Chronic loss of sleep damages health and disturbs the quality of life.Long-lasting sleep deprivation(SD)as well as sleep abnormalities are substantial risk factors for major depressive disorder,although the underlying...Chronic loss of sleep damages health and disturbs the quality of life.Long-lasting sleep deprivation(SD)as well as sleep abnormalities are substantial risk factors for major depressive disorder,although the underlying mechanisms are not clear.Here,we showed that chronic SD in mice promotes a gradual elevation of extracellular ATP,which activates astroglial P2X7 receptors(P2X7Rs).Activated P2X7Rs,in turn,selectively down-regulated the expression of 5-HT2B receptors(5-HT2BRs)in astrocytes.Stimulation of P2X7Rs induced by SD selectively suppressed the phosphorylation of AKT and FoxO3 a in astrocytes,but not in neurons.The overexpression of FoxO3a in astrocytes inhibited the expression of 5-HT2BRs.Down-regulation of 5-HT2BsRs instigated by SD suppressed the activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2.This latter cascade promoted the release of arachidonic acid and prostaglandin E2.The depression-like behaviors induced by SD were alleviated in P2X7R-KO mice.Our study reveals the mechanism underlying chronic SD-induced depression-like behaviors and suggests 5-HT2BRs as a key target for exploring therapeutic strategies aimed at the depression evoked by sleep disorders.展开更多
The nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) were cloned and/or established as xenobiotic receptors in 1998.Due to their activities in the transcriptional regulation of phas...The nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) were cloned and/or established as xenobiotic receptors in 1998.Due to their activities in the transcriptional regulation of phase I and phase II enzymes as well as drug transporters,PXR and CAR have been defined as the master regulators of xenobiotic responses.The discovery of PXR and CAR provides the essential molecular basis by which drugs and other xenobiotic compounds regulate the expression of xenobiotic enzymes and transporters.This article is intended to provide a historical overview on the discovery of PXR and CAR as xenobiotic receptors.展开更多
Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive as...Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive astrocytes,inhibits NSC proliferation by suppressing protein aggregate clearance through the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1(UCHL1)-proteasome system post-SCI.However,the potential molecular mechanism by which C3a modulates NSC activation via this pathway remains unclear.Here,we revealed that C3a/C3a receptor(C3aR)signaling activated NF-κB p65,which in turn inhibited Nrf2 activity and UCHL1 expression,resulting in diminished proteasome activity and the accumulation of protein aggregates,and ultimately impaired NSC activation.Both knockdown of NF-κB p65 and Nrf2 upregulation restored UCHL1 expression and proteasome activity in vitro,promoting NSC activation by enhancing protein aggregate clearance.Mechanistically,we found that NF-κB p65 regulated Nrf2 activity through a dual mechanism:(1)promoting Keap1-dependent ubiquitination and proteasome degradation of Nrf2;(2)inhibiting protein kinase C-mediated Nrf2 phosphorylation and nuclear translocation.Using the dual-luciferase reporter assay and chromatin immunoprecipitation(ChIP)analysis,we further identified UCHL1 as a direct transcriptional target of Nrf2.Importantly,in vivo experiments using SCI mice confirmed that either C3aR blockade,NF-κB p65 knockdown,or Nrf2 overexpression could rescue SCI-induced UCHL1 downregulation.Together,this study uncovers the C3a-NF-κB p65-Nrf2-UCHL1-proteasome axis as a critical regulator of NSC activation after SCI.This may provide novel molecular targets and intervention strategies for SCI repair.展开更多
