Pub Date : 2024-10-13DOI: 10.1016/j.neuint.2024.105881
Neuronal death is the key cause of ischemic stroke. Acupuncture (Acu) is a recognized method for the treatment and amelioration of cerebral ischemia. However, the molecular mechanism of Acu for treating ischemic stroke has not yet been detailedly elucidated. Based our microarray analysis results, mitochondrial ribosomal protein L41 (MRPL41), which is related to apoptosis, was identified as the target of Acu. MRPL41 expression was increased in middle cerebral artery occlusion/reperfusion (MCAO/R) model and reduced after Acu treatment. Following, MCAO/R model and oxygen and glucose deprivation/reoxygenation (OGD/R) model were established to explore the effect of MRPL41. Knockdown of MRPL41 increased cell viability and ani-apoptotic protein (Bcl-2) expression, and reduced apoptosis intensity and pro-apoptotic protein (Bax and Cleaved caspase-3) of OGD/R neurons. In vivo, MRPL41 silencing decreased neurological severity score, shrank infarct area, reduced encephaledema and neuron apoptosis. In addition, reduction of MRPL41 caused loss of p53. Our data uncover that Acu targets MRPL41, following with inhibiting neuron apoptosis via p53 pathway, thereby ameliorating ischemic stroke.
神经元死亡是缺血性中风的主要原因。针灸（Acupuncture，Acu）是公认的治疗和改善脑缺血的方法。然而，针灸治疗缺血性中风的分子机制尚未得到详细阐明。根据我们的芯片分析结果，与细胞凋亡有关的线粒体核糖体蛋白 L41（MRPL41）被确定为 Acu 的靶点。MRPL41在大脑中动脉闭塞/再灌注（MCAO/R）模型中表达增加，而在Acu治疗后表达减少。随后，建立了MCAO/R模型和氧和葡萄糖剥夺/再氧合（OGD/R）模型来探讨MRPL41的作用。敲除MRPL41增加了OGD/R神经元的细胞活力和抗凋亡蛋白（Bcl-2）的表达，降低了细胞凋亡强度和促凋亡蛋白（Bax和Caspase-3）的表达。在体内，MRPL41沉默可降低神经系统严重程度评分，缩小梗死面积，减轻脑水肿和神经元凋亡。此外，MRPL41的减少会导致p53的缺失。我们的数据发现，Acu以MRPL41为靶点，通过p53通路抑制神经元凋亡，从而改善缺血性中风。
{"title":"MRPL41, as a target for acupuncture, promotes neuron apoptosis in models of ischemic stroke via activating p53 pathway","authors":"","doi":"10.1016/j.neuint.2024.105881","DOIUrl":"10.1016/j.neuint.2024.105881","url":null,"abstract":"<div><div>Neuronal death is the key cause of ischemic stroke. Acupuncture (Acu) is a recognized method for the treatment and amelioration of cerebral ischemia. However, the molecular mechanism of Acu for treating ischemic stroke has not yet been detailedly elucidated. Based our microarray analysis results, mitochondrial ribosomal protein L41 (MRPL41), which is related to apoptosis, was identified as the target of Acu. MRPL41 expression was increased in middle cerebral artery occlusion/reperfusion (MCAO/R) model and reduced after Acu treatment. Following, MCAO/R model and oxygen and glucose deprivation/reoxygenation (OGD/R) model were established to explore the effect of MRPL41. Knockdown of MRPL41 increased cell viability and ani-apoptotic protein (Bcl-2) expression, and reduced apoptosis intensity and pro-apoptotic protein (Bax and Cleaved caspase-3) of OGD/R neurons. <em>In vivo</em>, MRPL41 silencing decreased neurological severity score, shrank infarct area, reduced encephaledema and neuron apoptosis. In addition, reduction of MRPL41 caused loss of p53. Our data uncover that Acu targets MRPL41, following with inhibiting neuron apoptosis via p53 pathway, thereby ameliorating ischemic stroke.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1016/j.neuint.2024.105880
Protein aggregation serves as a critical pathological marker in a spectrum of neurodegenerative diseases (NDs), including the formation of amyloid β (Aβ) and Tau neurofibrillary tangles in Alzheimer's disease, as well as α-Synuclein (α-Syn) aggregates in Parkinson's disease, Parkinson's disease-related dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). A significant proportion of patients with amyotrophic lateral sclerosis (ALS) exhibit TDP-43 aggregates. Moreover, a confluence of brain protein pathologies, such as Aβ, Tau, α-Syn, and TDP-43, has been identified in individual NDs