In this editorial,we comment on the article by Wang et al.This manuscript explores the potential synergistic effects of combining zanubrutinib,a novel oral inhibitor of Bruton’s tyrosine kinase,with high-dose methotr...In this editorial,we comment on the article by Wang et al.This manuscript explores the potential synergistic effects of combining zanubrutinib,a novel oral inhibitor of Bruton’s tyrosine kinase,with high-dose methotrexate(HD-MTX)as a therapeutic intervention for primary central nervous system lymphoma(PCNSL).The study involves a retrospective analysis of 19 PCNSL patients,highlighting clinicopathological characteristics,treatment outcomes,and genomic biomarkers.The results indicate the combination’s good tolerance and strong antitumor activity,with an 84.2%overall response rate.The authors emphasize the potential of zanubrutinib to modulate key genomic features of PCNSL,particularly mutations in myeloid differentiation primary response 88 and cluster of differentiation 79B.Furthermore,the study investigates the role of circulating tumor DNA in cerebrospinal fluid for disease surveillance and treatment response monitoring.In essence,the study provides valuable insights into the potential of combining zanubrutinib with HD-MTX as a frontline therapeutic regimen for PCNSL.The findings underscore the importance of exploring alternative treatment modalities and monitoring genomic and liquid biopsy markers to optimize patient outcomes.While the findings suggest promise,the study’s limitations should be considered,and further research is needed to establish the clinical relevance of this therapeutic approach for PCNSL.展开更多
Toll-like receptor 4(TLR4) and protease-activated receptor 2(PAR2) play pivotal roles in the mammalian innate immune response.Notably,in addition to their involvement in detection of invading pathogens,PAR2 and TLR4 m...Toll-like receptor 4(TLR4) and protease-activated receptor 2(PAR2) play pivotal roles in the mammalian innate immune response.Notably,in addition to their involvement in detection of invading pathogens,PAR2 and TLR4 modulate the levels of cell death-induced sterile inflammation by activating pro-or anti-inflammatory downstream signaling cascades.Within the central nervous system,there is emerging evidence that both receptors are involved in synaptic transmission and brain plasticity.Furthermore,due to their prominent role in mediating neuroinflammation,PAR2 and TLR4 are associated with development and progression of neurodegenerative disorders including but not limited to Alzheimer's disease,Parkinson's disease and multiple sclerosis.In this article,we summarise the current knowledge on the cooperation between PAR2 and TLR4,discuss the potential cross-talk levels and highlight the impact of the cross-coupling on neuroinflammation.展开更多
Summary： Endothelial dysfunction induced by intermittent hypoxia （IH） participates in obstructive sleep apnea syndrome （OSAS）-associated cardiovascular disorders. Myeloid differentiation primary response 88 （My...Summary： Endothelial dysfunction induced by intermittent hypoxia （IH） participates in obstructive sleep apnea syndrome （OSAS）-associated cardiovascular disorders. Myeloid differentiation primary response 88 （MyD88） and tumor necrosis factor receptor-associated factor 6 （TRAF6） regulate nu- merous downstream adaptors like mitogen-activated protein kinases （MAPKs） and the subsequent oxidative stress and inflammatory responses. This study aimed to characterize the role of MyD88/TRAF6 in IH-treated cell function and its associated signaling. Human umbilical vein endo- thelial cells （HUVECs） were randomly exposed to IH or normoxia for 0, 2, 4 and 6 h. Western blot- ting was used to detect the expression pattern of target gene proteins [angiotensin 1 receptor （AT1R）, p-ERK1/2, p-p38MAPK, MyD88 and TRAF6], and the relationships among these target genes down-regulated by the corresponding inhibitors were studied. Finally, the influence of these target genes on proliferation of HUVECs was also assessed by EdU analysis. Protein levels of AT1R, TRAF6 and p-ERK1/2 were increased after IH exposure, with a slight rise in MyD88 and a dynamic change in p-p38MAPK. The down-regulation of TRAF6 by siRNA reduced ERK1/2 phosphorylation during IH without any effects on ATIR. Blockade of AT1R with valsartan decreased TRAF6 and p-ERK1/2 protein expression after IH exposure. ERK1/2 inhibition with PD98059 suppressed only AT1R expression. IH promoted HUVECs proliferation, which was significantly suppressed by the in- hibition of TRAF6, AT1R and ERK1/2. The findings demonstrate that TRAF6 regulates the prolifera- tion of HUVECs exposed to short-term IH by modulating cell signaling involving ERK1/2 down- stream of AT1R. Targeting the AT1R-TRAF6-p-ERK1/2 signaling pathway might be helpful in re- storing endothelial function.展开更多
