Acute lung injury(ALI)is a significant complication of sepsis,characterized by high morbidity,mortality,and poor prognosis.Neutrophils,as critical intrinsic immune cells in the lung,play a fundamental role in the deve...Acute lung injury(ALI)is a significant complication of sepsis,characterized by high morbidity,mortality,and poor prognosis.Neutrophils,as critical intrinsic immune cells in the lung,play a fundamental role in the development and progression of ALI.During ALI,neutrophils generate neutrophil extracellular traps(NETs),and excessive NETs can intensify inflammatory injury.Research indicates that Taohe Chengqi decoction(THCQD)can ameliorate sepsis-induced lung inflammation and modulate immune function.This study aimed to investigate the mechanisms by which THCQD improves ALI and its relationship with NETs in sepsis patients,seeking to provide novel perspectives and interventions for clinical treatment.The findings demonstrate that THCQD enhanced survival rates and reduced lung injury in the cecum ligation and puncture(CLP)-induced ALI mouse model.Furthermore,THCQD diminished neutrophil and macrophage infiltration,inflammatory responses,and the production of pro-inflammatory cytokines,including interleukin-1β(IL-1β),IL-6,and tumor necrosis factorα(TNF-α).Notably,subsequent experiments confirmed that THCQD inhibits NET formation both in vivo and in vitro.Moreover,THCQD significantly decreased the expression of peptidyl arginine deiminase 4(PAD4)protein,and molecular docking predicted that certain active compounds in THCQD could bind tightly to PAD4.PAD4 overexpression partially reversed THCQD’s inhibitory effects on PAD4.These findings strongly indicate that THCQD mitigates CLP-induced ALI by inhibiting PAD4-mediated NETs.展开更多
Plants defend themselves against pathogens by activating two interconnected layers of immunity:pattern-and effector-triggered immunity.Recent studies shed light on a number of unanswered questions in these pathways an...Plants defend themselves against pathogens by activating two interconnected layers of immunity:pattern-and effector-triggered immunity.Recent studies shed light on a number of unanswered questions in these pathways and demonstrate a conserved structural basis,in monocots and dicots,of signaling through the EDS1:PAD4:ADR1 module,downstream of Toll/interleukin-1 receptor(TIR)domain-containing immune receptors that cleave the dinucleotide nicotinamide adenine dinucleotide(NAD+).The studies define a new function for TIR domain proteins in monocots and suggest that the signaling molecule 5″-phosphoribosyl(pRib)-AMP is derived from the TIR product 2′-adenosine diphosphate ribose(2′cADPR).These findings have important implications for developing the strategies to breed resistant crops.展开更多
[目的]探讨PAD4通过JAK/STAT3通路调控三阴性乳腺癌(TNBC)细胞增殖的潜在机制。[方法]采用乳腺正常细胞系及TNBC细胞系进行实验,通过慢病毒感染TNBC细胞系以敲低或过表达PAD4并使用JAK激动剂和抑制剂处理细胞。使用细胞计数试剂盒(CCK-8...[目的]探讨PAD4通过JAK/STAT3通路调控三阴性乳腺癌(TNBC)细胞增殖的潜在机制。[方法]采用乳腺正常细胞系及TNBC细胞系进行实验,通过慢病毒感染TNBC细胞系以敲低或过表达PAD4并使用JAK激动剂和抑制剂处理细胞。使用细胞计数试剂盒(CCK-8)检测细胞增殖水平,通过高通量测序和通路分析检测mRNA表达水平,免疫共沉淀检测JAK1分子相互作用,免疫印迹检测JAK和STAT3的磷酸化水平,以及RNA抽取与实时荧光定量PCR分析基因表达。[结果]PAD4在TNBC患者组织中的表达水平高于非TNBC患者(9.49±0.67 vs 14.43±2.30,P<0.05),且中位生存期更长(P<0.05)。敲低PAD4抑制TNBC细胞系的增殖(1.55±0.14 vs 1.00±0.05,P<0.05),而过表达PAD4则促进增殖(1.65±0.14 vs 3.03±0.13,P<0.05)。过表达PAD4使JAK/STAT3通路活性上升,表现为JAK和STAT3的磷酸化水平增加;敲低PAD4则使其磷酸化水平下降。使用JAK激动剂处理敲低PAD4的TNBC细胞系或使用JAK抑制剂处理过表达PAD4的TNBC细胞系后,细胞增殖水平无变化。[结论]PAD4在TNBC中高表达并通过激活JAK/STAT3通路促进细胞增殖(1.65±0.14 vs 3.03±0.13)。调控PAD4可能是TNBC治疗的潜在策略。展开更多
PAD4 is a promising epigenetic drug target for various cancers and immune diseases. In this work, we applied a Cu-catalyzed C–H arylation reaction of N-heteroarene to the synthesis of complex non-covalent PAD4 inhibi...PAD4 is a promising epigenetic drug target for various cancers and immune diseases. In this work, we applied a Cu-catalyzed C–H arylation reaction of N-heteroarene to the synthesis of complex non-covalent PAD4 inhibitors bearing a bi-heteroaryl pharmacophore. This strategy allowed us to access various analogs of C_2-aryl substituted benzimidazoles from a common benzimidazole core and easily accessible aryl iodides. Preliminary SAR studies revealed the indole motif of GSK-484 is critical to its activity. Replacing the N-cyclopropylmethyl group to N-benzyl group on the indole ring of GSK-484 resulted in more than5-fold increase in cell killing efficacy against 4T1 cell line.展开更多
