Pub Date : 2024-03-13DOI: 10.1007/s12031-024-02191-w
Jiayuan Liu, Li Peng, Lingwei He, Tianyue Yin, Yuhao Du, Mengmeng Yang, Ping Wu, Jun Li, Jiangbing Cao, Hongrui Zhu, Sheng Wang
Ischemic stroke is typified by hypoxia and a cascade of pathophysiological events, including metabolic dysfunction, ionic dysregulation, excitotoxicity, inflammatory infiltration, and oxidative stress. These ultimately result in neuronal apoptosis or necrosis with constrained neuroregenerative capabilities. In this study, neural stem cells (NSCs) under conditions of oxygen-glucose deprivation (OGD) in vitro and following middle cerebral artery occlusion (MCAO) in vivo were explored. Transcriptome sequencing revealed a decline in NSC differentiation and neurogenesis after OGD exposure, which was related to cellular senescence. This observation was corroborated by increased senescence markers in the MCAO mouse model, reduction in NSC numbers, and decline in neurogenesis. Importantly, iMSC-sEVs (induced mesenchymal stem cells-small extracellular vesicles) have the therapeutic potential to alleviate NSC senescence and rejuvenate their regenerative capacities both in vitro and in vivo. Moreover, iMSC-sEVs contribute to the recovery of cognitive function and synapse loss caused by MCAO.
{"title":"Induced Mesenchymal Stem Cells-Small Extracellular Vesicles Alleviate Post-stroke Cognitive Impairment by Rejuvenating Senescence of Neural Stem Cells.","authors":"Jiayuan Liu, Li Peng, Lingwei He, Tianyue Yin, Yuhao Du, Mengmeng Yang, Ping Wu, Jun Li, Jiangbing Cao, Hongrui Zhu, Sheng Wang","doi":"10.1007/s12031-024-02191-w","DOIUrl":"10.1007/s12031-024-02191-w","url":null,"abstract":"<p><p>Ischemic stroke is typified by hypoxia and a cascade of pathophysiological events, including metabolic dysfunction, ionic dysregulation, excitotoxicity, inflammatory infiltration, and oxidative stress. These ultimately result in neuronal apoptosis or necrosis with constrained neuroregenerative capabilities. In this study, neural stem cells (NSCs) under conditions of oxygen-glucose deprivation (OGD) in vitro and following middle cerebral artery occlusion (MCAO) in vivo were explored. Transcriptome sequencing revealed a decline in NSC differentiation and neurogenesis after OGD exposure, which was related to cellular senescence. This observation was corroborated by increased senescence markers in the MCAO mouse model, reduction in NSC numbers, and decline in neurogenesis. Importantly, iMSC-sEVs (induced mesenchymal stem cells-small extracellular vesicles) have the therapeutic potential to alleviate NSC senescence and rejuvenate their regenerative capacities both in vitro and in vivo. Moreover, iMSC-sEVs contribute to the recovery of cognitive function and synapse loss caused by MCAO.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-05DOI: 10.1007/s12031-024-02204-8
Yue Peng, Jiali He, Hongling Xiang, Lei Xie, Jin She, Donghui Cheng, Bei Liu, Jing Hu, Hao Qian
Mounting evidence suggests a significant correlation between depressive disorders and neurodegenerative conditions, encompassing Alzheimer's disease and Parkinson's disease (PD). Depression represents a substantial non-motor manifestation frequently identified in individuals with PD, posing a significant threat to patients' overall well-being and necessitating the implementation of effective management strategies. Despite its high prevalence, impacting over 40% of PD patients, the precise cellular and molecular mechanisms underlying depression and its relationship to dopaminergic system degeneration remain largely ambiguous. In this study, we presented our findings demonstrating distinct characteristics of cortical astrocytes in PD patients compared to reactivated glial cells in the substantia nigra. We identified a subset of differentially expressed genes associated with depressive disorders from PD-associated cortical astrocytes. Furthermore, we uncovered the potential involvement of the hypoxia signaling in driving cortical astrocytic dysfunctions. Through a comprehensive investigation utilizing transcriptome and chromatin accessibility analyses on cultured human astrocytes, we revealed that hypoxic treatment could induce similar expression changes observed in cortex from PD patients. Additionally, we provided evidence that activation of the HIF-1 signaling pathway suppressed the expression of key components of mitochondrial ribosomes and electron transport chain proteins COX2 and CYTB, resulting in abnormal mitochondrial membrane potential. Our results underscore the potential impact of glial metabolic abnormalities on the development of depressive disorders associated with Parkinson's disease.
