical animal models and ongoing or completed clinical studies about targeted therapy,which may contribute to a more favorable prognosis of HNC.Targeted therapy in combination with other therapies and its limitations were also discussed.
基金This work was supported by the Natural Science Foundation of China(32122052,U19A2003,82121003)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2020YFS0570,2020JDTD0028,2019YFS0514)+1 种基金the Science and Technology Project of Chengdu(2019-YF05-00784-SN)the Na-tional Key Research and Development Program of China(2020YFC2005500).
文摘Biotherapy has recently become a hotspot research topic with encouraging prospects in various fields due to a wide range of treatments applications,as demonstrated in preclinical and clinical studies.However,the broad applications of biotherapy have been limited by critical challenges,including the lack of safe and efficient de-livery systems and serious side effects.Due to the unique potentials of biomaterials,such as good biocompati-bility and bioactive properties,biomaterial-assisted biotherapy has been demonstrated to be an attractive strategy.The biomaterial-based delivery systems possess sufficient packaging capacity and versatile functions,enabling a sustained and localized release of drugs at the target sites.Furthermore,the biomaterials can provide a niche with specific extracellular conditions for the proliferation,differentiation,attachment,and migration of stem cells,leading to tissue regeneration.In this review,the state-of-the-art studies on the applications of bio-materials in biotherapy,including drug delivery,vaccine development,gene therapy,and stem cell therapy,have been summarized.The challenges and an outlook of biomaterial-assisted biotherapies have also been discussed.
基金This work was supported by the National Science Foundation for Excellent Young Scholars(32122052)National Natural Science Foundation Regional Innovation and Development(No.U19A2003)National Natural Science Foundation of China(82200018).Figure 1a was created by BioRender.
文摘The COVID-19 response strategies in Chinese mainland were recently adjusted due to the reduced pathogenicity and enhanced infectivity of Omicron subvariants.In Chengdu,China,an infection wave was predominantly induced by the BA.5 subvariant.It is crucial to determine whether the hybrid anti-SARS-CoV-2 immunity following BA.5 infection.
基金supported by the National Natural Science Foundation Regional Innovation and Development(No.U19A2003)the National Science Fund for Excellent Young Scholars National Science Fund for Excellent Young Scholars(No.32122052).
文摘The outbreak of coronavirus disease 2019(COVID-19)has posed great threats to global health and economy.Several effective vaccines are available now,but additional booster immunization is required to retain or increase the immune responses owing to waning immunity and the emergency of new variant strains.The deficiency of intramuscularly delivered vaccines to induce mucosal immunity urged the development of mucosal vaccines.Here,we developed an adjuvanted intranasal RBD vaccine and monitored its long-term immunogenicity against both wild-type and mutant strains of severe acute respiratory syndrome coronavirus-2(SARSCoV-2),including Omicron variants,in mice.Three-dose intranasal immunization with this vaccine induced and maintained high levels of neutralizing IgG antibodies in the sera for at least 1 year.Strong mucosal immunity was also provoked,including mucosal secretory IgA and lung-resident memory T cells(TRM).We also demonstrated that the long-term persistence of lung TRM cells is a consequence of local T-cell proliferation,rather than T-cell migration from lymph nodes.Our data suggested that the adjuvanted intranasal RBD vaccine is a promising vaccine candidate to establish robust,long-lasting,and broad protective immunity against SARS-CoV-2 both systemically and locally.
基金supported by the National Science Foundation for Excellent Young Scholars (32122052)National Natural Science Foundation Regional Innovation and Development (No.U19A2003).
文摘Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.
基金supported by the National Key Research and Development Program of China(No.2016YFA0201402)National Natural Science Foundation Regional Innovation and Development(U19A2003)The National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09733001).
文摘Dear Editor,The worldwide outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has urged the investigation of preventive vaccines.Recently,our team has developed a recombinant protein vaccine,targeting receptor binding domain(RBD)of the spike protein(S-RBD)of SARS-CoV-2,which could induce a potent antibody response and protect non-human primates from SARS-CoV-2 challenge.1 The recombinant RBD protein is proved as a potent antigen and a novel adjuvant is in demand for the effective stimulation of adaptive immunity.Therefore,to improve the efficacy of the vaccine and seek a novel adjuvant that can stimulate both humoral and cellular immunity,we investigated the potential of series of cationic nanocarriers as adjuvants of the recombinant S-RBD vaccine for SARS-CoV-2.As the surface charge of a nanocarrier might dramatically affect the immunogenicity of a vaccine and enhance and/or shape antigen-specific immune responses,we also used anionic nanocarriers and neutral nanocarriers as controls(Supplementary Table S1).S-RBD vaccines with adjuvant candidates were administered intranasally or intramuscularly in the present study.
基金This work was supported by the National Key Research and Development Program of China(No.2016YFA0201402)National Natural Science Foundation Regional Innovation and Development(U19A2003)The National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09733001).
文摘Dear Editor,The worldwide outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has urged the investigation of preventive vaccines.Recently,our team has developed a recombinant protein vaccine,targeting receptor binding domain(RBD)of the spike protein(S-RBD)of SARS-CoV-2,which could induce a potent antibody response and protect non-human primates from SARS-CoV-2 challenge.1 The recombinant RBD protein is proved as a potent antigen and a novel adjuvant is in demand for the effective stimulation of adaptive immunity.
基金supported by the National Key R&D Program of China(2020YFA0710700,X.L.Y.)the National Science and Technology Major Projects of New Drugs(2018ZX09201018-013,P.C.)+1 种基金the National Key Research and Development Program of China(No.2023YFC3403303,P.C.)the National Natural Science Foundation of China Young Student Basic Research Program(823B2065,A.A.)。
文摘Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age.Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells.Chronic inflammation contributes to a variety of age-related diseases,such as neurodegenerative disease,cancer,infectious disease,and autoimmune diseases.Although not fully understood,recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellular levels.Immunosenescence is associated with dysregulated signaling pathways(e.g.,overactivation of the NF-κB signaling pathway and downregulation of the melatonin signaling pathway)and abnormal immune cell responses with functional alterations and phenotypic shifts.These advances remarkably promote the development of countermeasures against immunosenescence for the treatment of age-related diseases.Some anti-immunosenescence treatments have already shown promising results in clinical trials.In this review,we discuss the molecular and cellular mechanisms of immunosenescence and summarize the critical role of immunosenescence in the pathogenesis of age-related diseases.Potential interventions to mitigate immunosenescence,including reshaping immune organs,targeting different immune cells or signaling pathways,and nutritional and lifestyle interventions,are summarized.Some treatment strategies have already launched into clinical trials.This study aims to provide a systematic and comprehensive introduction to the basic and clinical research progress of immunosenescence,thus accelerating research on immunosenescence in related diseases and promoting the development of targeted therapy.
