Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a cru...Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.展开更多
Cellular senescence is a signal transduction process which maintained genomic stability and stopped mammalian cell growth. Furthermore, cellular senescence induces a protective response to a variety of DNA damage. How...Cellular senescence is a signal transduction process which maintained genomic stability and stopped mammalian cell growth. Furthermore, cellular senescence induces a protective response to a variety of DNA damage. However, this process is also associated with apoptosis, upregulated secretion of inflammatory cytokine, and promoted surrounding tissue damage. When cellular senescence accumulates to a certain extent, it triggers geriatric diseases, such as chronic inflammation, immune senescence-associated tumors and incontrollable infections. Cellular senescence gene SENEX, which was cloned in 2004, has been demonstrated to play a unique gatekeeper function in human endothelial cells when stress-induced pre-mature senescence and apoptosis occurr. The phenomenon that CD4+CD25+ Treg cells accumulated in the aged population has been well studied in recent years. Now Treg accumulation related to immune-pathology has attracted more interest. CD4+CD25+ Treg did not decline and age, but accumulated and suppressed immunoreaction. The enhanced Treg number and function may be associated with stress-induced premature senescence-mediated unique cellular senescence protection mechanisms, and SENEX may play a critical role in this process. In this article, we summarize the cellular senescence and SENEX gene in the accumulation and functional activity of CD4+CD25+ Treg in the elderly.展开更多
目的探讨senex基因在急性髓系白血病(AML)中的表达水平,并探讨其在AML发生发展中的意义。方法应用实时荧光定量PCR检测senex基因在21例初诊AML患者(初诊组)、27例骨髓完全缓解的AML患者(缓解组)、19例骨髓复发的AML患者(复发组)以及12...目的探讨senex基因在急性髓系白血病(AML)中的表达水平,并探讨其在AML发生发展中的意义。方法应用实时荧光定量PCR检测senex基因在21例初诊AML患者(初诊组)、27例骨髓完全缓解的AML患者(缓解组)、19例骨髓复发的AML患者(复发组)以及12例对照者(对照组)的骨髓单个核细胞中的表达情况,比较4组之间的基因表达水平差异,并分析senex基因表达水平与临床特征和疗效的关联性。结果初诊组senex基因表达水平高于缓解组(4.06±2.72 vs 2.52±1.83,P=0.04)和对照组(4.06±2.72 vs 1.22±0.48,P=0.001),复发组senex基因表达水平高于对照组(3.27±2.54 vs 1.22±0.48,P=0.017),且各亚型之间以AML-M3的senex基因表达水平最高。AML患者senex基因mRNA表达水平与骨髓原始细胞比例存在相关性(rs=0.557,P=0.000)。此外分析AML初诊患者的临床特征显示1次化疗缓解的患者(n=14)的senex基因表达显著低于1次化疗未缓解的患者(n=7)(1.77±1.47 vs 4.85±2.20,P=0.003),并且1次化疗未缓解的患者预后均较差。结论 senex基因的异常表达可能与AML的发生发展以及预后密切相关。展开更多
The present study aimed to clarify the role of SENEX in malignant cell proliferation in diffuse large B-cell lymphoma(DLBCL).22 DLBCL patients(6 newly diagnosed cases,7 cases at complete remission,and 9 relapsed cases...The present study aimed to clarify the role of SENEX in malignant cell proliferation in diffuse large B-cell lymphoma(DLBCL).22 DLBCL patients(6 newly diagnosed cases,7 cases at complete remission,and 9 relapsed cases)were included in the study.Our results indicated that both SENEX gene and protein were significantly increased in peripheral blood mononuclear cells(PBMCs)and tumor cells of relapsed DLBCL patients,accompanied by overexpression of p21,p16,and phosphorylated retinoblastoma(Rb).Silencing the SENEX gene in a DLBCL cell line caused a significant decrease in cell proliferation and inhibited cell cycle progression in the G1 phase.Phosphorylated Rb and E2F1 were also decreased,and activation of the Rb/E2F1 pathway was obviously suppressed.To conclude,the SENEX gene promotes proliferation in PBMC and tumor cells of DLBCL patients by activating the Rb/E2F1 pathway,in a manner suggesting that increased SENEX expression affects the relapse of DLBCL and may serve as an important target for DLBCL therapy.展开更多
The total protein increased in the gills and decreased in the muscle of the freshwater field crab Oziotelphusa senex senex at days 1 and 2 on exposure to lethal concentrations and at days 1 and 10 to sublethal concent...The total protein increased in the gills and decreased in the muscle of the freshwater field crab Oziotelphusa senex senex at days 1 and 2 on exposure to lethal concentrations and at days 1 and 10 to sublethal concentrations of furadan, endosulfan, chlorpyrifos, and a mixture of these three in a 100:10: 1 ratio. The increase in the gill protein was greater on exposure to the sublethal concentrations than to the lethal concentrations while the decrease in