目的:研究[G ly14]-hum an in对β淀粉样蛋白1-42引起的神经干细胞毒性的作用。方法:用[G ly14]-hum an in和β淀粉样蛋白1-42处理神经干细胞,观察其对神经干细胞增殖、分化的影响。结果:较低浓度的[G ly14]-hum an in加入有β淀粉样蛋...目的:研究[G ly14]-hum an in对β淀粉样蛋白1-42引起的神经干细胞毒性的作用。方法:用[G ly14]-hum an in和β淀粉样蛋白1-42处理神经干细胞,观察其对神经干细胞增殖、分化的影响。结果:较低浓度的[G ly14]-hum an in加入有β淀粉样蛋白1-42处理的神经干细胞培养基,经过琼脂糖凝胶电泳分析及流式细胞测定DNA含量,神经干细胞显示出对β淀粉样蛋白1-42的耐受,而对照组则显示神经干细胞出现凋亡现象。高浓度的[G ly14]-hum an in加入培养基,经台盼蓝拒染法计数细胞,神经干细胞死亡率明显低于对照组,对照组神经干细胞出现大量死亡。结论:[G ly14]-hum an in不但具有抑制β淀粉样蛋白1-42对神经干细胞的毒性作用,而且在低浓度的情况下,可以促进神经干细胞的增殖和分化为神经元。展开更多
Amyloid β-peptide（Aβ） has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer ’s disease（AD）. Humanin（HN） is a secretory peptide that inhibits the neurotoxicity of Aβ. However, t...Amyloid β-peptide（Aβ） has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer ’s disease（AD）. Humanin（HN） is a secretory peptide that inhibits the neurotoxicity of Aβ. However, the mechanism（s） by which HN exerts its neuroprotection against Aβ-induced ADlike pathological changes and memory deficits are yet to be completely defined. In the present study,we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre- and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ1-42. HN also attenuated Aβ1-42-induced tau hyperphosphorylation,apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A（PP2A）catalytic subunit and thereby activating PP2 A. HN also inhibited apoptosis and reduced the oxidativestress induced by Aβ1-42. These findings provide novel mechanisms of action for the ability of HN to protect against Aβ1-42-induced AD-like pathological changes and memory deficits.展开更多
The method of laser capture microdissection (LCM) combined with suppressive subtractive hybridization (SSH) was developed to isolate specific germ cells from human testis sections and to identify the genes expressed d...The method of laser capture microdissection (LCM) combined with suppressive subtractive hybridization (SSH) was developed to isolate specific germ cells from human testis sections and to identify the genes expressed during differentiation and development. In the present study, over 10,000 primary spermatocytes and round spermatid cells were successfully isolated by LCM. Using the cDNAs from primary spermatocytes and round spermatids, SSH cDNAs library of primary spermatocyte-specific was constructed. The average insert size of the cDNA isolated from 75 randomly picked white clones was 500 bp, ranging from 250 bp to 1.7 kb. Using the dot-blot method, a total of 421 clones were examined, resulting in the identification of 390 positive clones emitting strong signals. Partial sequence of cDNAs prepared from each clone was determined with an overall success rate of 84.4%. Genes encoding cytochrome c oxidase II and the rescue factor-humanin were most frequently expressed in primary spermatocytes, suggesting their roles involved in meiosis.展开更多
Humanin is a potential therapeutic agent for Alzheimer’s disease, and its derivative, S14G-humanin, is 1 000-fold stronger in its neuroprotective effect against Alzheimer’s disease-relevant insults. Alt-hough effect...Humanin is a potential therapeutic agent for Alzheimer’s disease, and its derivative, S14G-humanin, is 1 000-fold stronger in its neuroprotective effect against Alzheimer’s disease-relevant insults. Alt-hough effective, the detailed molecular mechanism through which S14G-humanin exerts its effects remains unclear. Data from this study showed that fibril ar amyloid-beta 40 disturbed cel ular ho-meostasis through the cel membrane, increasing intracel ular calcium, generating reactive oxygen species, and decreasing the mitochondrial membrane potential. S14G-humanin restored these re-sponses. The results suggested that S14G-humanin blocked the effects of amyloid-beta 40 on the neuronal cel membrane, and restored the disturbed cel ular homeostasis, thereby exerting a neuroprotective effect on hippocampal neurons.展开更多