Objective:To investigate the hemostatic effect of modified Sijunzi Granules(MSG)in primary immune thrombocytopenia(ITP)zebrafish model and explore the potential mechanism.Methods:AB strain wild type zebrafish were tre...Objective:To investigate the hemostatic effect of modified Sijunzi Granules(MSG)in primary immune thrombocytopenia(ITP)zebrafish model and explore the potential mechanism.Methods:AB strain wild type zebrafish were treated with simvastatin(6μmol/L)for 24 h to establish the hemorrhage model(model control group).The zebrafish were treated with MSG at different doses(55.6,167,and 500μg/mL),respectively.The hemostatic effect was assessed by examining the intestinal bleeding and hemostatic rate.5-hydroxytryptamine(5-HT)content was determined using enzyme-linked immunosorbent assay(ELISA)assay.The expressions of5-HT2aR,5-HT2bR,and SERT genes were detected by quantitative real-time polymerase chain reaction(PCR).The protein expressions of protein kinase B(Akt),p-Akt,extracellular regulated protein kinases(Erk),and p-Erk were examined using Western blot analysis.Results:The intestinal bleeding rate was 37%,40%,and 80%in the55.6,167,and 500μg/mL dose of MSG,respectively,in which 55.6 and 167μg/mL MSG dose groups were associated with significantly decreased intestinal bleeding rate when compared with the model control group(70%,P<0.05).Significantly higher hemostatic rates were also observed in the 55.6μg/mL(54%)and 167μg/mL(52%)MSG dose groups(P<0.05).MSG increased the 5-HT content and mRNA expression levels of 5-HT2aR,5-HT2bR,and SERT(P<0.05).In addition,caspase3/7 activity was inhibited(P<0.05).Significant increase in p-Akt and p-Erk was also detected after treatment with MSG(P<0.05).Conclusions:MSG could reduce the incidence and severity of intestinal bleeding in zebrafish by activating MAPK/Erk and PI3K/Akt signal pathways through regulating the levels of 5-HT and its receptors,which may provide evidence for the treatment of ITP.展开更多
目的探讨膝关节骨关节炎患者血清可溶性核因子-κB受体激活剂配体(soluble receptor regulator of the nuclear factor-kappa B ligand,sRANKL)、巨噬细胞炎性蛋白-1β(macrophage inflammatory protein-1β,MIP-1β)、C1q肿瘤坏死因子...目的探讨膝关节骨关节炎患者血清可溶性核因子-κB受体激活剂配体(soluble receptor regulator of the nuclear factor-kappa B ligand,sRANKL)、巨噬细胞炎性蛋白-1β(macrophage inflammatory protein-1β,MIP-1β)、C1q肿瘤坏死因子相关蛋白-3(C1q/tumor necrosis factor-related protein 3,CTRP3)水平与病情严重程度及术后疾病转归的相关性。方法根据纳入及排除标准,选取2022年6月至2024年7月大庆油田总医院进行关节镜手术的106例膝关节骨关节炎患者为患病组,其中男56例,女50例;年龄56~73岁,平均(65.95±6.89)岁。根据MRI分级并结合患者病情程度分为2级组37例,3级组44例,4级组25例。根据术后疾病转归情况分为预后良好组74例,预后不良组32例。选择同期在本院体检的健康者106例为对照组,其中男53例,女53例;年龄53~72岁,平均(65.02±6.77)岁。经ELISA检测后,比较两组的血清sRANKL、MIP-1β、CTRP3水平,Spearman等级相关分析血清sRANKL、MIP-1β、CTRP3水平与病情严重程度相关性。Logistic回归分析患者预后不良的影响因素,绘制受试者工作特征(receiver operating characteristic,ROC)曲线分析血清sRANKL、MIP-1β、CTRP3对疾病转归的预测价值。结果患病组的血清sRANKL、MIP-1β显著高于对照组,CTRP3显著低于对照组(P<0.05)。3级、4级组的血清sRANKL、MIP-1β水平显著高于2级组,CTRP3水平显著低于2级组(P<0.05);且4级组的血清sRANKL、MIP-1β水平显著高于3级组,CTRP3水平显著低于3级组(P<0.05);sRANKL、MIP-1β与病情程度呈正相关(r=0.523,0.503,P<0.05),CTRP3水平与病情程度呈负相关(r=-0.508,P<0.05)。预后不良组受累间室个数、sRANKL、MIP-1β水平显著高于预后良好组(P<0.05),CTRP3显著低于预后良好组(P<0.05)。血清sRANKL、MIP-1β、CTRP3联合预测患者预后的曲线下面积(area under curve,AUC)为0.962,显著优于sRANKL(Z=2.532,P=0.011)、MIP-1β(Z=2.595,P=0.010)、CTRP3(Z=2.950,P=0.003)单独预测。sRANKL、MIP-1β水平升高是影响患者预后不良的危险因素,CTRP3水平升高是影响患者预后不良的保护因素(P<0.05)。结论膝关节骨关节炎患者血清sRANKL、MIP-1β水平升高,CTRP3水平降低,与病情程度及术后疾病转归具有一定相关性。展开更多
基金the National Natural Science Foundation of China(81871852,81200935,81671862,and 81871529)Liaoning Revitalization Talents Program(XLYC1807137)+1 种基金the Scientific Research Foundation for Overseas Scholars of the Education Ministry of China(20151098)the Natural Science Foundation of Liaoning Province,China(20170541030)。