cases, highlighting the intricate interplay among these proteins that is garnering heightened scrutiny. Importantly, protein aggregation is modulated by an array of factors, with burgeoning evidence suggesting that it frequently results from perturbations in protein homeostasis, influenced by the cellular membrane milieu, metal ion concentrations, post-translational modifications, and genetic mutations. This review delves into the pathological underpinnings of protein aggregation across various NDs and elucidates the intercommunication among disparate proteins within the same disease context. Additionally, we examine the pathogenic mechanisms by which diverse factors impinge upon protein aggregation, offering fresh perspectives for the future therapeutic intervention of NDs.
{"title":"Protein aggregation and its affecting mechanisms in neurodegenerative diseases","authors":"","doi":"10.1016/j.neuint.2024.105880","DOIUrl":"10.1016/j.neuint.2024.105880","url":null,"abstract":"<div><div>Protein aggregation serves as a critical pathological marker in a spectrum of neurodegenerative diseases (NDs), including the formation of amyloid β (Aβ) and Tau neurofibrillary tangles in Alzheimer's disease, as well as α-Synuclein (α-Syn) aggregates in Parkinson's disease, Parkinson's disease-related dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). A significant proportion of patients with amyotrophic lateral sclerosis (ALS) exhibit TDP-43 aggregates. Moreover, a confluence of brain protein pathologies, such as Aβ, Tau, α-Syn, and TDP-43, has been identified in individual NDs cases, highlighting the intricate interplay among these proteins that is garnering heightened scrutiny. Importantly, protein aggregation is modulated by an array of factors, with burgeoning evidence suggesting that it frequently results from perturbations in protein homeostasis, influenced by the cellular membrane milieu, metal ion concentrations, post-translational modifications, and genetic mutations. This review delves into the pathological underpinnings of protein aggregation across various NDs and elucidates the intercommunication among disparate proteins within the same disease context. Additionally, we examine the pathogenic mechanisms by which diverse factors impinge upon protein aggregation, offering fresh perspectives for the future therapeutic intervention of NDs.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142437884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1016/j.neuint.2024.105879
The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific receptor (PAC1R) are widely present in the central nervous system (CNS), and PACAP/PAC1R signaling has been implicated in anxiety-related behaviors. The locus coeruleus (LC), with its extensive noradrenergic (NA) projections throughout the CNS, is also implicated in anxiety. Although the LC exhibits a high expression of PAC1R, the precise role of PACAP/PAC1R signaling in the LC's involvement in anxiety remains unclear. Histochemical analysis confirmed high levels of PAC1R mRNA in the LC and showed that PAC1R gene transcripts were highly localized to NA neurons. Targeted deletion of PAC1R from these cells led to a hyperactive/low anxiety phenotype in the open field and elevated-plus maze tests. Retrograde neurocircuit tracing indicated PACAP neurons from the anterior insular cortex (aIC) and a few other regions projected axons to the LC. The selective activation of PACAP neurons in the aIC led to significantly increased anxiety behavior without a change in overall locomotor activity. Moreover, shRNA PACAP knockdown in the aIC in wild-type mice led to a selective decrease in anxiety. The present results identify an aIC to LC neurocircuit controlling anxiety that critically requires PACAP/PAC1R signaling.
