Particle size and surface properties are crucial for lymphatic drainage(LN),dendritic cell(DC)uptake,DC maturation,and antigen cross-presentation induced by nanovaccine injection,which lead to an effective cell-mediat...Particle size and surface properties are crucial for lymphatic drainage(LN),dendritic cell(DC)uptake,DC maturation,and antigen cross-presentation induced by nanovaccine injection,which lead to an effective cell-mediated immune response.However,the manner in which the particle size and surface properties of vaccine carriers such as mesoporous silica nanoparticles(MSNs)affect this immune response is unknown.We prepared 50,100,and 200 nm of MSNs that adsorbed ovalbumin antigen(OVA)while modifyingβ-glucan to enhance immunogenicity.The results revealed that these MSNs with different particle sizes were just as efficient in vitro,and MSNs withβ-glucan modification demonstrated higher efficacy.However,the in vivo results indicated that MSNs with smaller particle sizes have stronger lymphatic targeting efficiency and a greater ability to promote the maturation of DCs.The results also indicate thatβ-glucan-modified MSN,with a particle size of∼100 nm,has a great potential as a vaccine delivery vehicle and immune adjuvant and offers a novel approach for the delivery of multiple therapeutic agents that target other lymph-mediated diseases.展开更多
Hypothyroid heart disease is a syndrome that has a deficiency origin and an excess superficiality. Deficiency in origin is typified by a deficiency of kidney yang primarily, and the fundamental objective of treatment ...Hypothyroid heart disease is a syndrome that has a deficiency origin and an excess superficiality. Deficiency in origin is typified by a deficiency of kidney yang primarily, and the fundamental objective of treatment should be "regulating and tonifying". An excess of superficiality is closely related to phlegm, dampness, blood stasis, etc. The most appropriate treatment is a combined method of dredging and tonifying, which should be the primary approach. It is crucial to adhere to the theoretical principles of both dredging and tonifying in the treatment plan. This approach allows for the treatment of both the underlying cause and the presenting symptoms, which can facilitate the harmonization of qi and blood.展开更多
The NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome is an intracellular protein complex containing a nucleotide-binding oligomerization domain,leucine-rich repeats,and a pyrin domain.It i...The NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome is an intracellular protein complex containing a nucleotide-binding oligomerization domain,leucine-rich repeats,and a pyrin domain.It is a key regulator of inflammation in viral pneumonia(VP).Small-molecule inhibitors targeting various NLRP3 binding sites are advancing into early clinical trials,but their therapeutic utility is incompletely established.Xuanfei Baidu Formula(XF),clinically used for VP treatment,attenuates NLRP3 activation by hampering caspase-11 to impede polarization of pro-inflammatory macrophages in a model of lipopolysaccharide(LPS)-induced lung injury inmice.Herein,we demonstrate that XF attenuated influenza A virus(IAV)-induced lung inflammation as well as lung injury in immunocompetent(but not in macrophage-depleted)mice.RNA sequencing of sorted lung macrophages from IAV-infected mice revealed that XF inhibited activation of the NLRP3 inflammation and interleukin(IL)-1βproduction.Quantitative nuclear magnetic resonance of XF enabled us to develop XF-Comb1,a fixed-ratio combination of five bioactive compounds that recapitulated the bioactivity of XF in suppressing NLRP3 activation in macrophages in vitro and in vivo.Interestingly,XF-Comb1 inhibited assembly of the NLRP3 inflammasome through multi-site interactions with functional residues of NLRP3,apoptosis-associated speck-like protein containing caspase recruitment domain(ASC),and caspase-1.Taken together,this work advances the development of NLRP3 inhibitors by translating a complex herbal formula into defined bioactive compounds.展开更多