the muscle protein was greater on exposure to the lethal concentrations than to the sublethal concentrations. In the hepatopancreas, the protein content decreased on exposure to the lethal concentrations, but, in contrast, increased on exposure to the sublethal concentrations. These results clearly indicate that changes in the protein content are not only organ-dependent but also concentration-dependent, i.e., lethal versus sublethal. Irrespective of the changes in the total protein, the levels of free amino acids and the activities of protease, alanine and aspartate aminotransferases, and glutamate dehydrogenase increased in all the three organs of the crabs exposed to the lethal and sublethal concentrations, (more in lethal than in sublethal) and increased at a greater rate over time of exposure. Ammonia toxicity, measured by an increase in the hemolymph ammonia and a decrease in the urea, was also observed at the lethal concentrations of all the three pesticides. The ammonia and urea levels increased in the crabs exposed to the sublethal concentrations. Although the effect of each pesticide on the protein metabolism was similar, the degree of toxicity was the lowest on exposure to furadan, intermediate on exposure to endosulfan and chlorpyrifos, and cumulative on exposure to a mixture of the three pesticides展开更多
There is a growing body of research indicating that drones can disturb animals.However,it is usu-ally unclear whether the disturbance is due to visual or auditory cues.Here,we examined the effect of drone flights on t...There is a growing body of research indicating that drones can disturb animals.However,it is usu-ally unclear whether the disturbance is due to visual or auditory cues.Here,we examined the effect of drone flights on the behavior of great dusky swifts Cypseloides senex and white collared swifts Streptoprocne zonaris in 2 breeding sites where drone noise was obscured by environmental noise from waterfalls and any disturbance must be largely visual.We performed 12 experimental flights with a multirotor drone at different vertical,horizontal,and diagonal distances from the colonies.From all flights,17%caused<1%of birds to temporarily a bandon the breeding site,50%caused half to abandon,and 33%caused more than half to abandon.We found that the diagonal distance explained 98.9%of the variability of the disturbance percentage and while at distances>50 m the disturbance percentage does not exceed 20%,at<40 m the disturbance percentage increase to>60%.We recommend that flights with a multirotor drone during the breeding period should be con-ducted at a distance of>50 m and that recreational flights should be discouraged or conducted at larger distances(e.g.100 m)in nesting birds areas such as waterfalls,canyons,and caves.展开更多
基金This work was supported by the Major Subject of Science and Technology of Anhui Province(Grant Number:201903a07020030).
文摘Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.
文摘Cellular senescence is a signal transduction process which maintained genomic stability and stopped mammalian cell growth. Furthermore, cellular senescence induces a protective response to a variety of DNA damage. However, this process is also associated with apoptosis, upregulated secretion of inflammatory cytokine, and promoted surrounding tissue damage. When cellular senescence accumulates to a certain extent, it triggers geriatric diseases, such as chronic inflammation, immune senescence-associated tumors and incontrollable infections. Cellular senescence gene SENEX, which was cloned in 2004, has been demonstrated to play a unique gatekeeper function in human endothelial cells when stress-induced pre-mature senescence and apoptosis occurr. The phenomenon that CD4+CD25+ Treg cells accumulated in the aged population has been well studied in recent years. Now Treg accumulation related to immune-pathology has attracted more interest. CD4+CD25+ Treg did not decline and age, but accumulated and suppressed immunoreaction. The enhanced Treg number and function may be associated with stress-induced premature senescence-mediated unique cellular senescence protection mechanisms, and SENEX may play a critical role in this process. In this article, we summarize the cellular senescence and SENEX gene in the accumulation and functional activity of CD4+CD25+ Treg in the elderly.
