Stem cell-based therapies have been proposed as a potential treatment for neural regeneration following closed head injury.We previously reported that induced neural stem cells exert beneficial effects on neural regen...Stem cell-based therapies have been proposed as a potential treatment for neural regeneration following closed head injury.We previously reported that induced neural stem cells exert beneficial effects on neural regeneration via cell replacement.However,the neural regeneration efficiency of induced neural stem cells remains limited.In this study,we explored differentially expressed genes and long non-coding RNAs to clarify the mechanism underlying the neurogenesis of induced neural stem cells.We found that H19 was the most downregulated neurogenesis-associated lnc RNA in induced neural stem cells compared with induced pluripotent stem cells.Additionally,we demonstrated that H19 levels in induced neural stem cells were markedly lower than those in induced pluripotent stem cells and were substantially higher than those in induced neural stem cell-derived neurons.We predicted the target genes of H19 and discovered that H19 directly interacts with mi R-325-3p,which directly interacts with Ctbp2 in induced pluripotent stem cells and induced neural stem cells.Silencing H19 or Ctbp2 impaired induced neural stem cell proliferation,and mi R-325-3p suppression restored the effect of H19 inhibition but not the effect of Ctbp2 inhibition.Furthermore,H19 silencing substantially promoted the neural differentiation of induced neural stem cells and did not induce apoptosis of induced neural stem cells.Notably,silencing H19 in induced neural stem cell grafts markedly accelerated the neurological recovery of closed head injury mice.Our results reveal that H19 regulates the neurogenesis of induced neural stem cells.H19 inhibition may promote the neural differentiation of induced neural stem cells,which is closely associated with neurological recovery following closed head injury.展开更多
Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells ...Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.展开更多
Purpose:The present study summarized cases of children(n=32)with medulloblastoma(MB)who were treated using stratified therapy based on risk grading and also discussed the factors affecting prognosis.Methods:According ...Purpose:The present study summarized cases of children(n=32)with medulloblastoma(MB)who were treated using stratified therapy based on risk grading and also discussed the factors affecting prognosis.Methods:According to the risk stratification criteria,the cases were divided into the following four risk groups:low,standard,high,and very high.The 5-year overall survival(OS)and progression-free survival(PFS)rates were summarized.Further,the effects on the prognosis of tumor size,tumor stage,degree of resection,treatment mode,metastatic recurrence,molecular typing,and risk stratification were analyzed.Results:In the present study,following surgery,3 cases abandoned radiotherapy(RT)and chemotherapy(CHT),7 cases(<3 years of age)received only CHT,and 22 cases received combined RT and CHT.Total and near-total tumor resections were performed in 29 cases(90.6%).Subtotal resections were performed in 3 cases,and there were no surgery-related deaths.The average follow-up duration was 47 months.The average 5-year PFS and OS rates were 57.3%±7.2%and 68.7%±8.6%,respectively.The OS and PFS rates were significantly correlated with tumor-risk stratification,molecular staging,tumor stage,treatment mode,and recurrence after surgery(p<0.01).The degree of tumor resection,pathological type,and the presence of preoperative implantation were secondary factors affecting the prognosis(p<0.05).Age was correlated with the PFS rate.There was no correlation between age/tumor location/tumor size and prognosis(p>0.05).Favorable prognostic factors in the low-and standard-risk groups were stage M0,wingless-type MB,postoperative RT combined with CHT,no postoperative recurrence,age≥3 years,and total tumor resection.Conclusions:Personalized treatment strategies based on the risk stratification of MB and postoperative stratified comprehensive treatment could help improve the prognosis for MB.展开更多
Antiepileptic drugs are the preferred treatment approach for epileptic patients. However, informal treatment is important for intractable epilepsy. In this study, 500 epileptic patients were recruited from the General...Antiepileptic drugs are the preferred treatment approach for epileptic patients. However, informal treatment is important for intractable epilepsy. In this study, 500 epileptic patients were recruited from the General Hospital of Beijing Military Area Command of Chinese PLA during the period of October 2009 to January 2012. These involved patients that had been medically treated for at least 1 year. Information on the initial treatment and changes to treatment regimens for each patient was collected through questionnaires. The survey results showed that 52.3% of the epileptic patients searched for treatment after the first seizure, and the mean numbers of seizures was 12.8; 59.8% of the epileptic patients were diagnosed at the first visit, and the mean onset time was 17 months after the first seizure. After diagnosis, patients were treated for an average of 20 days, and the median time was 1 day. Formal anti-epileptic drugs were selected as the first treatment regimen by 67.8% of patients, and 77.5% of these drugs were monotherapies. The mean and median numbers of seizure were respectively 36.9 and 3.0 times before the first regimen was changed. The regimen was changed within the first 6 months by 46.6% of patients, and after the first and second years of treatment, the proportions increased to 54.0% and 71.8%, respectively. In total, 78.5% of the regi- mens were changed to informal treatments. The informal treatment of epilepsy in China is common, being initiated by either patients or physicians. Enhancing epileptic treatment services in hospital, improving physicians＇ professional quality, and strengthening health propaganda may promote the normalization of drug treatment of epilepsy in China.展开更多
