Signal transducer and activator of transcription 3 (STAT3) is a recently characterized transcription factor which is essential to liver regeneration. We have previously reported that hepatic stimulator substance (HSS)...Signal transducer and activator of transcription 3 (STAT3) is a recently characterized transcription factor which is essential to liver regeneration. We have previously reported that hepatic stimulator substance (HSS), a novel growthpromoting substance, phosphorylated the epidermal growth factor (EGF) receptors and activated downstream RasMAP kinase (extracellular signal-regulated kinases, ERK1/2) cascade. However, whether HSS signal is related to STAT3pathway remains unclear. The present study is aiming to explore the regulatory effect of activation of ERK1/2 evoked by HSS on STAT3 phosphorylation and STAT3 signaling. Human hepatoma cell line HepG2 was stably transfected with HSS cDNA and HSS expression was measured by Northern blot. The results showed that the transfection of HSS into HepG2 resulted in remarkable increase in cellular proliferation as compared with the non-transfected cells, and it was further proved that the cellular proliferation in the HSS-transfected cells was related to ERK1/2 activation. Treatment of the cells with 50 μM of PD98059, an ERK1/2 specific upstream inhibitor, resulted in ERK1/2 inactivation completely.Inhibition of ERK1/2 allowed the tyrosine of STAT3 to be phosphorylated in a dose-dependent manner to PD98059.Furthermore, transient transfection of STAT3 mutant (STAT3S727A) into HSS-bearing cells could remarkably reverse the inhibitory effect of ERK1/2 on STAT3 phosphorylation. Based upon these results, it is concluded that ERK1/2negatively modulates STAT3 phosphorylation and this function is dependent on residual serine-727 (S727) of STAT3.展开更多
Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in diverse cellular events, including cell proliferation, differentiation and apoptosis. TNF is also involved in many types of disea...Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in diverse cellular events, including cell proliferation, differentiation and apoptosis. TNF is also involved in many types of diseases. In recent years, the molecular mechanisms of TNF functions have been intensively investigated. Studies from many laboratories have demonstrated that the TNF-mediated diverse biological responses are achieved through activating multiple signal- ing pathways. Especially the activation of transcription factors NF-κB and AP-1 plays a critical role in mediating these cellular responses. Several proteins, including FADD, the death domain kinase RIP and the TNF receptor associated factor TRAF2 have been identified as the key effectors of TNF signaling. Recently, we found that the effector mol- ecules of TNF signaling, such as RIP and TRAF2, are also involved in other cellular responses. These finding suggests that RIP and TRAF2 serve a broader role than as just an effector of TNF signaling.展开更多
OBJECTIVE: Inactivation of the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3) signaling axis plays a crucial role in determining the fate of neural stem cells(NSCs).Qingnaoyizhi decocti...OBJECTIVE: Inactivation of the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3) signaling axis plays a crucial role in determining the fate of neural stem cells(NSCs).Qingnaoyizhi decoction(QNYZD) has been used for the treatment of vascular dementia and has shown to improve synaptic remodeling. The aim of this study was to evaluate the effect of cerebrospinal fluid(CSF) containing QNYZD(CSF-QNYZD) on the differentiation of cultured NSCs and the involvement of the JAK2/STAT3 pathway.METHODS: The protein expression levels of glial fibrillary acidic protein(GFAP), tubulin, drosophila mothers against decapentaplegic protein(SMAD-1), STAT3, and phosphorylated-STAT3 were detected by western immunoblot analysis in the groups: control, CSF, JAK/STAT inhibitor(AG490),CSF-QNYZD, and CSF-XDZ(CSF-Xidezhen). The differentiation of NSCs was determined by immunofluorescence staining. The proliferation of NSCs was measured using the Cell Counting Kit-8 proliferation assay.RESULTS: Compared with the control group,CSF-QNYZD and AG490 significantly increased the number and expression of tubulin-positive cells, reduced the number and expression of GFAP-positive cells, and down-regulated the expression of p-STAT3. However, CSF-QNYZD also decreased the expression of SMAD-1 and STAT3.CONCLUSION: Enhanced neuronal differentiation may be associated with the down-regulation of glial differentiation instead of promoting proliferationin treated NSCs. Furthermore, QNYZD may play a direct role in suppressing the formation of GFAP-positive cells and enhancing neuronal differentiation by inhibiting JAK2/STAT3 activation. Overall, these results provide insights into the possible mechanism underlying QNYZD-mediated neurogenesis.展开更多