{"title":"Potential Impact of Hypoxic Astrocytes on the Aggravation of Depressive Symptoms in Parkinson's Disease.","authors":"Yue Peng, Jiali He, Hongling Xiang, Lei Xie, Jin She, Donghui Cheng, Bei Liu, Jing Hu, Hao Qian","doi":"10.1007/s12031-024-02204-8","DOIUrl":"10.1007/s12031-024-02204-8","url":null,"abstract":"<p><p>Mounting evidence suggests a significant correlation between depressive disorders and neurodegenerative conditions, encompassing Alzheimer's disease and Parkinson's disease (PD). Depression represents a substantial non-motor manifestation frequently identified in individuals with PD, posing a significant threat to patients' overall well-being and necessitating the implementation of effective management strategies. Despite its high prevalence, impacting over 40% of PD patients, the precise cellular and molecular mechanisms underlying depression and its relationship to dopaminergic system degeneration remain largely ambiguous. In this study, we presented our findings demonstrating distinct characteristics of cortical astrocytes in PD patients compared to reactivated glial cells in the substantia nigra. We identified a subset of differentially expressed genes associated with depressive disorders from PD-associated cortical astrocytes. Furthermore, we uncovered the potential involvement of the hypoxia signaling in driving cortical astrocytic dysfunctions. Through a comprehensive investigation utilizing transcriptome and chromatin accessibility analyses on cultured human astrocytes, we revealed that hypoxic treatment could induce similar expression changes observed in cortex from PD patients. Additionally, we provided evidence that activation of the HIF-1 signaling pathway suppressed the expression of key components of mitochondrial ribosomes and electron transport chain proteins COX2 and CYTB, resulting in abnormal mitochondrial membrane potential. Our results underscore the potential impact of glial metabolic abnormalities on the development of depressive disorders associated with Parkinson's disease.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-29DOI: 10.1007/s12031-024-02188-5
Ying-Qin Li, Fa-Huan Song, Ke Zhong, Guang-Yin Yu, Prince Last Mudenda Zilundu, Ying-Ying Zhou, Rao Fu, Ying Tang, Ze-Min Ling, Xiaoying Xu, Li-Hua Zhou
{"title":"Correction to: Pre-Injection of Small Interfering RNA (siRNA) Promotes c-Jun Gene Silencing and Decreases the Survival Rate of Axotomy-Injured Spinal Motoneurons in Adult Mice.","authors":"Ying-Qin Li, Fa-Huan Song, Ke Zhong, Guang-Yin Yu, Prince Last Mudenda Zilundu, Ying-Ying Zhou, Rao Fu, Ying Tang, Ze-Min Ling, Xiaoying Xu, Li-Hua Zhou","doi":"10.1007/s12031-024-02188-5","DOIUrl":"10.1007/s12031-024-02188-5","url":null,"abstract":"","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139988924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-26DOI: 10.1007/s12031-024-02202-w
{"title":"Akira Arimura Foundation 2025-2026 Young Investigator Grant Application Procedures.","authors":"","doi":"10.1007/s12031-024-02202-w","DOIUrl":"10.1007/s12031-024-02202-w","url":null,"abstract":"","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139970541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-22DOI: 10.1007/s12031-023-02187-y
Li Lin, Xiao-Na Li, Zhen-Yan Xie, Yong-Zhen Hu, Qing-Shan Long, Yi-Qi Wen, Xiao-Bing Wei, Li-Yang Zhang, Xue-Song Li
