Despite improvements in surgical techniques and adjuvant chemotherapy, the overall mortality rates in pan- creatic cancer have generally remained relatively un-changed and the 5-year survival rate is actually below 2%...Despite improvements in surgical techniques and adjuvant chemotherapy, the overall mortality rates in pan- creatic cancer have generally remained relatively un-changed and the 5-year survival rate is actually below 2%. This paper will address the importance of achieving an early diagnosis and identifying markers for prog- nosis and response to therapy such as genes, proteins, microP, NAs or epigenetic modifications. However, there are still major hurdles when translating investigational biomarkers into routine clinical practice. Furthermore, novel ways of secondary screening in high-risk individu- als, such as artificial neural networks and modern imaging, will be discussed. Drug resistance is ubiquitous in pancreatic cancer. Several mechanisms of drug resistance have already been revealed, including human equilibrative nucleoside transporter-1 status, multidrug resistance proteins, aberrant signaling pathways, mi-croRNAs, stromal influence, epithelial-mesenchymal transition-type cells and recently the presence of can- cer stem cells/cancer-initiating cells. These factors must be considered when developing more customized types of intervention （＇personalized medicine＇S. In the future, multifunctional nanoparticles that combine a specific targeting agent, an imaging probe, a cell-penetrating agent, a biocompatible polymer and an anti-cancer drug may become valuable for the management of pa- tients with pancreatic cancer.展开更多
Since their discovery over 100 years ago, sphingolipids have caught the eyes and the imagination of scientists.Modern science has made many new insights on the cell biology and day-to-day functions of many integral sp...Since their discovery over 100 years ago, sphingolipids have caught the eyes and the imagination of scientists.Modern science has made many new insights on the cell biology and day-to-day functions of many integral sphingolipids, especially those of ceramide. Ceramide is recognized as a vital second messenger in the signal transduction process mediated by receptors of many cytokines and growth factors.A great part of our current understanding of ceramide has been achieved from apoptosis-related studies, however recent data in the fields of immunology, endocrinology and neurobiology, also suggest a fundamental involvement of ceramide in the onset of diseases. Therefore, understanding the biology of ceramide could be a key to unraveling many biological mechanisms and provide information for the treatment of some common diseases.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
Wnts are a highly conserved family of Upid-modified glycoproteins that work as morphogens to activate several signaling pathways, leading to remodeling of the cytoskeleton and the regulation of gene transcription. Wnt...Wnts are a highly conserved family of Upid-modified glycoproteins that work as morphogens to activate several signaling pathways, leading to remodeling of the cytoskeleton and the regulation of gene transcription. Wnt signaling regulates multiple cellular functions and cell systems, including the development and maintenance of midbrain dopaminergic （m DA） neurons. These neurons are of consid- erable interest for regenerative medicine because their degeneration results in Parkinson＇s disease （PD）. This review focuses on new advances in understanding key functions of Wnts in mDA neuron development and using novel tools to regulate Wnt signaling in re- generative medicine for PD. Particularly, recent reports indicate that appropriate levels of Wnt signaling are essential to improve the quantity and quality of stem ceil- or reprogrammed ceU-derived mDA neurons to be used in drug discovery and cell replacement therapy for PD.展开更多
During the past three decades, the Wingless-type MMTV integration site （Wnt） signaling cascade has emerged as an essential system regulating multiple processes in developing and adult brain. Accumulating evidence po...During the past three decades, the Wingless-type MMTV integration site （Wnt） signaling cascade has emerged as an essential system regulating multiple processes in developing and adult brain. Accumulating evidence points to a dysregulation of Wnt signaling in major neurodegenerative pathologies including Parkinson＇s disease （PD）, a common neurodegenerative disorder characterized by the pro- gressive loss of midbrain dopaminergic （mDA） neurons and deregulated activation of astrocytes and microglia. This review highlights the emerging link between Wnt signaling and key inflammatory pathways during mDA neuron damage/repair in PD progression. In particular, we summarize recent evidence documenting that aging and neurotoxicant exposure strongly antagonize Wnt/β-catenin signaling in mDA neurons and subventricular zone （SVZ） neuroprogenitors via astrocyte-microglial interactions. Dysregulation of the crosstalk between Wnt/β-catenin signaling and anti-oxidant/anti-inflammatory pathways delineate novel mechanisms driving the decline of SVZ plasticity with age and the limited nigrostriatal dopaminergic self-repair in PD. These findings hold a promise in devetoping therapies that target Wnt/β-catenin signaling to enhance endogenous restoration and neuronal outcome in age-dependent diseases, such as PD.展开更多