{"title":"The pivotal role of PACAP/PAC1R signaling from the anterior insular cortex to the locus coeruleus on anxiety-related behaviors of mice","authors":"","doi":"10.1016/j.neuint.2024.105879","DOIUrl":"10.1016/j.neuint.2024.105879","url":null,"abstract":"<div><div>The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific receptor (PAC1R) are widely present in the central nervous system (CNS), and PACAP/PAC1R signaling has been implicated in anxiety-related behaviors. The locus coeruleus (LC), with its extensive noradrenergic (NA) projections throughout the CNS, is also implicated in anxiety. Although the LC exhibits a high expression of PAC1R, the precise role of PACAP/PAC1R signaling in the LC's involvement in anxiety remains unclear. Histochemical analysis confirmed high levels of PAC1R mRNA in the LC and showed that PAC1R gene transcripts were highly localized to NA neurons. Targeted deletion of PAC1R from these cells led to a hyperactive/low anxiety phenotype in the open field and elevated-plus maze tests. Retrograde neurocircuit tracing indicated PACAP neurons from the anterior insular cortex (aIC) and a few other regions projected axons to the LC. The selective activation of PACAP neurons in the aIC led to significantly increased anxiety behavior without a change in overall locomotor activity. Moreover, shRNA PACAP knockdown in the aIC in wild-type mice led to a selective decrease in anxiety. The present results identify an aIC to LC neurocircuit controlling anxiety that critically requires PACAP/PAC1R signaling.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142445857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-09DOI: 10.1016/j.neuint.2024.105875
The relationship between olfactory dysfunction and alcohol intake is unobvious. Chronic alcohol intake results in reduced olfactory acuity and olfactory discrimination and addiction in humans. However, alcohol is a beverage with distinctive odors, which usually works as a cue to induce addictive memories and craving behavior. Whether olfactory impairment increase or decrease alcohol consumption remains an important but unclear issue. In this study, we measured ethanol (EtOH) consumption in the two-bottle choice EtOH drinking test, two bottle choice EtOH/sucrose drinking test and the drinking in the dark (DID) test during the olfactory loss. We also recorded local field potentials (LFPs) from the brain reward system, the ventral tegmental area (VTA), nucleus accumbens (NAc), and piriform cortex (Pir) one and four weeks after the induction of olfactory epithelium lesions using zinc sulfate (ZnSO4) in mice. The results showed that the EtOH consumption and preference were increased during the period of olfactory dysfunction. 1 week after the olfactory injury, LFP powers in the reward system at low- and high-gamma bands decreased significantly, coherence between the Pir and the reward system was also decrease. 4 weeks after the ZnSO4 treatment, LFP powers were reversed, but the coherence between VTA and NAc was decreased, indicating lasting effects post-recovery. This study demonstrates that olfactory dysfunction increased EtOH consumption in mice, which was accompanied by decreased LFP power and coherence in the reward system, which suggest that olfactory deficits changed activities in the reward system and could alter reward-seeking behaviors, which provide insights into the neurobiology of alcohol addiction.