为明确the new Pad、iPhone4s是否具备专业显示设备的显示性能,以液晶专业显示器A为参考,对这3个显示设备的时间稳定性、不同亮度下不同颜色显示的空间均匀性、不同亮度下色域覆盖率、色品恒定性、通道相加性、设备色域6个方面的性能进...为明确the new Pad、iPhone4s是否具备专业显示设备的显示性能,以液晶专业显示器A为参考,对这3个显示设备的时间稳定性、不同亮度下不同颜色显示的空间均匀性、不同亮度下色域覆盖率、色品恒定性、通道相加性、设备色域6个方面的性能进行了测试。实验结果表明:iPhone4s在时间稳定性、颜色显示的空间均匀性以及色域覆盖率的稳定性方面优于the new Pad;the new Pad在通道可加性、色品恒定性方面优于iPhone4s;3个显示设备中the new Pad的色域覆盖率最大,iPhone4s的最小;the new Pad各项性能与专业显示器A的相近。The new Pad基本达到专业显示设备的显示性能要求,可作为专业显示设备的辅助设备使用,iPhone4s没有达到专业显示设备的显示性能要求,不适合作为专业显示设备的辅助设备使用。展开更多
Objective： The aim of the research was to study peptidylarginine deiminase type 4 （PAD4/PADI4） expression and its tumodgenic mechanism in hepatocellular carcinomas. Methods： Expressions of PADI4 and p53 were inves...Objective： The aim of the research was to study peptidylarginine deiminase type 4 （PAD4/PADI4） expression and its tumodgenic mechanism in hepatocellular carcinomas. Methods： Expressions of PADI4 and p53 were investigated in tumors and non-tumor tissues by Western blot in patients with hepatocellular carcinomas. We constructed plasmid of PADI4-Flag and transfected it in Hela cells to investigate the mechanism. Results： Western blot analysis showed higher PADI4 expression in hepatocellular carcinomas than in the surrounding healthy tissues. Furthermore, by Western blot, we detected decreased p53 levels in the tumor tissues of patients with hepatocellular carcinomas compared to surrounding healthy tissues. In Hela cells transfected with PcDNA3.0-Flag-PADI4 plasmid, the expression of p53 decreased obviously. Conclusion： Our results suggest that PADI4 elevated in the tissues of hepatocellular carcinomas and induced tumorigenic by down-regulating p53 expression.展开更多
Plant intracellular nucleotide-binding leucine-rich repeat(NLR)receptors with an N-terminal Toll/Interleukin-1 recep-tor(TIR)domain detect pathogen effectors to produce TIR-catalyzed signaling molecules for activation...Plant intracellular nucleotide-binding leucine-rich repeat(NLR)receptors with an N-terminal Toll/Interleukin-1 recep-tor(TIR)domain detect pathogen effectors to produce TIR-catalyzed signaling molecules for activation of plant immunity.Plant immune signaling by TIR-containing NLR(TNL)proteins converges on Enhanced Disease Suscepti-bility 1(EDS1)and its direct partners Phytoalexin Deficient 4(PAD4)or Senescence-Associated Gene 101(SAG101).TNL signaling also require helper NLRs N requirement gene 1(NRG1)and activated disease resistance 1(ADR1).In two recent remarkable papers published in Science,the authors show that the TIR-containing proteins catalyze and produce two types of signaling molecules,ADPr-ATP/diADPR and pRib-AMP/ADP.Importantly,they demonstrate that EDS1-SAG101 and EDS1-PAD4 modules are the receptor complexes for ADPr-ATP/diADPRp and Rib-AMP/ADP,respec-tively,which allosterically promote EDS1-SAG101 interaction with NRG1 and EDS1-PAD4 interaction with ADR1.Thus,two different small molecules catalyzed by TIR-containing proteins selectively activate the downstream two distinct branches of EDS1-mediated immune signalings.These breakthrough studies significantly advance our understanding of TNL downstream signaling pathway.展开更多
基金supporteded by the National Natural ScienceFoundation of China(Nos.82374183,82405092,82204991,82274246,and 82374341)the Planned Science TechnologyProjectofGuangzhouCity(Nos.2023A03J0419and2023A03J0420)+3 种基金the General Project of Natural Science Foundationof Guangdong Province(No.2023A1515011090)Hong KongScholars Program 2024(No.XJ2024005)the Basic and AppliedBasic Research Foundation of Guangdong Province(No.2021A151510809)the Project of Administration of TraditionalChinese Medicine of Guangdong Province of China(No.20223013).