文摘Despite improvements in surgical techniques and adjuvant chemotherapy, the overall mortality rates in pan- creatic cancer have generally remained relatively un-changed and the 5-year survival rate is actually below 2%. This paper will address the importance of achieving an early diagnosis and identifying markers for prog- nosis and response to therapy such as genes, proteins, microP, NAs or epigenetic modifications. However, there are still major hurdles when translating investigational biomarkers into routine clinical practice. Furthermore, novel ways of secondary screening in high-risk individu- als, such as artificial neural networks and modern imaging, will be discussed. Drug resistance is ubiquitous in pancreatic cancer. Several mechanisms of drug resistance have already been revealed, including human equilibrative nucleoside transporter-1 status, multidrug resistance proteins, aberrant signaling pathways, mi-croRNAs, stromal influence, epithelial-mesenchymal transition-type cells and recently the presence of can- cer stem cells/cancer-initiating cells. These factors must be considered when developing more customized types of intervention （＇personalized medicine＇S. In the future, multifunctional nanoparticles that combine a specific targeting agent, an imaging probe, a cell-penetrating agent, a biocompatible polymer and an anti-cancer drug may become valuable for the management of pa- tients with pancreatic cancer.
文摘Since their discovery over 100 years ago, sphingolipids have caught the eyes and the imagination of scientists.Modern science has made many new insights on the cell biology and day-to-day functions of many integral sphingolipids, especially those of ceramide. Ceramide is recognized as a vital second messenger in the signal transduction process mediated by receptors of many cytokines and growth factors.A great part of our current understanding of ceramide has been achieved from apoptosis-related studies, however recent data in the fields of immunology, endocrinology and neurobiology, also suggest a fundamental involvement of ceramide in the onset of diseases. Therefore, understanding the biology of ceramide could be a key to unraveling many biological mechanisms and provide information for the treatment of some common diseases.
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.
文摘Wnts are a highly conserved family of Upid-modified glycoproteins that work as morphogens to activate several signaling pathways, leading to remodeling of the cytoskeleton and the regulation of gene transcription. Wnt signaling regulates multiple cellular functions and cell systems, including the development and maintenance of midbrain dopaminergic （m DA） neurons. These neurons are of consid- erable interest for regenerative medicine because their degeneration results in Parkinson＇s disease （PD）. This review focuses on new advances in understanding key functions of Wnts in mDA neuron development and using novel tools to regulate Wnt signaling in re- generative medicine for PD. Particularly, recent reports indicate that appropriate levels of Wnt signaling are essential to improve the quantity and quality of stem ceil- or reprogrammed ceU-derived mDA neurons to be used in drug discovery and cell replacement therapy for PD.
文摘During the past three decades, the Wingless-type MMTV integration site （Wnt） signaling cascade has emerged as an essential system regulating multiple processes in developing and adult brain. Accumulating evidence points to a dysregulation of Wnt signaling in major neurodegenerative pathologies including Parkinson＇s disease （PD）, a common neurodegenerative disorder characterized by the pro- gressive loss of midbrain dopaminergic （mDA） neurons and deregulated activation of astrocytes and microglia. This review highlights the emerging link between Wnt signaling and key inflammatory pathways during mDA neuron damage/repair in PD progression. In particular, we summarize recent evidence documenting that aging and neurotoxicant exposure strongly antagonize Wnt/β-catenin signaling in mDA neurons and subventricular zone （SVZ） neuroprogenitors via astrocyte-microglial interactions. Dysregulation of the crosstalk between Wnt/β-catenin signaling and anti-oxidant/anti-inflammatory pathways delineate novel mechanisms driving the decline of SVZ plasticity with age and the limited nigrostriatal dopaminergic self-repair in PD. These findings hold a promise in devetoping therapies that target Wnt/β-catenin signaling to enhance endogenous restoration and neuronal outcome in age-dependent diseases, such as PD.