Peptidyl arginine deiminase 4(PAD4)plays a pivotal role in infection and inflammatory diseases by facilitating the formation of neutrophil extracellular traps(NETs).However,the substrates of PAD4 and its exact role in...Peptidyl arginine deiminase 4(PAD4)plays a pivotal role in infection and inflammatory diseases by facilitating the formation of neutrophil extracellular traps(NETs).However,the substrates of PAD4 and its exact role in inflammatory bowel disease(IBD)remain unclear.In this study,we employed single-cell RNA sequencing(scRNA-seq)and substrate citrullination mapping to decipher the role of PAD4 in intestinal inflammation associated with IBD.Our results demonstrated that PAD4 deficiency alleviated colonic inflammation and restored intestinal barrier function in a dextran sulfate sodium(DSS)-induced colitis mouse model.scRNA-seq analysis revealed significant alterations in intestinal cell populations,with reduced neutrophil numbers and changes in epithelial subsets upon PAD4 deletion.Gene expression analysis highlighted pathways related to inflammation and epithelial cell function.Furthermore,we found that neutrophil-derived extracellular vesicles(EVs)carrying PAD4 were secreted into intestinal epithelial cells(IECs).Within IECs,PAD4 citrullinates mitochondrial creatine kinase 1(CKMT1)at the R242 site,leading to reduced CKMT1 protein stability via the autophagy pathway.This action compromises mitochondrial homeostasis,impairs intestinal barrier integrity,and induces IECs apoptosis.IEC-specific depletion of CKMT1 exacerbated intestinal inflammation and apoptosis in mice with colitis.Clinical analysis of IBD patients revealed elevated levels of PAD4,increased CKMT1 citrullination,and decreased CKMT1 expression.In summary,our findings highlight the crucial role of PAD4 in IBD,where it modulates IECs plasticity via CKMT1 citrullination,suggesting that PAD4 may be a potential therapeutic target for IBD.展开更多
基金supported by the Doctoral Start-up Foundation of Liaoning Province,China(Grant No.:2021-BS-127)China Medical University,China Medical University Cancer Hospital in animal experiments.
文摘Particle size and surface properties are crucial for lymphatic drainage(LN),dendritic cell(DC)uptake,DC maturation,and antigen cross-presentation induced by nanovaccine injection,which lead to an effective cell-mediated immune response.However,the manner in which the particle size and surface properties of vaccine carriers such as mesoporous silica nanoparticles(MSNs)affect this immune response is unknown.We prepared 50,100,and 200 nm of MSNs that adsorbed ovalbumin antigen(OVA)while modifyingβ-glucan to enhance immunogenicity.The results revealed that these MSNs with different particle sizes were just as efficient in vitro,and MSNs withβ-glucan modification demonstrated higher efficacy.However,the in vivo results indicated that MSNs with smaller particle sizes have stronger lymphatic targeting efficiency and a greater ability to promote the maturation of DCs.The results also indicate thatβ-glucan-modified MSN,with a particle size of∼100 nm,has a great potential as a vaccine delivery vehicle and immune adjuvant and offers a novel approach for the delivery of multiple therapeutic agents that target other lymph-mediated diseases.
基金Supported by Natural Science Foundation Project of Liaoning Province(2019-ZD-0956).
文摘Hypothyroid heart disease is a syndrome that has a deficiency origin and an excess superficiality. Deficiency in origin is typified by a deficiency of kidney yang primarily, and the fundamental objective of treatment should be "regulating and tonifying". An excess of superficiality is closely related to phlegm, dampness, blood stasis, etc. The most appropriate treatment is a combined method of dredging and tonifying, which should be the primary approach. It is crucial to adhere to the theoretical principles of both dredging and tonifying in the treatment plan. This approach allows for the treatment of both the underlying cause and the presenting symptoms, which can facilitate the harmonization of qi and blood.
基金supported by the National Natural Science Foundation of China(82141201,82405164,82204878,and 32170872)the Haihe Laboratory of Modern Chinese Medicine(Research and development of a universal treatment formula for respiratory viral infections)+3 种基金the National Key Research and Development Program of China(2021YFC1712905,2021YFC1712904,2020YFA0708004,2021YFE0200300,and 2023YFC2306202)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-D-202002,ZYYCXTD-D-202001)the China Postdoctoral Science Foundation(2023M742626)the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(CPSF)(GZC20231927).