Previous research has found that an adaptive response to ferroptosis involving glutathione peroxidase 4 (GPX4) is triggered after intracerebral hemorrhage. However, little is known about the mechanisms underlying adaptive responses to ferroptosis. To explore the mechanisms underlying adaptive responses to ferroptosis after intracerebral hemorrhage, we used hemin-treated HT22 cells to mimic brain injury after hemorrhagic stroke in vitro to evaluate the antioxidant enzymes and performed bioinformatics analysis based on the mRNA sequencing data. Further, we determined the expression of GSTO2 in hemin-treated hippocampal neurons and in a mouse model of hippocampus-intracerebral hemorrhage (h-ICH) by using Western blot. After hemin treatment, the antioxidant enzymes GPX4, Nrf2, and glutathione (GSH) were upregulated, suggesting that an adaptive response to ferroptosis was triggered. Furthermore, we performed mRNA sequencing to explore the underlying mechanism, and the results showed that 2234 genes were differentially expressed. Among these, ten genes related to ferroptosis (Acsl1, Ftl1, Gclc, Gclm, Hmox1, Map1lc3b, Slc7a11, Slc40a1, Tfrc, and Slc39a14) were altered after hemin treatment. In addition, analysis of the data retrieved from the GO database for the ten targeted genes showed that 20 items on biological processes, 17 items on cellular components, and 19 items on molecular functions were significantly enriched. Based on the GO data, we performed GSEA and found that the glutathione metabolic process was significantly enriched in the hemin phenotype. Notably, the expression of glutathione S-transferase omega (GSTO2), which is involved in glutathione metabolism, was decreased after hemin treatment, and overexpression of Gsto2 decreased lipid reactive oxygen species level in hemin-exposed HT22 cells. In addition, the expression of GSTO2 was also decreased in a mouse model of hippocampus-intracerebral hemorrhage (h-ICH). The decreased expression of GSTO2 in the glutathione metabolic process may be involved in ferroptotic neuronal injury following hemorrhagic stroke.
以往的研究发现,脑内出血后会引发对铁中毒的适应性反应,其中涉及谷胱甘肽过氧化物酶 4 (GPX4)。然而,人们对铁中毒适应性反应的机制知之甚少。为了探索脑出血后对铁氧化的适应性反应的机制,我们使用hemin处理的HT22细胞模拟出血性中风后的体外脑损伤,评估抗氧化酶,并根据mRNA测序数据进行生物信息学分析。此外,我们还利用 Western 印迹法测定了 GSTO2 在血清素处理过的海马神经元和海马-脑内出血(h-ICH)小鼠模型中的表达。在海明处理后,抗氧化酶GPX4、Nrf2和谷胱甘肽(GSH)上调,这表明铁变态反应的适应性反应被触发。此外,我们还进行了 mRNA 测序以探索其潜在机制。其中,10个与铁突变相关的基因(Acsl1、Ftl1、Gclc、Gclm、Hmox1、Map1lc3b、Slc7a11、Slc40a1、Tfrc和Slc39a14)在赫敏处理后发生了改变。此外,对从 GO 数据库中检索到的 10 个目标基因的数据进行分析后发现,20 个生物过程项目、17 个细胞组分项目和 19 个分子功能项目被显著富集。根据 GO 数据,我们进行了 GSEA,发现谷胱甘肽代谢过程在 hemin 表型中明显富集。值得注意的是,参与谷胱甘肽代谢的谷胱甘肽S-转移酶ω(GSTO2)在hemin处理后表达量减少,而过表达Gsto2可降低hemin暴露的HT22细胞的脂质活性氧水平。此外,在海马-脑内出血(h-ICH)小鼠模型中,GSTO2 的表达也有所下降。谷胱甘肽代谢过程中 GSTO2 表达的降低可能与出血性脑卒中后的铁变态反应性神经元损伤有关。
{"title":"Pivotal Role of GSTO2 in Ferroptotic Neuronal Injury After Intracerebral Hemorrhage","authors":"Li Lin, Xiao-Na Li, Zhen-Yan Xie, Yong-Zhen Hu, Qing-Shan Long, Yi-Qi Wen, Xiao-Bing Wei, Li-Yang Zhang, Xue-Song Li","doi":"10.1007/s12031-023-02187-y","DOIUrl":"https://doi.org/10.1007/s12031-023-02187-y","url":null,"abstract":"<p>Previous research has found that an adaptive response to ferroptosis involving glutathione peroxidase 4 (GPX4) is triggered after intracerebral hemorrhage. However, little is known about the mechanisms underlying adaptive responses to ferroptosis. To explore the mechanisms underlying adaptive responses to ferroptosis after intracerebral hemorrhage, we used hemin-treated HT22 cells to mimic brain injury after hemorrhagic stroke in vitro to evaluate the antioxidant enzymes and performed bioinformatics analysis based on the mRNA sequencing data. Further, we determined the expression of GSTO2 in hemin-treated hippocampal neurons and in a mouse model of hippocampus-intracerebral hemorrhage (h-ICH) by using Western blot. After hemin treatment, the antioxidant enzymes GPX4, Nrf2, and glutathione (GSH) were upregulated, suggesting that an adaptive response to ferroptosis was triggered. Furthermore, we performed mRNA sequencing to explore the underlying mechanism, and the results showed that 2234 genes were differentially expressed. Among these, ten genes related to ferroptosis (Acsl1, Ftl1, Gclc, Gclm, Hmox1, Map1lc3b, Slc7a11, Slc40a1, Tfrc, and Slc39a14) were altered after hemin treatment. In addition, analysis of the data retrieved from the GO database for the ten targeted genes showed that 20 items on biological processes, 17 items on cellular components, and 19 items on molecular