文摘Acute lung injury(ALI)is a significant complication of sepsis,characterized by high morbidity,mortality,and poor prognosis.Neutrophils,as critical intrinsic immune cells in the lung,play a fundamental role in the development and progression of ALI.During ALI,neutrophils generate neutrophil extracellular traps(NETs),and excessive NETs can intensify inflammatory injury.Research indicates that Taohe Chengqi decoction(THCQD)can ameliorate sepsis-induced lung inflammation and modulate immune function.This study aimed to investigate the mechanisms by which THCQD improves ALI and its relationship with NETs in sepsis patients,seeking to provide novel perspectives and interventions for clinical treatment.The findings demonstrate that THCQD enhanced survival rates and reduced lung injury in the cecum ligation and puncture(CLP)-induced ALI mouse model.Furthermore,THCQD diminished neutrophil and macrophage infiltration,inflammatory responses,and the production of pro-inflammatory cytokines,including interleukin-1β(IL-1β),IL-6,and tumor necrosis factorα(TNF-α).Notably,subsequent experiments confirmed that THCQD inhibits NET formation both in vivo and in vitro.Moreover,THCQD significantly decreased the expression of peptidyl arginine deiminase 4(PAD4)protein,and molecular docking predicted that certain active compounds in THCQD could bind tightly to PAD4.PAD4 overexpression partially reversed THCQD’s inhibitory effects on PAD4.These findings strongly indicate that THCQD mitigates CLP-induced ALI by inhibiting PAD4-mediated NETs.
基金B.K's laboratory was funded by the National Health and Medical Research Council(NHMRC AustraliaInvestigator grant 2025931)+1 种基金the Australian Research Council(ARCDiscovery Project DP220102832).
文摘Plants defend themselves against pathogens by activating two interconnected layers of immunity:pattern-and effector-triggered immunity.Recent studies shed light on a number of unanswered questions in these pathways and demonstrate a conserved structural basis,in monocots and dicots,of signaling through the EDS1:PAD4:ADR1 module,downstream of Toll/interleukin-1 receptor(TIR)domain-containing immune receptors that cleave the dinucleotide nicotinamide adenine dinucleotide(NAD+).The studies define a new function for TIR domain proteins in monocots and suggest that the signaling molecule 5″-phosphoribosyl(pRib)-AMP is derived from the TIR product 2′-adenosine diphosphate ribose(2′cADPR).These findings have important implications for developing the strategies to breed resistant crops.