文摘Chronic loss of sleep damages health and disturbs the quality of life.Long-lasting sleep deprivation(SD)as well as sleep abnormalities are substantial risk factors for major depressive disorder,although the underlying mechanisms are not clear.Here,we showed that chronic SD in mice promotes a gradual elevation of extracellular ATP,which activates astroglial P2X7 receptors(P2X7Rs).Activated P2X7Rs,in turn,selectively down-regulated the expression of 5-HT2B receptors(5-HT2BRs)in astrocytes.Stimulation of P2X7Rs induced by SD selectively suppressed the phosphorylation of AKT and FoxO3 a in astrocytes,but not in neurons.The overexpression of FoxO3a in astrocytes inhibited the expression of 5-HT2BRs.Down-regulation of 5-HT2BsRs instigated by SD suppressed the activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2.This latter cascade promoted the release of arachidonic acid and prostaglandin E2.The depression-like behaviors induced by SD were alleviated in P2X7R-KO mice.Our study reveals the mechanism underlying chronic SD-induced depression-like behaviors and suggests 5-HT2BRs as a key target for exploring therapeutic strategies aimed at the depression evoked by sleep disorders.
基金supported in part by the Joseph Koslow Endowed Professorship from the University of Pittsburgh School of Pharmacy
文摘The nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) were cloned and/or established as xenobiotic receptors in 1998.Due to their activities in the transcriptional regulation of phase I and phase II enzymes as well as drug transporters,PXR and CAR have been defined as the master regulators of xenobiotic responses.The discovery of PXR and CAR provides the essential molecular basis by which drugs and other xenobiotic compounds regulate the expression of xenobiotic enzymes and transporters.This article is intended to provide a historical overview on the discovery of PXR and CAR as xenobiotic receptors.
基金supported by the National Natural Science Foundation of China(82071362 and 82270669)Key Project of the Regional Joint Fund of Guangdong Province(2023B1515120077)+3 种基金Basic Research Program of Shenzhen Science and Technology Innovation Commission(JCYJ20210324123001003 and JCYJ20220530144801003)Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research(ZDSYS20230626091402006)the Innovation and Entrepreneurship Training Program for College Students,Sun Yat-sen University(20242150)the Leading Innovation and Entrepreneurship Team Program of Zhejiang Province,China(2023R01005).
文摘Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive astrocytes,inhibits NSC proliferation by suppressing protein aggregate clearance through the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1(UCHL1)-proteasome system post-SCI.However,the potential molecular mechanism by which C3a modulates NSC activation via this pathway remains unclear.Here,we revealed that C3a/C3a receptor(C3aR)signaling activated NF-κB p65,which in turn inhibited Nrf2 activity and UCHL1 expression,resulting in diminished proteasome activity and the accumulation of protein aggregates,and ultimately impaired NSC activation.Both knockdown of NF-κB p65 and Nrf2 upregulation restored UCHL1 expression and proteasome activity in vitro,promoting NSC activation by enhancing protein aggregate clearance.Mechanistically,we found that NF-κB p65 regulated Nrf2 activity through a dual mechanism:(1)promoting Keap1-dependent ubiquitination and proteasome degradation of Nrf2;(2)inhibiting protein kinase C-mediated Nrf2 phosphorylation and nuclear translocation.Using the dual-luciferase reporter assay and chromatin immunoprecipitation(ChIP)analysis,we further identified UCHL1 as a direct transcriptional target of Nrf2.Importantly,in vivo experiments using SCI mice confirmed that either C3aR blockade,NF-κB p65 knockdown,or Nrf2 overexpression could rescue SCI-induced UCHL1 downregulation.Together,this study uncovers the C3a-NF-κB p65-Nrf2-UCHL1-proteasome axis as a critical regulator of NSC activation after SCI.This may provide novel molecular targets and intervention strategies for SCI repair.