Hypoxia-inducible factor-1(HIF-1)is a key heterodimeric transcription factor for the cellular adaptive response to hypoxia,a common feature of the microenvironment in solid tumors.The transcriptional activity,protein ...Hypoxia-inducible factor-1(HIF-1)is a key heterodimeric transcription factor for the cellular adaptive response to hypoxia,a common feature of the microenvironment in solid tumors.The transcriptional activity,protein stabilization,protein-protein interactions and cellular localization of HIF-1α,an oxygen-sensitive subunit of HIF-1,are mainly modulated by various post-translational modifications.Recently,we reported that polycomb chromobox 4(Cbx4)governs the transcriptional activity of HIF-1αby enhancing its sumoylation at K391 and K477,through which Cbx4 potentiates angiogenesis of hepatocellular carcinoma.This review summarizes the current knowledge of HIF-1α sumoylation and its roles in the pathogenesis of cancer.展开更多
We report a new strategy to prepare gold nanoflowers （AuNFs） using a two-step seed-mediated method. The as-prepared AuNFs were employed as surface-enhance Raman scattering （SERS） substrates, showing strong signal ...We report a new strategy to prepare gold nanoflowers （AuNFs） using a two-step seed-mediated method. The as-prepared AuNFs were employed as surface-enhance Raman scattering （SERS） substrates, showing strong signal enhancement. We further found that iodide ions （I^-） could selectively induce the morphological transformation of AuNFs to spheres, resulting in a blue-shift of the localized surface plasmon resonance （LSPR） bands, a color change of the AuNFs solution from blue to red, and decreased SERS activity. This behavior allows the AuNFs to be used in the determination of I^-.展开更多
The thioredoxin system plays a role in a variety of physiological functions, including cell growth, differenti- ation, apoptosis, tumorigenesis, and immunity. We previously confirmed that butaselen （BS）, a novel thi...The thioredoxin system plays a role in a variety of physiological functions, including cell growth, differenti- ation, apoptosis, tumorigenesis, and immunity. We previously confirmed that butaselen （BS）, a novel thioredoxin reductase inhibitor, can inhibit the growth of various human cancer cell lines, yet the underlying mechanism remains elusive. In this study, we investigated the anti-tumor effect of BS in vivo through regulating the immune system of KM mice. We found that BS inhibits tumor proliferation by promoting the activation of splenic lymphocytes in mice. BS can elevate the percentage of CD^4-CD8^＋ T lymphocytes and the secretion of downstream cytokines in mice via downregulating the expression of programmed death-ligand 1 （PD-L1） on the tumor cells＇ surface in vivo. Further study in HepG2 and BEL-7402 cells showed that decrease of PD-L1 level after BS treatment was achieved by inhibiting signal transducer and activator of transcription 3 （STAT3） phosphorylation. Taken together, our results suggest that BS has a role in promoting the immune response by reducing PD-L1 expression via the STAT3 pathway, and subsequently suppresses tumorigenesis.展开更多
Willed-movement training has been demonstrated to be a promising approach to increase motor per- formance and neural plasticity in ischemic rats. However, little is known regarding the molecular signals that are in- v...Willed-movement training has been demonstrated to be a promising approach to increase motor per- formance and neural plasticity in ischemic rats. However, little is known regarding the molecular signals that are in- volved in neural plasticity following willed-movement training. To investigate the potential signals related to neural plasticity following willed-movement training, littermate rats were randomly assigned into three groups： middle cerebral artery occlusion, environmental modification, and willed-movement training. The infarct volume was measured 18 d after occlusion of the right middle cerebral artery. Reverse transcription-polymerase chain reaction （PCR） and im- munofluorescence staining were used to detect the changes in the signal transducer and activator of transcription 3 （STAT3） mRNA and protein, respectively. A chromatin immunoprecipitation was used to investigate whether STAT3 bound to plasticity-related genes, such as brain-derived neurotrophic factor （BDNF）, synaptophysin, and protein in- teracting with C kinase 1 （PICK1）. In this study, we demonstrated that STAT3 mRNA and protein were markedly increased following 15-d willed-movement training in the ischemic hemispheres of the treated rats. STAT3 bound to BDNF, PICK1, and synaptophysin promoters in the neocortical cells of rats. These data suggest that the increased STAT3 levels after willed-movement training might play critical roles in the neural plasticity by directly regulating plasticity-related genes.展开更多
基金This work was supported by the National Natural Science Foundation of China(No.39870285,No.0070342).
