The peripheral immune system has emerged as a regulator of neurodegenerative diseases such as Alzheimer’s disease.Microglia are resident immune cells in the brain that may orchestrate communication between the centra...The peripheral immune system has emerged as a regulator of neurodegenerative diseases such as Alzheimer’s disease.Microglia are resident immune cells in the brain that may orchestrate communication between the central nervous system and peripheral immune system,though the mechanisms are unclear.Here,we found that gamma-type immunoglobulin,a product originating from peripheral blood B cells,localized in the brain parenchyma of multiple mouse models with amyloid pathology,and was enriched on microglia but not on other brain cell types.Further experiments showed that gamma-type immunoglobulin bound to microglial cell membranes and led to diverse transcriptomic changes,including upregulation of pathways related to phagocytosis and immunity.Functional assays demonstrated that gamma-type immunoglobulin enhanced microglial phagocytic capacity for amyloid-beta fibrils via its Fc fragment,but not Fab fragment,fragment.Our data indicate that microglia,when exposed to gamma-type immunoglobulin,exhibit an enhanced capacity for clearing amyloid-beta fibrils,potentially via the gamma-type immunoglobulin Fc fragment signaling pathway.This suggests that parenchymal gamma-type immunoglobulin should be further investigated to determine whether it may play a beneficial role against Alzheimer’s disease by enhancing microglial function.展开更多
Background:Modified Qiangli Dingxuan Tablets(ZYSJ)is an optimized formulation derived from the classic Chinese patent medicine Qiangli Dingxuan Tablet.It targets the pathological features associated with metabolic hyp...Background:Modified Qiangli Dingxuan Tablets(ZYSJ)is an optimized formulation derived from the classic Chinese patent medicine Qiangli Dingxuan Tablet.It targets the pathological features associated with metabolic hypertension(MH)and metabolic disorders,although its antihypertensive mechanism remains unclear.Methods:A rat model of metabolic hypertension was established using a high-sugar,high-fat diet combined with progressively increasing concentrations of ethanol.Blood pressure,serum lipids,inflammatory cytokines,and endothelial function markers were assessed.Serum pharmacochemistry combined with network pharmacology was employed to predict key targets and pathways,followed by in vivo validation using qRT-PCR,Western blotting,immunofluorescence,and immunohistochemistry.Results:ZYSJ significantly reduced blood pressure and serum lipid levels in model rats.Thirty absorbed bioactive components were identified.Mechanistic studies revealed that ZYSJ downregulated the TLR4/MyD88/NF-κB signaling pathway at both the mRNA and protein levels,upregulated endothelial nitric oxide synthase(eNOS)expression,and decreased the levels of inflammatory cytokines(TNF-α,IL-1β,IL-6),thereby improving vascular endothelial function.Conclusion:ZYSJ effectively lowers blood pressure and serum lipids in rats with metabolic hypertension.Its mechanism of action is closely associated with regulation of the TLR4/MyD88/NF-κB signaling pathway,improvement of vascular endothelial function,and alleviation of inflammation.展开更多
Ischemic stroke represents a significant global health challenge,frequently associated with intricate pathophysiological alterations.During ischemic stroke,the generation of reactive oxygen species markedly increases,...Ischemic stroke represents a significant global health challenge,frequently associated with intricate pathophysiological alterations.During ischemic stroke,the generation of reactive oxygen species markedly increases,leading to direct neuronal damage as well as initiating a cascade of inflammatory responses.This oxidative stress can also disturb the equilibrium of the gut microbiota,resulting in dysbiosis.In turn,an imbalance in gut microbiota can further exacerbate the production of reactive oxygen species and contribute to a pro-inflammatory environment within the body.This creates a vicious cycle that not only promotes the progression of stroke but also leads to adverse functional outcomes.The neuroinflammation and intestinal microbiota dysbiosis that occur following