基金Supported by Natural Science Foundation of Zhejiang Province(No.LQ23H270001)。
文摘Objective:To investigate the hemostatic effect of modified Sijunzi Granules(MSG)in primary immune thrombocytopenia(ITP)zebrafish model and explore the potential mechanism.Methods:AB strain wild type zebrafish were treated with simvastatin(6μmol/L)for 24 h to establish the hemorrhage model(model control group).The zebrafish were treated with MSG at different doses(55.6,167,and 500μg/mL),respectively.The hemostatic effect was assessed by examining the intestinal bleeding and hemostatic rate.5-hydroxytryptamine(5-HT)content was determined using enzyme-linked immunosorbent assay(ELISA)assay.The expressions of5-HT2aR,5-HT2bR,and SERT genes were detected by quantitative real-time polymerase chain reaction(PCR).The protein expressions of protein kinase B(Akt),p-Akt,extracellular regulated protein kinases(Erk),and p-Erk were examined using Western blot analysis.Results:The intestinal bleeding rate was 37%,40%,and 80%in the55.6,167,and 500μg/mL dose of MSG,respectively,in which 55.6 and 167μg/mL MSG dose groups were associated with significantly decreased intestinal bleeding rate when compared with the model control group(70%,P<0.05).Significantly higher hemostatic rates were also observed in the 55.6μg/mL(54%)and 167μg/mL(52%)MSG dose groups(P<0.05).MSG increased the 5-HT content and mRNA expression levels of 5-HT2aR,5-HT2bR,and SERT(P<0.05).In addition,caspase3/7 activity was inhibited(P<0.05).Significant increase in p-Akt and p-Erk was also detected after treatment with MSG(P<0.05).Conclusions:MSG could reduce the incidence and severity of intestinal bleeding in zebrafish by activating MAPK/Erk and PI3K/Akt signal pathways through regulating the levels of 5-HT and its receptors,which may provide evidence for the treatment of ITP.
文摘目的探讨膝关节骨关节炎患者血清可溶性核因子-κB受体激活剂配体(soluble receptor regulator of the nuclear factor-kappa B ligand,sRANKL)、巨噬细胞炎性蛋白-1β(macrophage inflammatory protein-1β,MIP-1β)、C1q肿瘤坏死因子相关蛋白-3(C1q/tumor necrosis factor-related protein 3,CTRP3)水平与病情严重程度及术后疾病转归的相关性。方法根据纳入及排除标准,选取2022年6月至2024年7月大庆油田总医院进行关节镜手术的106例膝关节骨关节炎患者为患病组,其中男56例,女50例;年龄56~73岁,平均(65.95±6.89)岁。根据MRI分级并结合患者病情程度分为2级组37例,3级组44例,4级组25例。根据术后疾病转归情况分为预后良好组74例,预后不良组32例。选择同期在本院体检的健康者106例为对照组,其中男53例,女53例;年龄53~72岁,平均(65.02±6.77)岁。经ELISA检测后,比较两组的血清sRANKL、MIP-1β、CTRP3水平,Spearman等级相关分析血清sRANKL、MIP-1β、CTRP3水平与病情严重程度相关性。Logistic回归分析患者预后不良的影响因素,绘制受试者工作特征(receiver operating characteristic,ROC)曲线分析血清sRANKL、MIP-1β、CTRP3对疾病转归的预测价值。结果患病组的血清sRANKL、MIP-1β显著高于对照组,CTRP3显著低于对照组(P<0.05)。3级、4级组的血清sRANKL、MIP-1β水平显著高于2级组,CTRP3水平显著低于2级组(P<0.05);且4级组的血清sRANKL、MIP-1β水平显著高于3级组,CTRP3水平显著低于3级组(P<0.05);sRANKL、MIP-1β与病情程度呈正相关(r=0.523,0.503,P<0.05),CTRP3水平与病情程度呈负相关(r=-0.508,P<0.05)。预后不良组受累间室个数、sRANKL、MIP-1β水平显著高于预后良好组(P<0.05),CTRP3显著低于预后良好组(P<0.05)。血清sRANKL、MIP-1β、CTRP3联合预测患者预后的曲线下面积(area under curve,AUC)为0.962,显著优于sRANKL(Z=2.532,P=0.011)、MIP-1β(Z=2.595,P=0.010)、CTRP3(Z=2.950,P=0.003)单独预测。sRANKL、MIP-1β水平升高是影响患者预后不良的危险因素,CTRP3水平升高是影响患者预后不良的保护因素(P<0.05)。结论膝关节骨关节炎患者血清sRANKL、MIP-1β水平升高,CTRP3水平降低,与病情程度及术后疾病转归具有一定相关性。
