Synaptic dysfunction and abnormal processing of amyloid precursor protein(APP) are early pathological features in Alzheimer’s disease(AD). Recently, noncoding RNAs such as micro RNAs(mi RNAs) and circular RNAs(circ R...Synaptic dysfunction and abnormal processing of amyloid precursor protein(APP) are early pathological features in Alzheimer’s disease(AD). Recently, noncoding RNAs such as micro RNAs(mi RNAs) and circular RNAs(circ RNAs) have been reported to contribute to the pathogenesis of AD. We found an age-dependent elevation of mi R-138 in APP/PS1(presenilin-1) mice. Mi R-138 inhibited the expression of ADAM10 [a disintegrin and metalloproteinase domain-containing protein 10], promoted amyloid beta(Ab) production, and induced synaptic and learning/memory deficits in APP/PS1 mice, while its suppression alleviated the AD-like phenotype in these mice. Overexpression of sirtuin 1(Sirt1), a target of mi R-138, ameliorated the mi R-138-induced inhibition of ADAM10 and elevation of Ab in vitro. The circ RNA HDAC9(circ HDAC9) was predicted to contain a mi R-138 binding site in several databases. Its expression was inversely correlated with mi R-138 in both Ab-oligomertreated N2 a cells and APP/PS1 mice, and it co-localized with mi R-138 in the cytoplasm of N2 a cells. Circ HDAC9 acted as a mi R-138 sponge, decreasing mi R-138 expression, and reversing the Sirt1 suppression and excessive Ab production induced by mi R-138 in vitro. Moreover,circ HDAC9 was decreased in the serum of both AD patients and individuals with mild cognitive impairment.These results suggest that the circ HDAC9/mi R-138/Sirt1 pathway mediates synaptic function and APP processing in AD, providing a potential therapeutic target for its treatment.展开更多
Background:Mild traumatic brain injury(mTBI)is a common neurological trauma that can lead to cognitive impairment.The sirtuin-1(SIRT-1)/peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α)pathway ...Background:Mild traumatic brain injury(mTBI)is a common neurological trauma that can lead to cognitive impairment.The sirtuin-1(SIRT-1)/peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α)pathway has been reported to have neuroprotective effects in rats with craniocerebral injury.We evaluated potential mechanisms underlying electroacupuncture-mediated recovery of cognitive function after mTBI,focusing on the SIRT-1/PGC-1α/mitochondrial pathway.Methods:We included forty 6-week-old male Sprague-Dawley rats in this study.Rats were randomly divided into four groups:controlled cortical impactor(CCI,n=10),sham operation(sham,n=10),electroacupuncture-treated CCI(CCI+EA,n=10),and electroacupuncture-treated sham(sham+EA,n=10)group.Randomization was performed by assigning a random number to each rat and using a random number table.The mTBI rat model was established using a controllable cortical impactor.Electroacupuncture therapy was performed on the back of rats,by inserting acupuncture needles to the specific acupoints and setting appropriate parameters for treatment.We evaluated spatial learning and memory functions with the Morris water maze test.We performed quantitative real-time polymerase chain reaction(qRT-PCR),western blotting,adenosine triphosphate(ATP)determination,and mitochondrial respiratory chain complex I(MRCC I)determination on rat hippocampal tissue.We analyzed SIRT-1/PGC-1α expression levels and the results of mitochondrial function assays,and compared differences between groups using bilateral Student’s t-tests.Results:Compared with the sham group,SIRT-1/PGC-1α expression was downregulated in the hippocampus of CCI group(P<0.01).Although this expression was upregulated following electroacupuncture,it did not reach the levels observed in the sham group(P<0.05).Compared with the sham group,MRCC I and ATP levels in the CCI group were significantly reduced,and increased after electroacupuncture(P<0.01).In the Morris water maze,electroacupuncture reduced the incubation period of ra展开更多