文摘[目的]探讨PAD4通过JAK/STAT3通路调控三阴性乳腺癌(TNBC)细胞增殖的潜在机制。[方法]采用乳腺正常细胞系及TNBC细胞系进行实验,通过慢病毒感染TNBC细胞系以敲低或过表达PAD4并使用JAK激动剂和抑制剂处理细胞。使用细胞计数试剂盒(CCK-8)检测细胞增殖水平,通过高通量测序和通路分析检测mRNA表达水平,免疫共沉淀检测JAK1分子相互作用,免疫印迹检测JAK和STAT3的磷酸化水平,以及RNA抽取与实时荧光定量PCR分析基因表达。[结果]PAD4在TNBC患者组织中的表达水平高于非TNBC患者(9.49±0.67 vs 14.43±2.30,P<0.05),且中位生存期更长(P<0.05)。敲低PAD4抑制TNBC细胞系的增殖(1.55±0.14 vs 1.00±0.05,P<0.05),而过表达PAD4则促进增殖(1.65±0.14 vs 3.03±0.13,P<0.05)。过表达PAD4使JAK/STAT3通路活性上升,表现为JAK和STAT3的磷酸化水平增加;敲低PAD4则使其磷酸化水平下降。使用JAK激动剂处理敲低PAD4的TNBC细胞系或使用JAK抑制剂处理过表达PAD4的TNBC细胞系后,细胞增殖水平无变化。[结论]PAD4在TNBC中高表达并通过激活JAK/STAT3通路促进细胞增殖(1.65±0.14 vs 3.03±0.13)。调控PAD4可能是TNBC治疗的潜在策略。
基金supported by the National Natural Science Foundation of China(21502098,21672105,21725204,91753124)Natural Science Foundation of Tianjin(17JCYBJC19700,18JCZDJC32800)+1 种基金Qingdao National Laboratory for Marine Science and Technologythe State Key Laboratory of Elemento-Organic Chemistry at Nankai University
文摘PAD4 is a promising epigenetic drug target for various cancers and immune diseases. In this work, we applied a Cu-catalyzed C–H arylation reaction of N-heteroarene to the synthesis of complex non-covalent PAD4 inhibitors bearing a bi-heteroaryl pharmacophore. This strategy allowed us to access various analogs of C_2-aryl substituted benzimidazoles from a common benzimidazole core and easily accessible aryl iodides. Preliminary SAR studies revealed the indole motif of GSK-484 is critical to its activity. Replacing the N-cyclopropylmethyl group to N-benzyl group on the indole ring of GSK-484 resulted in more than5-fold increase in cell killing efficacy against 4T1 cell line.
文摘为明确the new Pad、iPhone4s是否具备专业显示设备的显示性能,以液晶专业显示器A为参考,对这3个显示设备的时间稳定性、不同亮度下不同颜色显示的空间均匀性、不同亮度下色域覆盖率、色品恒定性、通道相加性、设备色域6个方面的性能进行了测试。实验结果表明:iPhone4s在时间稳定性、颜色显示的空间均匀性以及色域覆盖率的稳定性方面优于the new Pad;the new Pad在通道可加性、色品恒定性方面优于iPhone4s;3个显示设备中the new Pad的色域覆盖率最大,iPhone4s的最小;the new Pad各项性能与专业显示器A的相近。The new Pad基本达到专业显示设备的显示性能要求,可作为专业显示设备的辅助设备使用,iPhone4s没有达到专业显示设备的显示性能要求,不适合作为专业显示设备的辅助设备使用。
文摘Objective： The aim of the research was to study peptidylarginine deiminase type 4 （PAD4/PADI4） expression and its tumodgenic mechanism in hepatocellular carcinomas. Methods： Expressions of PADI4 and p53 were investigated in tumors and non-tumor tissues by Western blot in patients with hepatocellular carcinomas. We constructed plasmid of PADI4-Flag and transfected it in Hela cells to investigate the mechanism. Results： Western blot analysis showed higher PADI4 expression in hepatocellular carcinomas than in the surrounding healthy tissues. Furthermore, by Western blot, we detected decreased p53 levels in the tumor tissues of patients with hepatocellular carcinomas compared to surrounding healthy tissues. In Hela cells transfected with PcDNA3.0-Flag-PADI4 plasmid, the expression of p53 decreased obviously. Conclusion： Our results suggest that PADI4 elevated in the tissues of hepatocellular carcinomas and induced tumorigenic by down-regulating p53 expression.
基金support from the National Natural Science Foundation of China(31925032 and 31870143).
文摘Plant intracellular nucleotide-binding leucine-rich repeat(NLR)receptors with an N-terminal Toll/Interleukin-1 recep-tor(TIR)domain detect pathogen effectors to produce TIR-catalyzed signaling molecules for activation of plant immunity.Plant immune signaling by TIR-containing NLR(TNL)proteins converges on Enhanced Disease Suscepti-bility 1(EDS1)and its direct partners Phytoalexin Deficient 4(PAD4)or Senescence-Associated Gene 101(SAG101).TNL signaling also require helper NLRs N requirement gene 1(NRG1)and activated disease resistance 1(ADR1).In two recent remarkable papers published in Science,the authors show that the TIR-containing proteins catalyze and produce two types of signaling molecules,ADPr-ATP/diADPR and pRib-AMP/ADP.Importantly,they demonstrate that EDS1-SAG101 and EDS1-PAD4 modules are the receptor complexes for ADPr-ATP/diADPRp and Rib-AMP/ADP,respec-tively,which allosterically promote EDS1-SAG101 interaction with NRG1 and EDS1-PAD4 interaction with ADR1.Thus,two different small molecules catalyzed by TIR-containing proteins selectively activate the downstream two distinct branches of EDS1-mediated immune signalings.These breakthrough studies significantly advance our understanding of TNL downstream signaling pathway.