Previous studies show that transient axonal glycoprotein-1, a ligand of amyloid precursor pro- tein, increases the secretion of amyloid precursor protein intracellular domain and is involved in apoptosis in Alzheimer...Previous studies show that transient axonal glycoprotein-1, a ligand of amyloid precursor pro- tein, increases the secretion of amyloid precursor protein intracellular domain and is involved in apoptosis in Alzheimer＇s disease. In this study, we examined the effects of transient axonal glyco- protein-1 on U251 glioma cells. 3-（4,5-Dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay showed that transient axonal glycoprotein-1 did not inhibit the proliferation of U251 cells, but promoted cell viability. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that transient axonal glycoprotein-1 did not induce U251 cell apoptosis. Real-time PCR revealed that transient axonal glycoprotein-1 substantially upregulated levels of amyloid precursor protein intracellular C-terminal domain, and p53 and epidermal growth factor recep- tor mRNA expression. Thus, transient axonal glycoprotein-1 increased apoptosis-related gene expression in U251 cells without inducing apoptosis. Instead, transient axonal glycoprotein-1 promoted the proliferation of these glioma cells.展开更多
Studies have confirmed that iron induces epilepsy onset, and iron ion-induced epilepsy in anima models closely resembles the clinical situation. Models of post-traumatic epilepsy （PTE） were established by intracorti...Studies have confirmed that iron induces epilepsy onset, and iron ion-induced epilepsy in anima models closely resembles the clinical situation. Models of post-traumatic epilepsy （PTE） were established by intracortical injection of FeCl2 using stereotactic techniques. Electron microscopy revealed neuronal degeneration, with shrinkage of the neuronal soma, hyperplasia of rough endoplasmic reticulum, ribosomal detachment from the endoplasmic reticulum, and vacuolar degeneration of glial cells in the right frontal lobe of FeCl2-induced PTE rats. With prolonged time injuries became more severe and neuronal apoptosis was observed. Synapses in the hippocampal neuropil significantly increased （primarily type I/excitatory synapses） at day 14 following injury. Type II synapses （inhibitory synapse） were observed in the rat hippocampus at day 30. Cortical neuronal degeneration, apoptosis, glial cell proliferation, and ultrastructural hippocampal changes, in particular changes in type of neuronal synapse, play an important role in PTE onset.展开更多
Biopolymer microbeads present substantial benefits for cell expansion,tissue engineering,and drug release applications.However,a fabrication system capable of producing homogeneous microspheres with high precision and...Biopolymer microbeads present substantial benefits for cell expansion,tissue engineering,and drug release applications.However,a fabrication system capable of producing homogeneous microspheres with high precision and controllability for cell proliferation,passaging,harvesting and downstream application is limited.Therefore,we developed a co-flow microfluidics-based system for the generation of uniform and size-controllable gelatin-based microcarriers(GMs)for mesenchymal stromal cells(MSCs)expansion and tissue engineering.Our evaluation of GMs revealed superior homogeneity and efficiency of cellular attachment,expansion and harvest,and MSCs expanded on GMs exhibited high viability while retaining differentiation multipotency.Optimization of passaging and harvesting protocols was achieved through the addition of blank GMs and treatment with collagenase,respectively.Furthermore,we demonstrated that MSC-loaded GMs were printable and could serve as building blocks for tissue regeneration scaffolds.These results suggested that our platform held promise for the fabrication of uniform GMs with downstream application of MSC culture,expansion and tissue engineering.展开更多
Cognitive impairment often occurs after post traumatic brain injury. In addition, recovery of cognitive impairment is largely dependent on spontaneous repair and the severity of secondary insult. The tetrahedral frame...Cognitive impairment often occurs after post traumatic brain injury. In addition, recovery of cognitive impairment is largely dependent on spontaneous repair and the severity of secondary insult. The tetrahedral framework nucleic acid is a novel nanostructure has been shown to have a positive biological effect in promoting regeneration and anti-inflammation. To explore the treatment effect of tetrahedral framework nucleic acids for cognitive impairment recovery post traumatic brain injury, we established a mouse model of traumatic brain injury and verified the efficacy of tetrahedral framework nucleic acids in promoting cognitive impairment recovery post traumatic brain injury. The results show that the tetrahedral framework nucleic acids promoted the recovery of post-traumatic cognitive function by enhancing the proliferation of endogenous neural stem cells. Besides, tetrahedral framework nucleic acids modulated the neuroinflammatory response in the acute phase by inhibiting excessive astrocyte and microglial activation. Taken together, the results of the study indicate tetrahedral framework nucleic acids for treatment of cognitive impairment post traumatic brain injury.展开更多