文摘The NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome is an intracellular protein complex containing a nucleotide-binding oligomerization domain,leucine-rich repeats,and a pyrin domain.It is a key regulator of inflammation in viral pneumonia(VP).Small-molecule inhibitors targeting various NLRP3 binding sites are advancing into early clinical trials,but their therapeutic utility is incompletely established.Xuanfei Baidu Formula(XF),clinically used for VP treatment,attenuates NLRP3 activation by hampering caspase-11 to impede polarization of pro-inflammatory macrophages in a model of lipopolysaccharide(LPS)-induced lung injury inmice.Herein,we demonstrate that XF attenuated influenza A virus(IAV)-induced lung inflammation as well as lung injury in immunocompetent(but not in macrophage-depleted)mice.RNA sequencing of sorted lung macrophages from IAV-infected mice revealed that XF inhibited activation of the NLRP3 inflammation and interleukin(IL)-1βproduction.Quantitative nuclear magnetic resonance of XF enabled us to develop XF-Comb1,a fixed-ratio combination of five bioactive compounds that recapitulated the bioactivity of XF in suppressing NLRP3 activation in macrophages in vitro and in vivo.Interestingly,XF-Comb1 inhibited assembly of the NLRP3 inflammasome through multi-site interactions with functional residues of NLRP3,apoptosis-associated speck-like protein containing caspase recruitment domain(ASC),and caspase-1.Taken together,this work advances the development of NLRP3 inhibitors by translating a complex herbal formula into defined bioactive compounds.
基金National Natural Science Foundation of China(No.82100587,No.82170567)National Key R&D Program of China(No.2023YFC2413801,China)+6 种基金Shanghai Sailing Program(No.21YF1458700)China National Postdoctoral Program for Innovative Talents(No.BX20220288)China Postdoctoral Science Foundation(No.2022M720138)Program of Shanghai Academic Research Leader(No.22XD1425000)Deep Blue Project of Naval Medical University(Pilot Talent Plan)Basic Medical Research Project of the First Affiliated Hospital of Naval Medical University(No.2023PY06)“Changying”Talent Program of Changhai Hospital of Naval Medical University,and the“Changjian”Talent Program of Changhai Hospital of Naval Medical University.
文摘Peptidyl arginine deiminase 4(PAD4)plays a pivotal role in infection and inflammatory diseases by facilitating the formation of neutrophil extracellular traps(NETs).However,the substrates of PAD4 and its exact role in inflammatory bowel disease(IBD)remain unclear.In this study,we employed single-cell RNA sequencing(scRNA-seq)and substrate citrullination mapping to decipher the role of PAD4 in intestinal inflammation associated with IBD.Our results demonstrated that PAD4 deficiency alleviated colonic inflammation and restored intestinal barrier function in a dextran sulfate sodium(DSS)-induced colitis mouse model.scRNA-seq analysis revealed significant alterations in intestinal cell populations,with reduced neutrophil numbers and changes in epithelial subsets upon PAD4 deletion.Gene expression analysis highlighted pathways related to inflammation and epithelial cell function.Furthermore,we found that neutrophil-derived extracellular vesicles(EVs)carrying PAD4 were secreted into intestinal epithelial cells(IECs).Within IECs,PAD4 citrullinates mitochondrial creatine kinase 1(CKMT1)at the R242 site,leading to reduced CKMT1 protein stability via the autophagy pathway.This action compromises mitochondrial homeostasis,impairs intestinal barrier integrity,and induces IECs apoptosis.IEC-specific depletion of CKMT1 exacerbated intestinal inflammation and apoptosis in mice with colitis.Clinical analysis of IBD patients revealed elevated levels of PAD4,increased CKMT1 citrullination,and decreased CKMT1 expression.In summary,our findings highlight the crucial role of PAD4 in IBD,where it modulates IECs plasticity via CKMT1 citrullination,suggesting that PAD4 may be a potential therapeutic target for IBD.