ischemic stroke are critical contributors to stroke progression and adverse functional outcomes.We previously developed manganese-iron Prussian blue nanozymes,characterized by a multi-enzyme structure and a porous design,that exhibit strong antioxidant properties.However,the therapeutic effects of manganese-iron Prussian blue nanozymes on ischemic stroke and their mechanisms of action remain have not been fully elucidated.To investigate this,we constructed a mouse model of middle cerebral artery occlusion and administered manganese-iron Prussian blue nanozymes via gastric gavage.Our results demonstrated that these nanozymes substantially reduced infarct volume,improved neurological function,restored gut microbiota balance,and increased levels of short-chain fatty acids in the mouse model.Treatment of lipopolysaccharide-treated BV-2 cells with short-chain fatty acids markedly decreased the expression levels of components of the Toll-like receptor 4/nuclear factor kappa B signaling pathway,including Toll-like receptor 4,inhibitor of nuclear factor kappa-B kinase subunit alpha,and pp65.These findings suggest that manganese-iron Prussian blue nanozymes can correct gut microbiota dysbiosis and increase short-chain fatty acid production by modulating the Toll-like receptor 4/nuclear factor kappa B signaling pathway,thereby providing therapeutic benefits in the context of ischemic stroke.展开更多
背景:肿瘤双向调控因子核因子κB激活激酶的研究成果逐年增多,但是却没有相关文献计量学分析。目的:通过文献计量学分析肿瘤逃避因子核因子κB激活激酶的研究现状、热点及趋势。方法:基于Web of Science核心合集中的SCIE数据库筛选近10...背景:肿瘤双向调控因子核因子κB激活激酶的研究成果逐年增多,但是却没有相关文献计量学分析。目的:通过文献计量学分析肿瘤逃避因子核因子κB激活激酶的研究现状、热点及趋势。方法:基于Web of Science核心合集中的SCIE数据库筛选近10年来核因子κB激活激酶相关研究文献,导入Cite Space 6.3.R1软件中分别以国家(地区)、作者、机构、参考文献和关键词5个选项进行文献计量及可视化分析,并运用Origin 2021软件绘制相关统计图。结果与结论:核因子κB激活激酶的发文量、文献共被引次数呈现上升的趋势,Chen,Dan-Dan、Gui,Jian-Fang、Qin,Qiwei和Li,Shun 4位作者发文量最多(11篇),中国科学院、中国科学院大学、浙江大学、中国农业科学院、武汉大学的发文量较大(>50篇)。近10年来关于核因子κB激活激酶的研究热点主要集中在innate immunity、c GAS-STING pathway、NF-κB、inflammation、optineurin、expression、cancer等模块。结果表明,近年来各国学者在相关领域进行了持续且深入的研究,核因子κB激活激酶在自身免疫系统、信号通路、基因表达、肿瘤防治等方面显示出巨大的科研潜力。但是学者之间、机构之间的学术合作并不紧密,今后学者应加强合作与交流,把握核因子κB激活激酶的研究热点与趋势,拓展在疾病领域中的研究范围,为进一步阐明疾病的药效机制和病理变化提供更多证据。展开更多
Benzalkonium chloride(BAC)is widely employed as a broad-spectrum biocide and has emerged as a significant environmental pollutant.Polymyxin B(PB)serves as the last-line defense for the treatment of Gram-negative patho...Benzalkonium chloride(BAC)is widely employed as a broad-spectrum biocide and has emerged as a significant environmental pollutant.Polymyxin B(PB)serves as the last-line defense for the treatment of Gram-negative pathogens.Previous studies reported that BAC-adapted Pseudomonas aeruginosa increased the tolerance to PB.Herein,we present the novel finding that the combination of BAC and PB exhibited synergistic antibacterial effects against P.aeruginosa.Time-killing assay demonstrated a significant reduction in bacterial cell viability.Scanning electron microscopy,zeta potential analysis,hydrophobicity measurements,and fluorescence probe analyses collectively revealed severe disruption of the cell envelope and membrane potential induced by the combination of BAC and PB.Transcriptomic analysis revealed that the BAC-PB combination notably downreg-ulated the expression of genes involved in lipid A modification and cell envelope production,including phoPQ,pmrAB,bamABCDE,lptABCDEG,lolB,yidC,and murJ.Additionally,the combination group exhibited augmented production of reactive oxygen species and diminished ATP synthesis.The expression of the genes associated with substance metabolism and energy generation was significantly impeded.This study provides significant implica-tions for the interactions of biocides and antibiotics on Gram-negative pathogens,while also addressing antibiotic resistance and developing the external treatment strategy for Pseudomonas-infected wounds and burns.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82171082(to ZX),32000727(to TZ),32370731(to YZ)Guangdong Basic and Applied Basic Research Foundation,No.2024A151501069(to ZX)+1 种基金Shenzhen Science and Technology Program,Nos.JCYJ20210324101603009(to ZX),GJHZ20220913142807015(to TZ),JCYJ20220531100204010(to TZ),JCYJ20230807091308018(to YZ)Shenzhen Medical Research Funds,No.A2303068(to TZ).