Treatment for disorders of consciousness （DOCs） is still a Gordian knot. Evidence-based guidelines on the treatment of DOC patients are not currently available, while neuromodulation techniques are seen as a potenti...Treatment for disorders of consciousness （DOCs） is still a Gordian knot. Evidence-based guidelines on the treatment of DOC patients are not currently available, while neuromodulation techniques are seen as a potential treatment. Multiple neuromodulation therapies have been applied. This article reviews the most relevant studies in the literature in order to describe a clear picture of the current state of neuromodulation therapies that could be used to treat DOC patients. Both invasive and noninvasive brain stimulation is discussed. Significant behavioral improvements in prolonged DOCs under neuromodulation therapies are rare. The efficacy of various such therapies remains a matter of debate. Further clinical investigations of existing techniques in larger samples properly controlling for spontaneous recovery are needed, and new approaches are awaited.展开更多
Uch37 is a de-ubiquitinating enzyme that is activated by Rpn13 and involved in the proteasomal degradation of proteins. The full-length Uch37 was shown to exhibit low iso-peptidase activity and is thought to be auto-i...Uch37 is a de-ubiquitinating enzyme that is activated by Rpn13 and involved in the proteasomal degradation of proteins. The full-length Uch37 was shown to exhibit low iso-peptidase activity and is thought to be auto-inhibited. Structural comparisons revealed that within a homo- dimer of Uch37, each of the catalytic domains was blocking the other＇s ubiquitin （Ub）-binding site. This blockage likely prevented Ub from entering the active site of Uch37 and might form the basis of auto-inhibition. To understand the mode of auto-inhibition clearly and shed light on the activation mechanism of Uch37 by Rpn13, we investigated the Uch37-Rpn13 complex using a combi- nation of mutagenesis, biochemical, NMR, and small- angle X-ray scattering （SAXS） techniques. Our results also proved that Uch37 oligomerized in solution and had very low activity against the fluorogenic substrate ubi- quitin-7-amino-4-methylcoumarin （Ub-AMC） of de-ubiq- uitinating enzymes. Uch37AHb＇Hc＇KEKE, a truncation removal of the C-terminal extension region （residues 256- 329） converted oligomeric Uch37 into a monomeric form that exhibited iso-peptidase activity comparable to that of a truncation-containing the Uch37 catalytic domain only. We also demonstrated that Rpn13C （Rpn13 residues 270- 407） could disrupt the oligomerization of Uch37 by sequestering Uch37 and forming a Uch37-Rpn13 com- plex. Uch37 was activated in such a complex, exhibiting 12-fold-higher activity than Uch37 alone. Time-resolved SAXS （TR-SAXS） and FRET experiments supported the proposed mode of auto-inhibition and the activation mechanism of Uch37 by Rpn13. Rpn13 activated Uch37 by forming a 1：1 stoichiometric complex in which the active site of Uch37 was accessible to Ub.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82271397(to MG),82001293(to MG),82171355(to RX),81971295(to RX)and 81671189(to RX)。
文摘Stem cell-based therapies have been proposed as a potential treatment for neural regeneration following closed head injury.We previously reported that induced neural stem cells exert beneficial effects on neural regeneration via cell replacement.However,the neural regeneration efficiency of induced neural stem cells remains limited.In this study,we explored differentially expressed genes and long non-coding RNAs to clarify the mechanism underlying the neurogenesis of induced neural stem cells.We found that H19 was the most downregulated neurogenesis-associated lnc RNA in induced neural stem cells compared with induced pluripotent stem cells.Additionally,we demonstrated that H19 levels in induced neural stem cells were markedly lower than those in induced pluripotent stem cells and were substantially higher than those in induced neural stem cell-derived neurons.We predicted the target genes of H19 and discovered that H19 directly interacts with mi R-325-3p,which directly interacts with Ctbp2 in induced pluripotent stem cells and induced neural stem cells.Silencing H19 or Ctbp2 impaired induced neural stem cell proliferation,and mi R-325-3p suppression restored the effect of H19 inhibition but not the effect of Ctbp2 inhibition.Furthermore,H19 silencing substantially promoted the neural differentiation of induced neural stem cells and did not induce apoptosis of induced neural stem cells.Notably,silencing H19 in induced neural stem cell grafts markedly accelerated the neurological recovery of closed head injury mice.Our results reveal that H19 regulates the neurogenesis of induced neural stem cells.H19 inhibition may promote the neural differentiation of induced neural stem cells,which is closely associated with neurological recovery following closed head injury.