functions were significantly enriched. Based on the GO data, we performed GSEA and found that the glutathione metabolic process was significantly enriched in the hemin phenotype. Notably, the expression of glutathione S-transferase omega (GSTO2), which is involved in glutathione metabolism, was decreased after hemin treatment, and overexpression of Gsto2 decreased lipid reactive oxygen species level in hemin-exposed HT22 cells. In addition, the expression of GSTO2 was also decreased in a mouse model of hippocampus-intracerebral hemorrhage (h-ICH). The decreased expression of GSTO2 in the glutathione metabolic process may be involved in ferroptotic neuronal injury following hemorrhagic stroke.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139918792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Galanin-like peptide (GALP) is a neuropeptide that was first isolated and identified from the porcine hypothalamus. Studies have described an anti-obesity effect of GALP. We previously found that intracerebroventricular administration of GALP in mice resulted in an increase in respiratory exchange rate 12 to 16 h later. GALP may also affect glucose metabolism, but the detailed mechanism has not been elucidated. In this study, we investigated the effects of GALP on glucose and lipid metabolism in the liver. Nine-week-old male C57BL / 6 J mice were administered a single intracerebroventricular dose of saline or GALP and dissected 16 h later. There were no significant between-group differences in body weight and blood glucose levels. With regard to gene and protein expression, G6Pase associated with hepatic gluconeogenesis was significantly reduced in the GALP group. In addition, the hepatokines selenoprotein P and fetuin-A, which induce insulin resistance in the liver, were significantly decreased in the GALP group. These results suggest that intracerebroventricular administration of GALP decreases the expression of key hepatokines, thereby enhancing glucose metabolism.
{"title":"Effect of Intracerebroventricular Administration of Galanin-Like Peptide on Hepatokines in C57BL/6 J Mice","authors":"Satoshi Hirako, Nobuhiro Wada, Yuzuru Iizuka, Takahiro Hirabayashi, Haruaki Kageyama, Hyounju Kim, Naoko Kaibara, Naoko Yanagisawa, Fumiko Takenoya, Seiji Shioda","doi":"10.1007/s12031-024-02200-y","DOIUrl":"https://doi.org/10.1007/s12031-024-02200-y","url":null,"abstract":"<p>Galanin-like peptide (GALP) is a neuropeptide that was first isolated and identified from the porcine hypothalamus. Studies have described an anti-obesity effect of GALP. We previously found that intracerebroventricular administration of GALP in mice resulted in an increase in respiratory exchange rate 12 to 16 h later. GALP may also affect glucose metabolism, but the detailed mechanism has not been elucidated. In this study, we investigated the effects of GALP on glucose and lipid metabolism in the liver. Nine-week-old male C57BL / 6 J mice were administered a single intracerebroventricular dose of saline or GALP and dissected 16 h later. There were no significant between-group differences in body weight and blood glucose levels. With regard to gene and protein expression, G6Pase associated with hepatic gluconeogenesis was significantly reduced in the GALP group. In addition, the hepatokines selenoprotein P and fetuin-A, which induce insulin resistance in the liver, were significantly decreased in the GALP group. These results suggest that intracerebroventricular administration of GALP decreases the expression of key hepatokines, thereby enhancing glucose metabolism.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139928408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-21DOI: 10.1007/s12031-024-02197-4
Jina Jiang, Tingting Qi, Li Li, Yunzhi Pan, Lijuan Huang, Lijuan Zhu, Dongyang Zhang, Xiaoqing Ma, Yinghui Qin