文摘目的探讨senex基因在急性髓系白血病(AML)中的表达水平,并探讨其在AML发生发展中的意义。方法应用实时荧光定量PCR检测senex基因在21例初诊AML患者(初诊组)、27例骨髓完全缓解的AML患者(缓解组)、19例骨髓复发的AML患者(复发组)以及12例对照者(对照组)的骨髓单个核细胞中的表达情况,比较4组之间的基因表达水平差异,并分析senex基因表达水平与临床特征和疗效的关联性。结果初诊组senex基因表达水平高于缓解组(4.06±2.72 vs 2.52±1.83,P=0.04)和对照组(4.06±2.72 vs 1.22±0.48,P=0.001),复发组senex基因表达水平高于对照组(3.27±2.54 vs 1.22±0.48,P=0.017),且各亚型之间以AML-M3的senex基因表达水平最高。AML患者senex基因mRNA表达水平与骨髓原始细胞比例存在相关性(rs=0.557,P=0.000)。此外分析AML初诊患者的临床特征显示1次化疗缓解的患者(n=14)的senex基因表达显著低于1次化疗未缓解的患者(n=7)(1.77±1.47 vs 4.85±2.20,P=0.003),并且1次化疗未缓解的患者预后均较差。结论 senex基因的异常表达可能与AML的发生发展以及预后密切相关。
基金supported by the National Natural Science Foundation of China(Grant No.81670179)the Research Fund Project of Anhui Medical University(No.2018xkj026)the National Natural Science Foundation Incubation Project of the Second Hospital of Anhui Medical University(No.2019GQFY11).
文摘The present study aimed to clarify the role of SENEX in malignant cell proliferation in diffuse large B-cell lymphoma(DLBCL).22 DLBCL patients(6 newly diagnosed cases,7 cases at complete remission,and 9 relapsed cases)were included in the study.Our results indicated that both SENEX gene and protein were significantly increased in peripheral blood mononuclear cells(PBMCs)and tumor cells of relapsed DLBCL patients,accompanied by overexpression of p21,p16,and phosphorylated retinoblastoma(Rb).Silencing the SENEX gene in a DLBCL cell line caused a significant decrease in cell proliferation and inhibited cell cycle progression in the G1 phase.Phosphorylated Rb and E2F1 were also decreased,and activation of the Rb/E2F1 pathway was obviously suppressed.To conclude,the SENEX gene promotes proliferation in PBMC and tumor cells of DLBCL patients by activating the Rb/E2F1 pathway,in a manner suggesting that increased SENEX expression affects the relapse of DLBCL and may serve as an important target for DLBCL therapy.
文摘The total protein increased in the gills and decreased in the muscle of the freshwater field crab Oziotelphusa senex senex at days 1 and 2 on exposure to lethal concentrations and at days 1 and 10 to sublethal concentrations of furadan, endosulfan, chlorpyrifos, and a mixture of these three in a 100:10: 1 ratio. The increase in the gill protein was greater on exposure to the sublethal concentrations than to the lethal concentrations while the decrease in the muscle protein was greater on exposure to the lethal concentrations than to the sublethal concentrations. In the hepatopancreas, the protein content decreased on exposure to the lethal concentrations, but, in contrast, increased on exposure to the sublethal concentrations. These results clearly indicate that changes in the protein content are not only organ-dependent but also concentration-dependent, i.e., lethal versus sublethal. Irrespective of the changes in the total protein, the levels of free amino acids and the activities of protease, alanine and aspartate aminotransferases, and glutamate dehydrogenase increased in all the three organs of the crabs exposed to the lethal and sublethal concentrations, (more in lethal than in sublethal) and increased at a greater rate over time of exposure. Ammonia toxicity, measured by an increase in the hemolymph ammonia and a decrease in the urea, was also observed at the lethal concentrations of all the three pesticides. The ammonia and urea levels increased in the crabs exposed to the sublethal concentrations. Although the effect of each pesticide on the protein metabolism was similar, the degree of toxicity was the lowest on exposure to furadan, intermediate on exposure to endosulfan and chlorpyrifos, and cumulative on exposure to a mixture of the three pesticides
文摘There is a growing body of research indicating that drones can disturb animals.However,it is usu-ally unclear whether the disturbance is due to visual or auditory cues.Here,we examined the effect of drone flights on the behavior of great dusky swifts Cypseloides senex and white collared swifts Streptoprocne zonaris in 2 breeding sites where drone noise was obscured by environmental noise from waterfalls and any disturbance must be largely visual.We performed 12 experimental flights with a multirotor drone at different vertical,horizontal,and diagonal distances from the colonies.From all flights,17%caused<1%of birds to temporarily a bandon the breeding site,50%caused half to abandon,and 33%caused more than half to abandon.We found that the diagonal distance explained 98.9%of the variability of the disturbance percentage and while at distances>50 m the disturbance percentage does not exceed 20%,at<40 m the disturbance percentage increase to>60%.We recommend that flights with a multirotor drone during the breeding period should be con-ducted at a distance of>50 m and that recreational flights should be discouraged or conducted at larger distances(e.g.100 m)in nesting birds areas such as waterfalls,canyons,and caves.