文摘Signal transducer and activator of transcription 3 (STAT3) is a recently characterized transcription factor which is essential to liver regeneration. We have previously reported that hepatic stimulator substance (HSS), a novel growthpromoting substance, phosphorylated the epidermal growth factor (EGF) receptors and activated downstream RasMAP kinase (extracellular signal-regulated kinases, ERK1/2) cascade. However, whether HSS signal is related to STAT3pathway remains unclear. The present study is aiming to explore the regulatory effect of activation of ERK1/2 evoked by HSS on STAT3 phosphorylation and STAT3 signaling. Human hepatoma cell line HepG2 was stably transfected with HSS cDNA and HSS expression was measured by Northern blot. The results showed that the transfection of HSS into HepG2 resulted in remarkable increase in cellular proliferation as compared with the non-transfected cells, and it was further proved that the cellular proliferation in the HSS-transfected cells was related to ERK1/2 activation. Treatment of the cells with 50 μM of PD98059, an ERK1/2 specific upstream inhibitor, resulted in ERK1/2 inactivation completely.Inhibition of ERK1/2 allowed the tyrosine of STAT3 to be phosphorylated in a dose-dependent manner to PD98059.Furthermore, transient transfection of STAT3 mutant (STAT3S727A) into HSS-bearing cells could remarkably reverse the inhibitory effect of ERK1/2 on STAT3 phosphorylation. Based upon these results, it is concluded that ERK1/2negatively modulates STAT3 phosphorylation and this function is dependent on residual serine-727 (S727) of STAT3.
文摘Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in diverse cellular events, including cell proliferation, differentiation and apoptosis. TNF is also involved in many types of diseases. In recent years, the molecular mechanisms of TNF functions have been intensively investigated. Studies from many laboratories have demonstrated that the TNF-mediated diverse biological responses are achieved through activating multiple signal- ing pathways. Especially the activation of transcription factors NF-κB and AP-1 plays a critical role in mediating these cellular responses. Several proteins, including FADD, the death domain kinase RIP and the TNF receptor associated factor TRAF2 have been identified as the key effectors of TNF signaling. Recently, we found that the effector mol- ecules of TNF signaling, such as RIP and TRAF2, are also involved in other cellular responses. These finding suggests that RIP and TRAF2 serve a broader role than as just an effector of TNF signaling.
基金Supported by 973 Project for Basic Research of Traditional Chinese Medicine(No.2010CB530405)the National Natural Science Foundation of China(Effects and Mechanisms of Storax on NF-ΚB-Mediated Inflammatory Response During Cerebral Ischemia-Reperfusion Injure,No.81273815)+1 种基金the Foundation for the Author of National Excellent Doctoral Dissertation of China(No.201082)the China Postdoctoral Fund of Sciences(The Effect of Cerebrospinal Fluid Containing Yishenhuazhuo Decotion on the Self-Renewal and Differentiation of Neural Stem Cell,No.2012M520587)
文摘OBJECTIVE: Inactivation of the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3) signaling axis plays a crucial role in determining the fate of neural stem cells(NSCs).Qingnaoyizhi decoction(QNYZD) has been used for the treatment of vascular dementia and has shown to improve synaptic remodeling. The aim of this study was to evaluate the effect of cerebrospinal fluid(CSF) containing QNYZD(CSF-QNYZD) on the differentiation of cultured NSCs and the involvement of the JAK2/STAT3 pathway.METHODS: The protein expression levels of glial fibrillary acidic protein(GFAP), tubulin, drosophila mothers against decapentaplegic protein(SMAD-1), STAT3, and phosphorylated-STAT3 were detected by western immunoblot analysis in the groups: control, CSF, JAK/STAT inhibitor(AG490),CSF-QNYZD, and CSF-XDZ(CSF-Xidezhen). The differentiation of NSCs was determined by immunofluorescence staining. The proliferation of NSCs was measured using the Cell Counting Kit-8 proliferation assay.RESULTS: Compared with the control group,CSF-QNYZD and AG490 significantly increased the number and expression of tubulin-positive cells, reduced the number and expression of GFAP-positive cells, and down-regulated the expression of p-STAT3. However, CSF-QNYZD also decreased the expression of SMAD-1 and STAT3.CONCLUSION: Enhanced neuronal differentiation may be associated with the down-regulation of glial differentiation instead of promoting proliferationin treated NSCs. Furthermore, QNYZD may play a direct role in suppressing the formation of GFAP-positive cells and enhancing neuronal differentiation by inhibiting JAK2/STAT3 activation. Overall, these results provide insights into the possible mechanism underlying QNYZD-mediated neurogenesis.