Neuronal apoptosis is crucial in the pathophysiology of ischemic stroke (IS), albeit its underly24ing mechanism remaining elusive. Investigating the mechanism of neuronal apoptosis in the context of IS holds substantial clinical value for enhancing the prognosis of IS patients. Notably, the MRPS9 gene plays a pivotal role in regulating mitochondrial function and maintaining structural integrity. Utilizing bioinformatic tactics and the extant gene expression data related to IS, we conducted differential analysis and weighted correlation network analysis (WGCNA) to select important modules. Subsequent gene interaction analysis via the STRING website facilitated the identification of the key gene-mitochondrial ribosomal protein S9 (MRPS9)-that affects the progression of IS. Moreover, possible downstream signaling pathways, namely PI3K/Akt/mTOR, were elucidated via Kyoto Encyclopedia of Gene and Genomes (KEGG) and Gene Ontology (GO) pathway analysis. Experimental models were established utilizing oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro and middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. Changes in gene and protein expression, as well as cell proliferation and apoptosis, were monitored through qPCR, WB, CCK8, and flow cytometry. An OGD/R cell model was further employed to investigate the role of MRPS9 in IS post transfusion of MRPS9 overexpression plasmids into cells. Further studies were conducted by transfecting overexpressed cells with PI3K/Akt/mTOR signaling pathway inhibitor LY294002 to unveil the mechanism of MRPS9 in IS. Bioinformatic analysis revealed a significant underexpression of MRPS9 in ischemic stroke patients. Correspondingly, in vitro experiments with HN cells subjected to OGD/R treatment demonstrated a marked reduction in MRPS9 expression, accompanied by a decline in cell viability, and an increase cell apoptosis. Notably, the overexpression of MRPS9 mitigated the OGD/R-induced decrease in cell viability and augmentation of apoptosis. In animal models, MRPS9 expression was significantly lower in the MCAO/R group compared to the sham surgery group. Further, the KEGG pathway analysis associated MRPS9 expression with the PI3K/Akt/mTOR signaling pathway. In cells treated with the specific PI3K/Akt/mTOR inhibitor LY294002, phosphorylation levels of Akt and mTOR were decreased, cell viability decreased, and apoptosis increased compared to the MRPS9 overexpression group. These findings collectively indicate that MRPS9 overexpression inhibits PI3K/Akt/mTOR pathway activation, thereby protecting neurons from apoptosis and impeding IS progression. However, the PI3K/Akt/mTOR inhibitor LY294002 is capable of counteracting the protective effect of MRPS9 overexpression on neuronal apoptosis and IS. Our observations underscore the potential protective role of MRPS9 in modulating neuronal apoptosis and in attenuating the pathophysiological developments associated with IS. This is achieved through the regulation
神经细胞凋亡在缺血性脑卒中(IS)的病理生理学中至关重要,但其基本24机制仍难以捉摸。研究 IS 中神经元凋亡的机制对于改善 IS 患者的预后具有重要的临床价值。值得注意的是,MRPS9 基因在调节线粒体功能和维持结构完整性方面发挥着关键作用。利用生物信息学策略和现有的与 IS 相关的基因表达数据,我们进行了差异分析和加权相关网络分析(WGCNA),以筛选出重要的模块。随后通过 STRING 网站进行基因相互作用分析,确定了影响 IS 进展的关键基因-线粒体核糖体蛋白 S9(MRPS9)。此外,通过京都基因与基因组百科全书(KEGG)和基因本体论(GO)通路分析,阐明了可能的下游信号通路,即 PI3K/Akt/mTOR 通路。利用体外氧-葡萄糖剥夺/再氧合(OGD/R)和小鼠大脑中动脉闭塞/再灌注(MCAO/R)建立了实验模型。通过 qPCR、WB、CCK8 和流式细胞术监测基因和蛋白质表达以及细胞增殖和凋亡的变化。我们还采用了一个 OGD/R 细胞模型,以研究 MRPS9 在向细胞中输注 MRPS9 过表达质粒后的 IS 中的作用。进一步的研究通过用PI3K/Akt/mTOR信号通路抑制剂LY294002转染过表达细胞来揭示MRPS9在IS中的作用机制。生物信息学分析表明,缺血性中风患者体内的MRPS9表达明显不足。与此对应的是,在体外实验中,经 OGD/R 处理的 HN 细胞显示 MRPS9 表达明显降低,同时细胞活力下降,细胞凋亡增加。值得注意的是,过表达 MRPS9 可减轻 OGD/R 引起的细胞活力下降和细胞凋亡增加。在动物模型中,与假手术组相比,MCAO/R 组的 MRPS9 表达明显较低。此外,KEGG通路分析将MRPS9的表达与PI3K/Akt/mTOR信号通路相关联。在使用特异性 PI3K/Akt/mTOR 抑制剂 LY294002 处理的细胞中,与 MRPS9 过表达组相比,Akt 和 mTOR 的磷酸化水平降低,细胞存活率下降,细胞凋亡增加。这些发现共同表明,MRPS9过表达可抑制PI3K/Akt/mTOR通路的激活,从而保护神经元免于凋亡并阻碍IS的进展。然而,PI3K/Akt/mTOR 抑制剂 LY294002 能够抵消 MRPS9 过表达对神经元凋亡和 IS 的保护作用。我们的观察强调了MRPS9在调节神经元凋亡和减轻与IS相关的病理生理发展方面的潜在保护作用。这是通过调节 PI3K/Akt/mTOR 通路实现的。这些见解为战略性诊断和治疗 IS 提供了新的视角和新的靶点。