文摘The peripheral immune system has emerged as a regulator of neurodegenerative diseases such as Alzheimer’s disease.Microglia are resident immune cells in the brain that may orchestrate communication between the central nervous system and peripheral immune system,though the mechanisms are unclear.Here,we found that gamma-type immunoglobulin,a product originating from peripheral blood B cells,localized in the brain parenchyma of multiple mouse models with amyloid pathology,and was enriched on microglia but not on other brain cell types.Further experiments showed that gamma-type immunoglobulin bound to microglial cell membranes and led to diverse transcriptomic changes,including upregulation of pathways related to phagocytosis and immunity.Functional assays demonstrated that gamma-type immunoglobulin enhanced microglial phagocytic capacity for amyloid-beta fibrils via its Fc fragment,but not Fab fragment,fragment.Our data indicate that microglia,when exposed to gamma-type immunoglobulin,exhibit an enhanced capacity for clearing amyloid-beta fibrils,potentially via the gamma-type immunoglobulin Fc fragment signaling pathway.This suggests that parenchymal gamma-type immunoglobulin should be further investigated to determine whether it may play a beneficial role against Alzheimer’s disease by enhancing microglial function.
基金supported by Natural science foundation of Zhejiang province(No.ZCLMS25H2801 to Ying-Jie Dong)Zhejiang Provincial"Vanguard"and"Leading Goose"R&D Tackling Program(No.2025C02183 to Su-Hong Chen)+1 种基金National Natural Science Foundation of China(No.82274134 to Su-Hong Chen and No.82404900 to Ying-Jie Dong)the Key Laboratory of Zhejiang Province(No.2012E10002 to Gui-Yuan Lv).
文摘Background:Modified Qiangli Dingxuan Tablets(ZYSJ)is an optimized formulation derived from the classic Chinese patent medicine Qiangli Dingxuan Tablet.It targets the pathological features associated with metabolic hypertension(MH)and metabolic disorders,although its antihypertensive mechanism remains unclear.Methods:A rat model of metabolic hypertension was established using a high-sugar,high-fat diet combined with progressively increasing concentrations of ethanol.Blood pressure,serum lipids,inflammatory cytokines,and endothelial function markers were assessed.Serum pharmacochemistry combined with network pharmacology was employed to predict key targets and pathways,followed by in vivo validation using qRT-PCR,Western blotting,immunofluorescence,and immunohistochemistry.Results:ZYSJ significantly reduced blood pressure and serum lipid levels in model rats.Thirty absorbed bioactive components were identified.Mechanistic studies revealed that ZYSJ downregulated the TLR4/MyD88/NF-κB signaling pathway at both the mRNA and protein levels,upregulated endothelial nitric oxide synthase(eNOS)expression,and decreased the levels of inflammatory cytokines(TNF-α,IL-1β,IL-6),thereby improving vascular endothelial function.Conclusion:ZYSJ effectively lowers blood pressure and serum lipids in rats with metabolic hypertension.Its mechanism of action is closely associated with regulation of the TLR4/MyD88/NF-κB signaling pathway,improvement of vascular endothelial function,and alleviation of inflammation.
基金supported by the Natural Science Foundation of Anhui Province of China,No.2208085Y32Scientific Research Plan Project of Anhui Province of China,No.2022AH020076the Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province,No.CXPJJH12000005-07-115(all to CT).