Alzheimer’s disease is a neurodegenerative disease induced by multiple interconnected mechanisms.Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-face...Alzheimer’s disease is a neurodegenerative disease induced by multiple interconnected mechanisms.Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-facet pathology.However,clinical translation of peptide drugs is greatly hampered by their low permeability into brain.Herein,a hybrid peptide HNSS is generated by merging two therapeutic peptides(SS31 and S-14 G Humanin(HNG)),using a different approach from the classical shuttle-therapeutic peptide conjugate design.HNSS demonstrated increased bio-permeability,with a 2-fold improvement in brain distribution over HNG,thanks to its structure mimicking the design of signal peptide-derived cell-penetrating peptides.HNSS efficiently alleviated mitochondrial dysfunction through the combined effects of mitochondrial targeting,ROS scavenging and p-STAT3 activation.Meanwhile,HNSS with increased Aβaffinity greatly inhibited Aβoligomerization/fibrillation,and interrupted Aβinteraction with neuron/microglia by reducing neuronal mitochondrial Aβdeposition and promoting microglial phagocytosis of Aβ.In3×Tg-AD transgenic mice,HNSS treatment efficiently inhibited brain neuron loss and improved the cognitive performance.This work validates the rational fusion design-based strategy for bio-permeability improvement and efficacy amplification,providing a paradigm for developing therapeutic peptide candidates against neurodegenerative disease.展开更多
阿尔采末病(A lzheimer's d isease,AD)严重威胁着老年人的健康与生存质量,由于其发病原因复杂、机制不明,目前尚缺乏有效的防治措施。Humanin是近年来发现的能特异性抑制AD相关毒性的分泌性短肽,通过自身二聚化在细胞外发挥神经保...阿尔采末病(A lzheimer's d isease,AD)严重威胁着老年人的健康与生存质量,由于其发病原因复杂、机制不明,目前尚缺乏有效的防治措施。Humanin是近年来发现的能特异性抑制AD相关毒性的分泌性短肽,通过自身二聚化在细胞外发挥神经保护作用。Humanin通过直接或间接作用抑制β-淀粉样蛋白(Aβ),以及家族性AD(FAD)基因如早老基因突变诱发的神经毒,而对AD不相关的毒性作用如凋亡诱导剂etoposide及Fas诱导的细胞死亡却不表现拮抗作用。因此,Humanin可通过特异性拮抗AD相关的神经毒而发挥重要的神经保护作用。展开更多
文摘目的:研究[G ly14]-hum an in对β淀粉样蛋白1-42引起的神经干细胞毒性的作用。方法:用[G ly14]-hum an in和β淀粉样蛋白1-42处理神经干细胞,观察其对神经干细胞增殖、分化的影响。结果:较低浓度的[G ly14]-hum an in加入有β淀粉样蛋白1-42处理的神经干细胞培养基,经过琼脂糖凝胶电泳分析及流式细胞测定DNA含量,神经干细胞显示出对β淀粉样蛋白1-42的耐受,而对照组则显示神经干细胞出现凋亡现象。高浓度的[G ly14]-hum an in加入培养基,经台盼蓝拒染法计数细胞,神经干细胞死亡率明显低于对照组,对照组神经干细胞出现大量死亡。结论:[G ly14]-hum an in不但具有抑制β淀粉样蛋白1-42对神经干细胞的毒性作用,而且在低浓度的情况下,可以促进神经干细胞的增殖和分化为神经元。
基金supported by the National Natural Science Foundation of China (81271402,31171028)Fundamental Research Funds for the Central Universities,China (2012QN130)
文摘Amyloid β-peptide（Aβ） has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer ’s disease（AD）. Humanin（HN） is a secretory peptide that inhibits the neurotoxicity of Aβ. However, the mechanism（s） by which HN exerts its neuroprotection against Aβ-induced ADlike pathological changes and memory deficits are yet to be completely defined. In the present study,we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre- and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ1-42. HN also attenuated Aβ1-42-induced tau hyperphosphorylation,apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A（PP2A）catalytic subunit and thereby activating PP2 A. HN also inhibited apoptosis and reduced the oxidativestress induced by Aβ1-42. These findings provide novel mechanisms of action for the ability of HN to protect against Aβ1-42-induced AD-like pathological changes and memory deficits.