基金supported by the National Natural Science Foundation of China,Nos.82271397(to MG),82001293(to MG),82171355(to RX),81971295(to RX),and 81671189(to RX)。
文摘Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.
基金funded by the Key Research and Development Project of the Science and Technology Department of Sichuan Province(No.2021YFS0010).
文摘Purpose:The present study summarized cases of children(n=32)with medulloblastoma(MB)who were treated using stratified therapy based on risk grading and also discussed the factors affecting prognosis.Methods:According to the risk stratification criteria,the cases were divided into the following four risk groups:low,standard,high,and very high.The 5-year overall survival(OS)and progression-free survival(PFS)rates were summarized.Further,the effects on the prognosis of tumor size,tumor stage,degree of resection,treatment mode,metastatic recurrence,molecular typing,and risk stratification were analyzed.Results:In the present study,following surgery,3 cases abandoned radiotherapy(RT)and chemotherapy(CHT),7 cases(<3 years of age)received only CHT,and 22 cases received combined RT and CHT.Total and near-total tumor resections were performed in 29 cases(90.6%).Subtotal resections were performed in 3 cases,and there were no surgery-related deaths.The average follow-up duration was 47 months.The average 5-year PFS and OS rates were 57.3%±7.2%and 68.7%±8.6%,respectively.The OS and PFS rates were significantly correlated with tumor-risk stratification,molecular staging,tumor stage,treatment mode,and recurrence after surgery(p<0.01).The degree of tumor resection,pathological type,and the presence of preoperative implantation were secondary factors affecting the prognosis(p<0.05).Age was correlated with the PFS rate.There was no correlation between age/tumor location/tumor size and prognosis(p>0.05).Favorable prognostic factors in the low-and standard-risk groups were stage M0,wingless-type MB,postoperative RT combined with CHT,no postoperative recurrence,age≥3 years,and total tumor resection.Conclusions:Personalized treatment strategies based on the risk stratification of MB and postoperative stratified comprehensive treatment could help improve the prognosis for MB.
基金supported by Beijing Natural Science Foundation,No.4132017
文摘Antiepileptic drugs are the preferred treatment approach for epileptic patients. However, informal treatment is important for intractable epilepsy. In this study, 500 epileptic patients were recruited from the General Hospital of Beijing Military Area Command of Chinese PLA during the period of October 2009 to January 2012. These involved patients that had been medically treated for at least 1 year. Information on the initial treatment and changes to treatment regimens for each patient was collected through questionnaires. The survey results showed that 52.3% of the epileptic patients searched for treatment after the first seizure, and the mean numbers of seizures was 12.8; 59.8% of the epileptic patients were diagnosed at the first visit, and the mean onset time was 17 months after the first seizure. After diagnosis, patients were treated for an average of 20 days, and the median time was 1 day. Formal anti-epileptic drugs were selected as the first treatment regimen by 67.8% of patients, and 77.5% of these drugs were monotherapies. The mean and median numbers of seizure were respectively 36.9 and 3.0 times before the first regimen was changed. The regimen was changed within the first 6 months by 46.6% of patients, and after the first and second years of treatment, the proportions increased to 54.0% and 71.8%, respectively. In total, 78.5% of the regi- mens were changed to informal treatments. The informal treatment of epilepsy in China is common, being initiated by either patients or physicians. Enhancing epileptic treatment services in hospital, improving physicians＇ professional quality, and strengthening health propaganda may promote the normalization of drug treatment of epilepsy in China.