{"title":"MRPS9-Mediated Regulation of the PI3K/Akt/mTOR Pathway Inhibits Neuron Apoptosis and Protects Ischemic Stroke.","authors":"Jina Jiang, Tingting Qi, Li Li, Yunzhi Pan, Lijuan Huang, Lijuan Zhu, Dongyang Zhang, Xiaoqing Ma, Yinghui Qin","doi":"10.1007/s12031-024-02197-4","DOIUrl":"10.1007/s12031-024-02197-4","url":null,"abstract":"<p><p>Neuronal apoptosis is crucial in the pathophysiology of ischemic stroke (IS), albeit its underly24ing mechanism remaining elusive. Investigating the mechanism of neuronal apoptosis in the context of IS holds substantial clinical value for enhancing the prognosis of IS patients. Notably, the MRPS9 gene plays a pivotal role in regulating mitochondrial function and maintaining structural integrity. Utilizing bioinformatic tactics and the extant gene expression data related to IS, we conducted differential analysis and weighted correlation network analysis (WGCNA) to select important modules. Subsequent gene interaction analysis via the STRING website facilitated the identification of the key gene-mitochondrial ribosomal protein S9 (MRPS9)-that affects the progression of IS. Moreover, possible downstream signaling pathways, namely PI3K/Akt/mTOR, were elucidated via Kyoto Encyclopedia of Gene and Genomes (KEGG) and Gene Ontology (GO) pathway analysis. Experimental models were established utilizing oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro and middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. Changes in gene and protein expression, as well as cell proliferation and apoptosis, were monitored through qPCR, WB, CCK8, and flow cytometry. An OGD/R cell model was further employed to investigate the role of MRPS9 in IS post transfusion of MRPS9 overexpression plasmids into cells. Further studies were conducted by transfecting overexpressed cells with PI3K/Akt/mTOR signaling pathway inhibitor LY294002 to unveil the mechanism of MRPS9 in IS. Bioinformatic analysis revealed a significant underexpression of MRPS9 in ischemic stroke patients. Correspondingly, in vitro experiments with HN cells subjected to OGD/R treatment demonstrated a marked reduction in MRPS9 expression, accompanied by a decline in cell viability, and an increase cell apoptosis. Notably, the overexpression of MRPS9 mitigated the OGD/R-induced decrease in cell viability and augmentation of apoptosis. In animal models, MRPS9 expression was significantly lower in the MCAO/R group compared to the sham surgery group. Further, the KEGG pathway analysis associated MRPS9 expression with the PI3K/Akt/mTOR signaling pathway. In cells treated with the specific PI3K/Akt/mTOR inhibitor LY294002, phosphorylation levels of Akt and mTOR were decreased, cell viability decreased, and apoptosis increased compared to the MRPS9 overexpression group. These findings collectively indicate that MRPS9 overexpression inhibits PI3K/Akt/mTOR pathway activation, thereby protecting neurons from apoptosis and impeding IS progression. However, the PI3K/Akt/mTOR inhibitor LY294002 is capable of counteracting the protective effect of MRPS9 overexpression on neuronal apoptosis and IS. Our observations underscore the potential protective role of MRPS9 in modulating neuronal apoptosis and in attenuating the pathophysiological developments associated with IS. This is achieved through the regulation","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139911691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-17DOI: 10.1007/s12031-024-02193-8
Hossam Tharwat Ali, Idris Sula, Abrar AbuHamdia, Sewar A. Elejla, Ahmed Elrefaey, Hiba Hamdar, Mohamed Elfil