基金supported by grants from the National Natural Science Foundation of China (91213304,31101044)the National Basic Research Program of China (NO2009CB918404)+1 种基金Shanghai Science & Technology Committee (11JC1406800)Shanghai Committee of Education and Doctoral Innovation Fund Projects from Shanghai Jiao Tong University School of Medicine
文摘Hypoxia-inducible factor-1(HIF-1)is a key heterodimeric transcription factor for the cellular adaptive response to hypoxia,a common feature of the microenvironment in solid tumors.The transcriptional activity,protein stabilization,protein-protein interactions and cellular localization of HIF-1α,an oxygen-sensitive subunit of HIF-1,are mainly modulated by various post-translational modifications.Recently,we reported that polycomb chromobox 4(Cbx4)governs the transcriptional activity of HIF-1αby enhancing its sumoylation at K391 and K477,through which Cbx4 potentiates angiogenesis of hepatocellular carcinoma.This review summarizes the current knowledge of HIF-1α sumoylation and its roles in the pathogenesis of cancer.
基金supported by the National Natural Science Foundation of China (21305113)the Chongqing Fundamental and Advanced Research Project (cstc2013jcyjA50008)+2 种基金the Fundamental Research Funds for the Central Universities (XDJK2015B029)the fund of State Key Laboratory of Electroanalytical Chemistry (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences) (SKLEAC201312)the Research Fund for the Doctor Program of Southwest University (swu111077)
文摘We report a new strategy to prepare gold nanoflowers （AuNFs） using a two-step seed-mediated method. The as-prepared AuNFs were employed as surface-enhance Raman scattering （SERS） substrates, showing strong signal enhancement. We further found that iodide ions （I^-） could selectively induce the morphological transformation of AuNFs to spheres, resulting in a blue-shift of the localized surface plasmon resonance （LSPR） bands, a color change of the AuNFs solution from blue to red, and decreased SERS activity. This behavior allows the AuNFs to be used in the determination of I^-.
基金Project supported by the National Natural Science Foundation of China(No.81372266)the National Science and Technology Major Project(No.2011zx09101-001-03)China
文摘The thioredoxin system plays a role in a variety of physiological functions, including cell growth, differenti- ation, apoptosis, tumorigenesis, and immunity. We previously confirmed that butaselen （BS）, a novel thioredoxin reductase inhibitor, can inhibit the growth of various human cancer cell lines, yet the underlying mechanism remains elusive. In this study, we investigated the anti-tumor effect of BS in vivo through regulating the immune system of KM mice. We found that BS inhibits tumor proliferation by promoting the activation of splenic lymphocytes in mice. BS can elevate the percentage of CD^4-CD8^＋ T lymphocytes and the secretion of downstream cytokines in mice via downregulating the expression of programmed death-ligand 1 （PD-L1） on the tumor cells＇ surface in vivo. Further study in HepG2 and BEL-7402 cells showed that decrease of PD-L1 level after BS treatment was achieved by inhibiting signal transducer and activator of transcription 3 （STAT3） phosphorylation. Taken together, our results suggest that BS has a role in promoting the immune response by reducing PD-L1 expression via the STAT3 pathway, and subsequently suppresses tumorigenesis.
基金Project supported by the National Natural Science Foundation of China(Nos.30973167,81472160,and 81173595)the China Postdoctoral Science Foundation(Nos.2011M501301 and 2012T50711)the China-Japan Friendship Hospital Youth Science and Technology Excellence Project(No.2014-QNYC-A-04)
文摘Willed-movement training has been demonstrated to be a promising approach to increase motor per- formance and neural plasticity in ischemic rats. However, little is known regarding the molecular signals that are in- volved in neural plasticity following willed-movement training. To investigate the potential signals related to neural plasticity following willed-movement training, littermate rats were randomly assigned into three groups： middle cerebral artery occlusion, environmental modification, and willed-movement training. The infarct volume was measured 18 d after occlusion of the right middle cerebral artery. Reverse transcription-polymerase chain reaction （PCR） and im- munofluorescence staining were used to detect the changes in the signal transducer and activator of transcription 3 （STAT3） mRNA and protein, respectively. A chromatin immunoprecipitation was used to investigate whether STAT3 bound to plasticity-related genes, such as brain-derived neurotrophic factor （BDNF）, synaptophysin, and protein in- teracting with C kinase 1 （PICK1）. In this study, we demonstrated that STAT3 mRNA and protein were markedly increased following 15-d willed-movement training in the ischemic hemispheres of the treated rats. STAT3 bound to BDNF, PICK1, and synaptophysin promoters in the neocortical cells of rats. These data suggest that the increased STAT3 levels after willed-movement training might play critical roles in the neural plasticity by directly regulating plasticity-related genes.