基金supported by grants from the National Natural Science Foundation of China,No.81171179,81272439the Key Sci-Tech Research Projects of Guangdong Province in China,No.2008A030201019the Guangzhou Municipal Science and Technology Project in China,No.09B52120112-2009J1-C418-2,No.2008A1-E4011-6
文摘Previous studies show that transient axonal glycoprotein-1, a ligand of amyloid precursor pro- tein, increases the secretion of amyloid precursor protein intracellular domain and is involved in apoptosis in Alzheimer＇s disease. In this study, we examined the effects of transient axonal glyco- protein-1 on U251 glioma cells. 3-（4,5-Dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay showed that transient axonal glycoprotein-1 did not inhibit the proliferation of U251 cells, but promoted cell viability. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that transient axonal glycoprotein-1 did not induce U251 cell apoptosis. Real-time PCR revealed that transient axonal glycoprotein-1 substantially upregulated levels of amyloid precursor protein intracellular C-terminal domain, and p53 and epidermal growth factor recep- tor mRNA expression. Thus, transient axonal glycoprotein-1 increased apoptosis-related gene expression in U251 cells without inducing apoptosis. Instead, transient axonal glycoprotein-1 promoted the proliferation of these glioma cells.
基金the Science and Technology Project of Fujian Province of China,No.2007F5045the New Century Talent Support Project of Higher Learning School of Fujian Province,No.NCETFJ-0702
文摘Studies have confirmed that iron induces epilepsy onset, and iron ion-induced epilepsy in anima models closely resembles the clinical situation. Models of post-traumatic epilepsy （PTE） were established by intracortical injection of FeCl2 using stereotactic techniques. Electron microscopy revealed neuronal degeneration, with shrinkage of the neuronal soma, hyperplasia of rough endoplasmic reticulum, ribosomal detachment from the endoplasmic reticulum, and vacuolar degeneration of glial cells in the right frontal lobe of FeCl2-induced PTE rats. With prolonged time injuries became more severe and neuronal apoptosis was observed. Synapses in the hippocampal neuropil significantly increased （primarily type I/excitatory synapses） at day 14 following injury. Type II synapses （inhibitory synapse） were observed in the rat hippocampus at day 30. Cortical neuronal degeneration, apoptosis, glial cell proliferation, and ultrastructural hippocampal changes, in particular changes in type of neuronal synapse, play an important role in PTE onset.
基金supported by the National Natural Science Foundation of China(Grant No.52075285)the Applied Basic Research Project of Sichuan Province(Grant No.2021YJ0563).
文摘Biopolymer microbeads present substantial benefits for cell expansion,tissue engineering,and drug release applications.However,a fabrication system capable of producing homogeneous microspheres with high precision and controllability for cell proliferation,passaging,harvesting and downstream application is limited.Therefore,we developed a co-flow microfluidics-based system for the generation of uniform and size-controllable gelatin-based microcarriers(GMs)for mesenchymal stromal cells(MSCs)expansion and tissue engineering.Our evaluation of GMs revealed superior homogeneity and efficiency of cellular attachment,expansion and harvest,and MSCs expanded on GMs exhibited high viability while retaining differentiation multipotency.Optimization of passaging and harvesting protocols was achieved through the addition of blank GMs and treatment with collagenase,respectively.Furthermore,we demonstrated that MSC-loaded GMs were printable and could serve as building blocks for tissue regeneration scaffolds.These results suggested that our platform held promise for the fabrication of uniform GMs with downstream application of MSC culture,expansion and tissue engineering.
基金supported by the National Key R&D Program of China (No. 2019YFA0110600)the National Natural Science Foundation of China (Nos. 81970916, 81971295, 92001216, 82171355)+2 种基金the China Postdoctoral Science Foundation (No. 2021M700699)Sichuan Province Youth Science and Technology Innovation Team (No. 2022JDTD0021)Research Funding from West China School/Hospital of Stomatology Sichuan University (No.RCDWJS2021–20)。
文摘Cognitive impairment often occurs after post traumatic brain injury. In addition, recovery of cognitive impairment is largely dependent on spontaneous repair and the severity of secondary insult. The tetrahedral framework nucleic acid is a novel nanostructure has been shown to have a positive biological effect in promoting regeneration and anti-inflammation. To explore the treatment effect of tetrahedral framework nucleic acids for cognitive impairment recovery post traumatic brain injury, we established a mouse model of traumatic brain injury and verified the efficacy of tetrahedral framework nucleic acids in promoting cognitive impairment recovery post traumatic brain injury. The results show that the tetrahedral framework nucleic acids promoted the recovery of post-traumatic cognitive function by enhancing the proliferation of endogenous neural stem cells. Besides, tetrahedral framework nucleic acids modulated the neuroinflammatory response in the acute phase by inhibiting excessive astrocyte and microglial activation. Taken together, the results of the study indicate tetrahedral framework nucleic acids for treatment of cognitive impairment post traumatic brain injury.