文摘In this editorial,we comment on the article by Wang et al.This manuscript explores the potential synergistic effects of combining zanubrutinib,a novel oral inhibitor of Bruton’s tyrosine kinase,with high-dose methotrexate(HD-MTX)as a therapeutic intervention for primary central nervous system lymphoma(PCNSL).The study involves a retrospective analysis of 19 PCNSL patients,highlighting clinicopathological characteristics,treatment outcomes,and genomic biomarkers.The results indicate the combination’s good tolerance and strong antitumor activity,with an 84.2%overall response rate.The authors emphasize the potential of zanubrutinib to modulate key genomic features of PCNSL,particularly mutations in myeloid differentiation primary response 88 and cluster of differentiation 79B.Furthermore,the study investigates the role of circulating tumor DNA in cerebrospinal fluid for disease surveillance and treatment response monitoring.In essence,the study provides valuable insights into the potential of combining zanubrutinib with HD-MTX as a frontline therapeutic regimen for PCNSL.The findings underscore the importance of exploring alternative treatment modalities and monitoring genomic and liquid biopsy markers to optimize patient outcomes.While the findings suggest promise,the study’s limitations should be considered,and further research is needed to establish the clinical relevance of this therapeutic approach for PCNSL.
文摘Toll-like receptor 4(TLR4) and protease-activated receptor 2(PAR2) play pivotal roles in the mammalian innate immune response.Notably,in addition to their involvement in detection of invading pathogens,PAR2 and TLR4 modulate the levels of cell death-induced sterile inflammation by activating pro-or anti-inflammatory downstream signaling cascades.Within the central nervous system,there is emerging evidence that both receptors are involved in synaptic transmission and brain plasticity.Furthermore,due to their prominent role in mediating neuroinflammation,PAR2 and TLR4 are associated with development and progression of neurodegenerative disorders including but not limited to Alzheimer's disease,Parkinson's disease and multiple sclerosis.In this article,we summarise the current knowledge on the cooperation between PAR2 and TLR4,discuss the potential cross-talk levels and highlight the impact of the cross-coupling on neuroinflammation.
基金supported by grants from the National Natural Science Foundation of China(No.81070067 and No.81370185)
文摘Summary： Endothelial dysfunction induced by intermittent hypoxia （IH） participates in obstructive sleep apnea syndrome （OSAS）-associated cardiovascular disorders. Myeloid differentiation primary response 88 （MyD88） and tumor necrosis factor receptor-associated factor 6 （TRAF6） regulate nu- merous downstream adaptors like mitogen-activated protein kinases （MAPKs） and the subsequent oxidative stress and inflammatory responses. This study aimed to characterize the role of MyD88/TRAF6 in IH-treated cell function and its associated signaling. Human umbilical vein endo- thelial cells （HUVECs） were randomly exposed to IH or normoxia for 0, 2, 4 and 6 h. Western blot- ting was used to detect the expression pattern of target gene proteins [angiotensin 1 receptor （AT1R）, p-ERK1/2, p-p38MAPK, MyD88 and TRAF6], and the relationships among these target genes down-regulated by the corresponding inhibitors were studied. Finally, the influence of these target genes on proliferation of HUVECs was also assessed by EdU analysis. Protein levels of AT1R, TRAF6 and p-ERK1/2 were increased after IH exposure, with a slight rise in MyD88 and a dynamic change in p-p38MAPK. The down-regulation of TRAF6 by siRNA reduced ERK1/2 phosphorylation during IH without any effects on ATIR. Blockade of AT1R with valsartan decreased TRAF6 and p-ERK1/2 protein expression after IH exposure. ERK1/2 inhibition with PD98059 suppressed only AT1R expression. IH promoted HUVECs proliferation, which was significantly suppressed by the in- hibition of TRAF6, AT1R and ERK1/2. The findings demonstrate that TRAF6 regulates the prolifera- tion of HUVECs exposed to short-term IH by modulating cell signaling involving ERK1/2 down- stream of AT1R. Targeting the AT1R-TRAF6-p-ERK1/2 signaling pathway might be helpful in re- storing endothelial function.