目的 探讨血清α-突触核蛋白(α-synuclein,α-syn)、沉默调节蛋白1(Sirtuin-1,SIRT1)水平与进展性脑梗死患者神经功能、梗死体积及预后的相关性。方法 回顾性分析100例急性脑梗死病例资料。根据脑梗死病情变化情况,分为进展组(n=45)和...目的 探讨血清α-突触核蛋白(α-synuclein,α-syn)、沉默调节蛋白1(Sirtuin-1,SIRT1)水平与进展性脑梗死患者神经功能、梗死体积及预后的相关性。方法 回顾性分析100例急性脑梗死病例资料。根据脑梗死病情变化情况,分为进展组(n=45)和非进展组(n=55)。依据入院时美国国立卫生研究院卒中量表(national institute of health stroke scale,NIHSS)评分、梗死体积及预后,对进展组病例进一步亚分组。比较不同神经功能缺损程度、梗死体积和预后结局,进展组病例血清α-syn、SIRT1水平差异及相关性,采用受试者工作特征(receiver operating characteristic,ROC)曲线分析α-syn、SIRT1对进展性脑梗死的诊断及预后预测价值。结果 进展组血清α-syn水平高于非进展组,SIRT1低于非进展组(均P<0.05)。SIRT1与α-syn联合预测进展性脑梗死的ROC曲线下面积(area under curve,AUC)为0.911(0.849~0.973),敏感度和特异度分别为84.38%和82.33%。随着神经功能缺损程度加重,进展性脑梗死患者血清α-syn水平呈现逐渐升高趋势,而SIRT1不断降低(P<0.05)。随着梗死体积增加,进展性脑梗死患者血清α-syn水平不断升高,而SIRT1表现为降低趋势(P<0.05)。与预后良好组比较,预后不良组血清SIRT1水平较低,α-syn水平偏高(P<0.05)。血清α-syn水平与进展性脑梗死患者神经功能缺损程度、梗死体积及预后不良均呈正相关(r=0.713、0.821、0.739,P<0.05)。血清SIRT1水平与进展性脑梗死患者神经功能缺损程度、梗死体积及预后不良均呈负相关(r=-0.694、-0.773,-0.633,P<0.05)。SIRT1与α-syn联合检测预测进展性脑梗死患者预后不良AUC为0.887(0.812~0.963),敏感度87.64%、特异度77.63%。结论 联合检测α-syn与SIRT1水平对预测脑梗死进展情况及预后不良具有较高价值,可为临床提供指导。展开更多
BACKGROUND Heat shock proteins(HSPs)are molecular chaperones that protect cells against cellular stresses or injury.However,it has been increasingly recognized that they also play crucial roles in regulating fundament...BACKGROUND Heat shock proteins(HSPs)are molecular chaperones that protect cells against cellular stresses or injury.However,it has been increasingly recognized that they also play crucial roles in regulating fundamental cellular processes.HSP20 has been implicated in cell proliferation,but conflicting studies have shown that it can either promote or suppress proliferation.The underlying mechanisms by which HSP20 regulates cell proliferation and pluripotency remain unexplored.While the effect of HSP20 on cell proliferation has been recognized,its role in inducing pluripotency in human-induced pluripotent stem cells(iPSCs)has not been addressed.AIM To evaluate the efficacy of HSP20 overexpression in human iPSCs and evaluate the ability to promote cell proliferation.The purpose of this study was to investigate whether overexpression of HSP20 in iPSCs can increase pluripotency and regeneration.METHODS We used iPSCs,which retain their potential for cell proliferation.HSP20 overexpression effectively enhanced cell proliferation and pluripotency.Overexpression of HSP20 in iPSCs was characterized by immunocytochemistry staining and realtime polymerase chain reaction.We also used cell culture,cell counting,western blotting,and flow cytometry analyses to validate HSP20 overexpression and its mechanism.RESULTS This study demonstrated that overexpression of HSP20 can increase the pluripotency in iPSCs.Furthermore,by overexpressing HSP20 in iPSCs,we showed that HSP20 upregulated proliferation markers,induced pluripotent genes,and drove cell proliferation in a sirtuin 1(SIRT1)-dependent manner.These data have practical applications in the field of stem cell-based therapies where the mass expansion of cells is needed to generate large quantities of stem cell-derived cells for transplantation purposes.CONCLUSION We found that the overexpression of HSP20 enhanced the proliferation of iPSCs in a SIRT1-dependent manner.Herein,we established the distinct crosstalk between HSP20 and SIRT1 in regulating cell proliferation and pluripot展开更多