基金supported by the National Natural Science Foundation of China (81771128)the Beijing Municipal Science & Technology Commission (Z171100001017162 and Z161100000516165)
文摘Treatment for disorders of consciousness （DOCs） is still a Gordian knot. Evidence-based guidelines on the treatment of DOC patients are not currently available, while neuromodulation techniques are seen as a potential treatment. Multiple neuromodulation therapies have been applied. This article reviews the most relevant studies in the literature in order to describe a clear picture of the current state of neuromodulation therapies that could be used to treat DOC patients. Both invasive and noninvasive brain stimulation is discussed. Significant behavioral improvements in prolonged DOCs under neuromodulation therapies are rare. The efficacy of various such therapies remains a matter of debate. Further clinical investigations of existing techniques in larger samples properly controlling for spontaneous recovery are needed, and new approaches are awaited.
基金This work was supported by the National Basic Research Program （973 Program） （Nos. 2014CB910400 and 2013CB911103）, the Ministry of Health of China （Grant No. 2013ZX10004-602）, National Key Technology Research and Development Program of the Ministry of Science and Technology of China （Grant No. 2014BAI07B02） and the National Natural Science Foundation of China （Grant Nos. 31330019, 31200559）. We would like to thank Dr. Li-Qin Li from the Institute of High Energy Physics, CAS and Professor Robert E. Cohen for the gen- erous gift of the hUch37 （C88A） plasmid and Xiaoxia Yu and Yu- anyuan Chen at the Protein Science Core Facility of IBP for their technical help with the AUC and SPR experiments. The authors would also like to thank the staff at beamline BL13.3.1 at ALS for their technical support with the SAXS data collection. BL13.3.1 is supported in part by the DOE program Inte- grated Diffraction Analysis Technologies （IDAT） and the DOE pro- gram Molecular Assemblies Genes and Genomics Integrated Efficiently （MAGGIE） under Contract Number DE-AC02-05CH11231 with the DOE. The ALS is supported by the Director, Office of Sci- ence, Office of Basic Energy Sciences of the DOE under Contract No. DE-AC02-05CH11231. Use of the Advanced Photon Source, an Office of the Science User Facility operated for the U.S. Department of Energy （DOE） Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02- 06CHl1357. BioCAT was supported by grants from the National Center for Research Resources （2P41RR008630-17） and the National Institute of General Medical Sciences （9 P41 GM103622- 17） from the National Institutes of Health. The authors would like to thank the staff at 121D and 181D for the setup support.
文摘Uch37 is a de-ubiquitinating enzyme that is activated by Rpn13 and involved in the proteasomal degradation of proteins. The full-length Uch37 was shown to exhibit low iso-peptidase activity and is thought to be auto-inhibited. Structural comparisons revealed that within a homo- dimer of Uch37, each of the catalytic domains was blocking the other＇s ubiquitin （Ub）-binding site. This blockage likely prevented Ub from entering the active site of Uch37 and might form the basis of auto-inhibition. To understand the mode of auto-inhibition clearly and shed light on the activation mechanism of Uch37 by Rpn13, we investigated the Uch37-Rpn13 complex using a combi- nation of mutagenesis, biochemical, NMR, and small- angle X-ray scattering （SAXS） techniques. Our results also proved that Uch37 oligomerized in solution and had very low activity against the fluorogenic substrate ubi- quitin-7-amino-4-methylcoumarin （Ub-AMC） of de-ubiq- uitinating enzymes. Uch37AHb＇Hc＇KEKE, a truncation removal of the C-terminal extension region （residues 256- 329） converted oligomeric Uch37 into a monomeric form that exhibited iso-peptidase activity comparable to that of a truncation-containing the Uch37 catalytic domain only. We also demonstrated that Rpn13C （Rpn13 residues 270- 407） could disrupt the oligomerization of Uch37 by sequestering Uch37 and forming a Uch37-Rpn13 com- plex. Uch37 was activated in such a complex, exhibiting 12-fold-higher activity than Uch37 alone. Time-resolved SAXS （TR-SAXS） and FRET experiments supported the proposed mode of auto-inhibition and the activation mechanism of Uch37 by Rpn13. Rpn13 activated Uch37 by forming a 1：1 stoichiometric complex in which the active site of Uch37 was accessible to Ub.