Neurotrauma is a significant cause of morbidity and mortality worldwide. For instance, traumatic brain injury (TBI) causes more than 30% of all injury-related deaths in the USA annually. The underlying cause and clinical sequela vary among cases. Patients are liable to both acute and chronic changes in the nervous system after such a type of injury. Cerebrovascular disruption has the most common and serious effect in such cases because cerebrovascular autoregulation, which is one of the main determinants of cerebral perfusion pressure, can be effaced in brain injuries even in the absence of evident vascular injury. Disruption of the blood–brain barrier regulatory function may also ensue whether due to direct injury to its structure or metabolic changes. Furthermore, the autonomic nervous system (ANS) can be affected leading to sympathetic hyperactivity in many patients. On a cellular scale, the neuroinflammatory cascade medicated by the glial cells gets triggered in response to TBI. Nevertheless, cellular and molecular reactions involved in cerebrovascular repair are not fully understood yet. Most studies were done on animals with many drawbacks in interpreting results. Therefore, future studies including human subjects are necessarily needed. This review will be of relevance to clinicians and researchers interested in understanding the underlying mechanisms in neurotrauma cases and the development of proper therapies as well as those with a general interest in the neurotrauma field.
{"title":"Nervous System Response to Neurotrauma: A Narrative Review of Cerebrovascular and Cellular Changes After Neurotrauma","authors":"Hossam Tharwat Ali, Idris Sula, Abrar AbuHamdia, Sewar A. Elejla, Ahmed Elrefaey, Hiba Hamdar, Mohamed Elfil","doi":"10.1007/s12031-024-02193-8","DOIUrl":"https://doi.org/10.1007/s12031-024-02193-8","url":null,"abstract":"<p>Neurotrauma is a significant cause of morbidity and mortality worldwide. For instance, traumatic brain injury (TBI) causes more than 30% of all injury-related deaths in the USA annually. The underlying cause and clinical sequela vary among cases. Patients are liable to both acute and chronic changes in the nervous system after such a type of injury. Cerebrovascular disruption has the most common and serious effect in such cases because cerebrovascular autoregulation, which is one of the main determinants of cerebral perfusion pressure, can be effaced in brain injuries even in the absence of evident vascular injury. Disruption of the blood–brain barrier regulatory function may also ensue whether due to direct injury to its structure or metabolic changes. Furthermore, the autonomic nervous system (ANS) can be affected leading to sympathetic hyperactivity in many patients. On a cellular scale, the neuroinflammatory cascade medicated by the glial cells gets triggered in response to TBI. Nevertheless, cellular and molecular reactions involved in cerebrovascular repair are not fully understood yet. Most studies were done on animals with many drawbacks in interpreting results. Therefore, future studies including human subjects are necessarily needed. This review will be of relevance to clinicians and researchers interested in understanding the underlying mechanisms in neurotrauma cases and the development of proper therapies as well as those with a general interest in the neurotrauma field.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139756642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-16DOI: 10.1007/s12031-024-02199-2
Megha Manoj, Siddarth Sowmyanarayan, Arjun V Kowshik, Jhinuk Chatterjee
The conventional method of one drug being used for one target has not yielded therapeutic solutions for Lewy body dementia (LBD), which is a leading progressive neurological disorder characterized by significant loss of neurons. The age-related disease is marked by memory loss, hallucinations, sleep disorder, mental health deterioration, palsy, and cognitive impairment, all of which have no known effective cure. The present study deploys a network medicine pipeline to repurpose drugs having considerable effect on the genes and proteins related to the diseases of interest. We utilized the novel SAveRUNNER algorithm to quantify the proximity of all drugs