基金supported by the National Natural Science Foundation of China (81500925)
文摘Synaptic dysfunction and abnormal processing of amyloid precursor protein(APP) are early pathological features in Alzheimer’s disease(AD). Recently, noncoding RNAs such as micro RNAs(mi RNAs) and circular RNAs(circ RNAs) have been reported to contribute to the pathogenesis of AD. We found an age-dependent elevation of mi R-138 in APP/PS1(presenilin-1) mice. Mi R-138 inhibited the expression of ADAM10 [a disintegrin and metalloproteinase domain-containing protein 10], promoted amyloid beta(Ab) production, and induced synaptic and learning/memory deficits in APP/PS1 mice, while its suppression alleviated the AD-like phenotype in these mice. Overexpression of sirtuin 1(Sirt1), a target of mi R-138, ameliorated the mi R-138-induced inhibition of ADAM10 and elevation of Ab in vitro. The circ RNA HDAC9(circ HDAC9) was predicted to contain a mi R-138 binding site in several databases. Its expression was inversely correlated with mi R-138 in both Ab-oligomertreated N2 a cells and APP/PS1 mice, and it co-localized with mi R-138 in the cytoplasm of N2 a cells. Circ HDAC9 acted as a mi R-138 sponge, decreasing mi R-138 expression, and reversing the Sirt1 suppression and excessive Ab production induced by mi R-138 in vitro. Moreover,circ HDAC9 was decreased in the serum of both AD patients and individuals with mild cognitive impairment.These results suggest that the circ HDAC9/mi R-138/Sirt1 pathway mediates synaptic function and APP processing in AD, providing a potential therapeutic target for its treatment.
基金funded by a scientic research fund from Beijing Jishuitan Hospital(No.ZR-202107).
文摘Background:Mild traumatic brain injury(mTBI)is a common neurological trauma that can lead to cognitive impairment.The sirtuin-1(SIRT-1)/peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α)pathway has been reported to have neuroprotective effects in rats with craniocerebral injury.We evaluated potential mechanisms underlying electroacupuncture-mediated recovery of cognitive function after mTBI,focusing on the SIRT-1/PGC-1α/mitochondrial pathway.Methods:We included forty 6-week-old male Sprague-Dawley rats in this study.Rats were randomly divided into four groups:controlled cortical impactor(CCI,n=10),sham operation(sham,n=10),electroacupuncture-treated CCI(CCI+EA,n=10),and electroacupuncture-treated sham(sham+EA,n=10)group.Randomization was performed by assigning a random number to each rat and using a random number table.The mTBI rat model was established using a controllable cortical impactor.Electroacupuncture therapy was performed on the back of rats,by inserting acupuncture needles to the specific acupoints and setting appropriate parameters for treatment.We evaluated spatial learning and memory functions with the Morris water maze test.We performed quantitative real-time polymerase chain reaction(qRT-PCR),western blotting,adenosine triphosphate(ATP)determination,and mitochondrial respiratory chain complex I(MRCC I)determination on rat hippocampal tissue.We analyzed SIRT-1/PGC-1α expression levels and the results of mitochondrial function assays,and compared differences between groups using bilateral Student’s t-tests.Results:Compared with the sham group,SIRT-1/PGC-1α expression was downregulated in the hippocampus of CCI group(P<0.01).Although this expression was upregulated following electroacupuncture,it did not reach the levels observed in the sham group(P<0.05).Compared with the sham group,MRCC I and ATP levels in the CCI group were significantly reduced,and increased after electroacupuncture(P<0.01).In the Morris water maze,electroacupuncture reduced the incubation period of ra