文摘The method of laser capture microdissection (LCM) combined with suppressive subtractive hybridization (SSH) was developed to isolate specific germ cells from human testis sections and to identify the genes expressed during differentiation and development. In the present study, over 10,000 primary spermatocytes and round spermatid cells were successfully isolated by LCM. Using the cDNAs from primary spermatocytes and round spermatids, SSH cDNAs library of primary spermatocyte-specific was constructed. The average insert size of the cDNA isolated from 75 randomly picked white clones was 500 bp, ranging from 250 bp to 1.7 kb. Using the dot-blot method, a total of 421 clones were examined, resulting in the identification of 390 positive clones emitting strong signals. Partial sequence of cDNAs prepared from each clone was determined with an overall success rate of 84.4%. Genes encoding cytochrome c oxidase II and the rescue factor-humanin were most frequently expressed in primary spermatocytes, suggesting their roles involved in meiosis.
基金supported by grants from Henan Medical Technologies R&D Program in China,No.200703023,201203130Henan Key Science and Technology Project in China,No.112102310684
文摘Humanin is a potential therapeutic agent for Alzheimer’s disease, and its derivative, S14G-humanin, is 1 000-fold stronger in its neuroprotective effect against Alzheimer’s disease-relevant insults. Alt-hough effective, the detailed molecular mechanism through which S14G-humanin exerts its effects remains unclear. Data from this study showed that fibril ar amyloid-beta 40 disturbed cel ular ho-meostasis through the cel membrane, increasing intracel ular calcium, generating reactive oxygen species, and decreasing the mitochondrial membrane potential. S14G-humanin restored these re-sponses. The results suggested that S14G-humanin blocked the effects of amyloid-beta 40 on the neuronal cel membrane, and restored the disturbed cel ular homeostasis, thereby exerting a neuroprotective effect on hippocampal neurons.
基金supported by National Natural Science Foundation of China(82273868 and 82073780)Shanghai Municipal Natural Science Foundation(19ZR1406200).
文摘Alzheimer’s disease is a neurodegenerative disease induced by multiple interconnected mechanisms.Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-facet pathology.However,clinical translation of peptide drugs is greatly hampered by their low permeability into brain.Herein,a hybrid peptide HNSS is generated by merging two therapeutic peptides(SS31 and S-14 G Humanin(HNG)),using a different approach from the classical shuttle-therapeutic peptide conjugate design.HNSS demonstrated increased bio-permeability,with a 2-fold improvement in brain distribution over HNG,thanks to its structure mimicking the design of signal peptide-derived cell-penetrating peptides.HNSS efficiently alleviated mitochondrial dysfunction through the combined effects of mitochondrial targeting,ROS scavenging and p-STAT3 activation.Meanwhile,HNSS with increased Aβaffinity greatly inhibited Aβoligomerization/fibrillation,and interrupted Aβinteraction with neuron/microglia by reducing neuronal mitochondrial Aβdeposition and promoting microglial phagocytosis of Aβ.In3×Tg-AD transgenic mice,HNSS treatment efficiently inhibited brain neuron loss and improved the cognitive performance.This work validates the rational fusion design-based strategy for bio-permeability improvement and efficacy amplification,providing a paradigm for developing therapeutic peptide candidates against neurodegenerative disease.
文摘阿尔采末病(A lzheimer's d isease,AD)严重威胁着老年人的健康与生存质量,由于其发病原因复杂、机制不明,目前尚缺乏有效的防治措施。Humanin是近年来发现的能特异性抑制AD相关毒性的分泌性短肽,通过自身二聚化在细胞外发挥神经保护作用。Humanin通过直接或间接作用抑制β-淀粉样蛋白(Aβ),以及家族性AD(FAD)基因如早老基因突变诱发的神经毒,而对AD不相关的毒性作用如凋亡诱导剂etoposide及Fas诱导的细胞死亡却不表现拮抗作用。因此,Humanin可通过特异性拮抗AD相关的神经毒而发挥重要的神经保护作用。