obtained from DrugBank with the disease associated gene dataset obtained from Phenopedia and targets in the human interactome. We found that most of the 154 FDA-approved drugs predicted by SAveRUNNER were used to treat nervous system disorders, but some off-label drugs like quinapril and selegiline were interestingly used to treat hypertension and Parkinson's disease (PD), respectively. Additionally, we performed gene set enrichment analysis using Connectivity Map (CMap) and pathway enrichment analysis using EnrichR to validate the efficacy of the drug candidates obtained from the pipeline approach. The investigation enabled us to identify the significant role of the synaptic vesicle pathway in our disease and accordingly finalize 8 suitable antidepressant drugs from the 154 drugs initially predicted by SAveRUNNER. These potential anti-LBD drugs are either selective or non-selective inhibitors of serotonin, dopamine, and norepinephrine transporters. The validated selective serotonin and norepinephrine inhibitors like milnacipran, protriptyline, and venlafaxine are predicted to manage LBD along with the affecting symptomatic issues.
{"title":"Identification of Potentially Repurposable Drugs for Lewy Body Dementia Using a Network-Based Approach.","authors":"Megha Manoj, Siddarth Sowmyanarayan, Arjun V Kowshik, Jhinuk Chatterjee","doi":"10.1007/s12031-024-02199-2","DOIUrl":"10.1007/s12031-024-02199-2","url":null,"abstract":"<p><p>The conventional method of one drug being used for one target has not yielded therapeutic solutions for Lewy body dementia (LBD), which is a leading progressive neurological disorder characterized by significant loss of neurons. The age-related disease is marked by memory loss, hallucinations, sleep disorder, mental health deterioration, palsy, and cognitive impairment, all of which have no known effective cure. The present study deploys a network medicine pipeline to repurpose drugs having considerable effect on the genes and proteins related to the diseases of interest. We utilized the novel SAveRUNNER algorithm to quantify the proximity of all drugs obtained from DrugBank with the disease associated gene dataset obtained from Phenopedia and targets in the human interactome. We found that most of the 154 FDA-approved drugs predicted by SAveRUNNER were used to treat nervous system disorders, but some off-label drugs like quinapril and selegiline were interestingly used to treat hypertension and Parkinson's disease (PD), respectively. Additionally, we performed gene set enrichment analysis using Connectivity Map (CMap) and pathway enrichment analysis using EnrichR to validate the efficacy of the drug candidates obtained from the pipeline approach. The investigation enabled us to identify the significant role of the synaptic vesicle pathway in our disease and accordingly finalize 8 suitable antidepressant drugs from the 154 drugs initially predicted by SAveRUNNER. These potential anti-LBD drugs are either selective or non-selective inhibitors of serotonin, dopamine, and norepinephrine transporters. The validated selective serotonin and norepinephrine inhibitors like milnacipran, protriptyline, and venlafaxine are predicted to manage LBD along with the affecting symptomatic issues.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139740106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-16DOI: 10.1007/s12031-024-02198-3
Farzaneh Aghababaei, Majid Nejati, Hadi Karami, Maryam Darvish, Hamed Mirzaei
{"title":"Correction: The Combination of 5-FU and Resveratrol Can Suppress the Growth of Glioblastoma Cells through Downregulation of TRPM2 and β-Catenin.","authors":"Farzaneh Aghababaei, Majid Nejati, Hadi Karami, Maryam Darvish, Hamed Mirzaei","doi":"10.1007/s12031-024-02198-3","DOIUrl":"10.1007/s12031-024-02198-3","url":null,"abstract":"","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139740105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}