文摘Ischemic stroke represents a significant global health challenge,frequently associated with intricate pathophysiological alterations.During ischemic stroke,the generation of reactive oxygen species markedly increases,leading to direct neuronal damage as well as initiating a cascade of inflammatory responses.This oxidative stress can also disturb the equilibrium of the gut microbiota,resulting in dysbiosis.In turn,an imbalance in gut microbiota can further exacerbate the production of reactive oxygen species and contribute to a pro-inflammatory environment within the body.This creates a vicious cycle that not only promotes the progression of stroke but also leads to adverse functional outcomes.The neuroinflammation and intestinal microbiota dysbiosis that occur following ischemic stroke are critical contributors to stroke progression and adverse functional outcomes.We previously developed manganese-iron Prussian blue nanozymes,characterized by a multi-enzyme structure and a porous design,that exhibit strong antioxidant properties.However,the therapeutic effects of manganese-iron Prussian blue nanozymes on ischemic stroke and their mechanisms of action remain have not been fully elucidated.To investigate this,we constructed a mouse model of middle cerebral artery occlusion and administered manganese-iron Prussian blue nanozymes via gastric gavage.Our results demonstrated that these nanozymes substantially reduced infarct volume,improved neurological function,restored gut microbiota balance,and increased levels of short-chain fatty acids in the mouse model.Treatment of lipopolysaccharide-treated BV-2 cells with short-chain fatty acids markedly decreased the expression levels of components of the Toll-like receptor 4/nuclear factor kappa B signaling pathway,including Toll-like receptor 4,inhibitor of nuclear factor kappa-B kinase subunit alpha,and pp65.These findings suggest that manganese-iron Prussian blue nanozymes can correct gut microbiota dysbiosis and increase short-chain fatty acid production by modulating the Toll-like receptor 4/nuclear factor kappa B signaling pathway,thereby providing therapeutic benefits in the context of ischemic stroke.
文摘背景:肿瘤双向调控因子核因子κB激活激酶的研究成果逐年增多,但是却没有相关文献计量学分析。目的:通过文献计量学分析肿瘤逃避因子核因子κB激活激酶的研究现状、热点及趋势。方法:基于Web of Science核心合集中的SCIE数据库筛选近10年来核因子κB激活激酶相关研究文献,导入Cite Space 6.3.R1软件中分别以国家(地区)、作者、机构、参考文献和关键词5个选项进行文献计量及可视化分析,并运用Origin 2021软件绘制相关统计图。结果与结论:核因子κB激活激酶的发文量、文献共被引次数呈现上升的趋势,Chen,Dan-Dan、Gui,Jian-Fang、Qin,Qiwei和Li,Shun 4位作者发文量最多(11篇),中国科学院、中国科学院大学、浙江大学、中国农业科学院、武汉大学的发文量较大(>50篇)。近10年来关于核因子κB激活激酶的研究热点主要集中在innate immunity、c GAS-STING pathway、NF-κB、inflammation、optineurin、expression、cancer等模块。结果表明,近年来各国学者在相关领域进行了持续且深入的研究,核因子κB激活激酶在自身免疫系统、信号通路、基因表达、肿瘤防治等方面显示出巨大的科研潜力。但是学者之间、机构之间的学术合作并不紧密,今后学者应加强合作与交流,把握核因子κB激活激酶的研究热点与趋势,拓展在疾病领域中的研究范围,为进一步阐明疾病的药效机制和病理变化提供更多证据。
基金supported by the National Natural Science Foundation of China(No.32170121).
文摘Benzalkonium chloride(BAC)is widely employed as a broad-spectrum biocide and has emerged as a significant environmental pollutant.Polymyxin B(PB)serves as the last-line defense for the treatment of Gram-negative pathogens.Previous studies reported that BAC-adapted Pseudomonas aeruginosa increased the tolerance to PB.Herein,we present the novel finding that the combination of BAC and PB exhibited synergistic antibacterial effects against P.aeruginosa.Time-killing assay demonstrated a significant reduction in bacterial cell viability.Scanning electron microscopy,zeta potential analysis,hydrophobicity measurements,and fluorescence probe analyses collectively revealed severe disruption of the cell envelope and membrane potential induced by the combination of BAC and PB.Transcriptomic analysis revealed that the BAC-PB combination notably downreg-ulated the expression of genes involved in lipid A modification and cell envelope production,including phoPQ,pmrAB,bamABCDE,lptABCDEG,lolB,yidC,and murJ.Additionally,the combination group exhibited augmented production of reactive oxygen species and diminished ATP synthesis.The expression of the genes associated with substance metabolism and energy generation was significantly impeded.This study provides significant implica-tions for the interactions of biocides and antibiotics on Gram-negative pathogens,while also addressing antibiotic resistance and developing the external treatment strategy for Pseudomonas-infected wounds and burns.