文摘目的 探讨血清α-突触核蛋白(α-synuclein,α-syn)、沉默调节蛋白1(Sirtuin-1,SIRT1)水平与进展性脑梗死患者神经功能、梗死体积及预后的相关性。方法 回顾性分析100例急性脑梗死病例资料。根据脑梗死病情变化情况,分为进展组(n=45)和非进展组(n=55)。依据入院时美国国立卫生研究院卒中量表(national institute of health stroke scale,NIHSS)评分、梗死体积及预后,对进展组病例进一步亚分组。比较不同神经功能缺损程度、梗死体积和预后结局,进展组病例血清α-syn、SIRT1水平差异及相关性,采用受试者工作特征(receiver operating characteristic,ROC)曲线分析α-syn、SIRT1对进展性脑梗死的诊断及预后预测价值。结果 进展组血清α-syn水平高于非进展组,SIRT1低于非进展组(均P<0.05)。SIRT1与α-syn联合预测进展性脑梗死的ROC曲线下面积(area under curve,AUC)为0.911(0.849~0.973),敏感度和特异度分别为84.38%和82.33%。随着神经功能缺损程度加重,进展性脑梗死患者血清α-syn水平呈现逐渐升高趋势,而SIRT1不断降低(P<0.05)。随着梗死体积增加,进展性脑梗死患者血清α-syn水平不断升高,而SIRT1表现为降低趋势(P<0.05)。与预后良好组比较,预后不良组血清SIRT1水平较低,α-syn水平偏高(P<0.05)。血清α-syn水平与进展性脑梗死患者神经功能缺损程度、梗死体积及预后不良均呈正相关(r=0.713、0.821、0.739,P<0.05)。血清SIRT1水平与进展性脑梗死患者神经功能缺损程度、梗死体积及预后不良均呈负相关(r=-0.694、-0.773,-0.633,P<0.05)。SIRT1与α-syn联合检测预测进展性脑梗死患者预后不良AUC为0.887(0.812~0.963),敏感度87.64%、特异度77.63%。结论 联合检测α-syn与SIRT1水平对预测脑梗死进展情况及预后不良具有较高价值,可为临床提供指导。
文摘BACKGROUND Heat shock proteins(HSPs)are molecular chaperones that protect cells against cellular stresses or injury.However,it has been increasingly recognized that they also play crucial roles in regulating fundamental cellular processes.HSP20 has been implicated in cell proliferation,but conflicting studies have shown that it can either promote or suppress proliferation.The underlying mechanisms by which HSP20 regulates cell proliferation and pluripotency remain unexplored.While the effect of HSP20 on cell proliferation has been recognized,its role in inducing pluripotency in human-induced pluripotent stem cells(iPSCs)has not been addressed.AIM To evaluate the efficacy of HSP20 overexpression in human iPSCs and evaluate the ability to promote cell proliferation.The purpose of this study was to investigate whether overexpression of HSP20 in iPSCs can increase pluripotency and regeneration.METHODS We used iPSCs,which retain their potential for cell proliferation.HSP20 overexpression effectively enhanced cell proliferation and pluripotency.Overexpression of HSP20 in iPSCs was characterized by immunocytochemistry staining and realtime polymerase chain reaction.We also used cell culture,cell counting,western blotting,and flow cytometry analyses to validate HSP20 overexpression and its mechanism.RESULTS This study demonstrated that overexpression of HSP20 can increase the pluripotency in iPSCs.Furthermore,by overexpressing HSP20 in iPSCs,we showed that HSP20 upregulated proliferation markers,induced pluripotent genes,and drove cell proliferation in a sirtuin 1(SIRT1)-dependent manner.These data have practical applications in the field of stem cell-based therapies where the mass expansion of cells is needed to generate large quantities of stem cell-derived cells for transplantation purposes.CONCLUSION We found that the overexpression of HSP20 enhanced the proliferation of iPSCs in a SIRT1-dependent manner.Herein,we established the distinct crosstalk between HSP20 and SIRT1 in regulating cell proliferation and pluripot
