It has been well established that the recovery ability of central nervous system （CNS） is very poor in adult mammals. As a result, CNS trauma generally leads to severe and persistent functional deficits. Thus, the i...It has been well established that the recovery ability of central nervous system （CNS） is very poor in adult mammals. As a result, CNS trauma generally leads to severe and persistent functional deficits. Thus, the investigation in this field becomes a ＂hot spot＂. Up to date, accumulating evidence supports the hypothesis that the failure of CNS neurons to regenerate is not due to their intrinsic inability to grow new axons, but due to their growth state and due to lack of a permissive growth environment. Therefore, any successful approaches to facilitate the regeneration of injured CNS axons will likely include multiple steps： keeping neurons alive in a certain growth-state, preventing the formation of a glial scar, overcoming inhibitory molecules present in the myelin debris, and giving direction to the growing axons. This brief review focused on the recent progress in the neuron regeneration of CNS in adult mammals.展开更多
Upon activation, tumor necrosis factor alpha （TNF-α） receptor can engage apoptotic or survival pathways. Inhibition of macromolecular synthesis is known to sensitize cells to TNF-α-induced cell death. It is believ...Upon activation, tumor necrosis factor alpha （TNF-α） receptor can engage apoptotic or survival pathways. Inhibition of macromolecular synthesis is known to sensitize cells to TNF-α-induced cell death. It is believed that this sensitization is due to the transcriptional blockade of genes regulated by NF-κB. Nevertheless, such evidence has remained elusive in the nervous system. Here, we show that TNF-α cannot normally induce apoptosis in PC12 cells or cortical neurons. However, cells treated with Actinomycin D （ActD） become susceptible to TNF-α-induced cell death through the activation of caspase-8, generation of tBid and activation of caspase-9 and -3. Analysis of several proteins involved in TNF-α receptor signaling showed no significant downregulation of NF-κB target genes, such as IAPs or FLIP, under such conditions. However, Bcl-XL protein levels, but not those of Bcl-2, Bax and Bak, are reduced by ActD or TNF-α/ ActD treatments. Moreover, Bcl-xL overexpression fully protects cells against TNF-α/ActD-induced cell death. When endogenous levels of Bcl-XL are specifically downregulated by lentiviral-based RNAi, cells no longer require ActD to be sensitive to TNF-α-triggered apoptosis. Furthermore, Bcl-xL downregulation does not affect TNF-α-mediated NF-κB activation. Altogether, our results demonstrate that Bcl-XL, and not Bci-2, FLIP or IAPs, acts as the endogenous regulator of neuronal resistance/sensitivity to TNF-α-induced apoptosis in an NF-κB-independent manner.展开更多
基金supported by the National Natural Science Foundation of China(No.30571909,No.30872666)the Youth Teacher Foundation of Jiangsu Pro-vince(No.BU134701)China,and the Medical Development Foundation of Soochow University(No.EE134615)
文摘It has been well established that the recovery ability of central nervous system （CNS） is very poor in adult mammals. As a result, CNS trauma generally leads to severe and persistent functional deficits. Thus, the investigation in this field becomes a ＂hot spot＂. Up to date, accumulating evidence supports the hypothesis that the failure of CNS neurons to regenerate is not due to their intrinsic inability to grow new axons, but due to their growth state and due to lack of a permissive growth environment. Therefore, any successful approaches to facilitate the regeneration of injured CNS axons will likely include multiple steps： keeping neurons alive in a certain growth-state, preventing the formation of a glial scar, overcoming inhibitory molecules present in the myelin debris, and giving direction to the growing axons. This brief review focused on the recent progress in the neuron regeneration of CNS in adult mammals.
文摘Upon activation, tumor necrosis factor alpha （TNF-α） receptor can engage apoptotic or survival pathways. Inhibition of macromolecular synthesis is known to sensitize cells to TNF-α-induced cell death. It is believed that this sensitization is due to the transcriptional blockade of genes regulated by NF-κB. Nevertheless, such evidence has remained elusive in the nervous system. Here, we show that TNF-α cannot normally induce apoptosis in PC12 cells or cortical neurons. However, cells treated with Actinomycin D （ActD） become susceptible to TNF-α-induced cell death through the activation of caspase-8, generation of tBid and activation of caspase-9 and -3. Analysis of several proteins involved in TNF-α receptor signaling showed no significant downregulation of NF-κB target genes, such as IAPs or FLIP, under such conditions. However, Bcl-XL protein levels, but not those of Bcl-2, Bax and Bak, are reduced by ActD or TNF-α/ ActD treatments. Moreover, Bcl-xL overexpression fully protects cells against TNF-α/ActD-induced cell death. When endogenous levels of Bcl-XL are specifically downregulated by lentiviral-based RNAi, cells no longer require ActD to be sensitive to TNF-α-triggered apoptosis. Furthermore, Bcl-xL downregulation does not affect TNF-α-mediated NF-κB activation. Altogether, our results demonstrate that Bcl-XL, and not Bci-2, FLIP or IAPs, acts as the endogenous regulator of neuronal resistance/sensitivity to TNF-α-induced apoptosis in an NF-κB-independent manner.