{"title":"Olfactory dysfunction decreased local field potential in the reward system and increased EtOH consumption in mice","authors":"","doi":"10.1016/j.neuint.2024.105875","DOIUrl":"10.1016/j.neuint.2024.105875","url":null,"abstract":"<div><div>The relationship between olfactory dysfunction and alcohol intake is unobvious. Chronic alcohol intake results in reduced olfactory acuity and olfactory discrimination and addiction in humans. However, alcohol is a beverage with distinctive odors, which usually works as a cue to induce addictive memories and craving behavior. Whether olfactory impairment increase or decrease alcohol consumption remains an important but unclear issue. In this study, we measured ethanol (EtOH) consumption in the two-bottle choice EtOH drinking test, two bottle choice EtOH/sucrose drinking test and the drinking in the dark (DID) test during the olfactory loss. We also recorded local field potentials (LFPs) from the brain reward system, the ventral tegmental area (VTA), nucleus accumbens (NAc), and piriform cortex (Pir) one and four weeks after the induction of olfactory epithelium lesions using zinc sulfate (ZnSO<sub>4</sub>) in mice. The results showed that the EtOH consumption and preference were increased during the period of olfactory dysfunction. 1 week after the olfactory injury, LFP powers in the reward system at low- and high-gamma bands decreased significantly, coherence between the Pir and the reward system was also decrease. 4 weeks after the ZnSO<sub>4</sub> treatment, LFP powers were reversed, but the coherence between VTA and NAc was decreased, indicating lasting effects post-recovery. This study demonstrates that olfactory dysfunction increased EtOH consumption in mice, which was accompanied by decreased LFP power and coherence in the reward system, which suggest that olfactory deficits changed activities in the reward system and could alter reward-seeking behaviors, which provide insights into the neurobiology of alcohol addiction.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-09DOI: 10.1016/j.neuint.2024.105878
The dynamic protective capacity of (poly)phenols, attributed to their potent antioxidant and anti-inflammatory properties, has been consistently reported. Due to their capacity to alter gut microbiome composition, further actions of (poly)phenols may be exerted through the modulation of the microbiota-gut-brain axis. However, the underlying mechanisms remain poorly defined. Here, we investigated the protective effect of a (poly)phenol-rich grape and blueberry extract (Memophenol™), on the microbiota-gut-brain axis in a model of chronic low-grade inflammation (0.5 mg/kg/wk lipopolysaccharide (LPS) for 8 weeks). Dietary supplementation of male C57BL/6 J mice with Memophenol™ prevented LPS-induced increases in the microbe-derived uremia-associated molecules, indoxyl sulfate (IS) and trimethylamine N-oxide (TMAO). These changes coincided with shifts in gut microbiome composition, notably Romboutsia and Desulfovibrio abundance, respectively. In the brain, LPS exposure disrupted the marginal localisation of the endothelial tight junction ZO-1 and downregulated ZO-1 mRNA expression to an extent closely correlated with TMAO and IS levels; a process prevented by Memophenol™ intake. Hippocampal mRNA sequencing analysis revealed significant downregulation in regulatory pathways of neurodegeneration with Memophenol™ intake. These findings may indicate a novel protective role of the (poly)phenol-rich grape and blueberry extract on the endothelial tight junction component ZO-1, acting through modulation of gut microbial metabolism.
{"title":"(Poly)phenol-rich grape and blueberry extract prevents LPS-induced disruption of the blood-brain barrier through the modulation of the gut microbiota-derived uremic toxins","authors":"","doi":"10.1016/j.neuint.2024.105878","DOIUrl":"10.1016/j.neuint.2024.105878","url":null,"abstract":"<div><div>The dynamic protective capacity of (poly)phenols, attributed to their potent antioxidant and anti-inflammatory properties, has been consistently reported. Due to their capacity to alter gut microbiome composition, further actions of (poly)phenols may be exerted through the modulation of the microbiota-gut-brain axis. However, the underlying mechanisms remain poorly defined. Here, we investigated the protective effect of a (poly)phenol-rich grape and blueberry extract (Memophenol™), on the microbiota-gut-brain axis in a model of chronic low-grade inflammation (0.5 mg/kg/wk lipopolysaccharide (LPS) for 8 weeks). Dietary supplementation of male C57BL/6 J mice with Memophenol™ prevented LPS-induced increases in the microbe-derived uremia-associated molecules, indoxyl sulfate (IS) and trimethylamine <em>N</em>-oxide (TMAO). These changes coincided with shifts in gut microbiome composition, notably <em>Romboutsia</em> and <em>Desulfovibrio</em> abundance, respectively. In the brain, LPS exposure disrupted the marginal localisation of the endothelial tight junction ZO-1 and downregulated ZO-1 mRNA expression to an extent closely correlated with TMAO and IS levels; a process prevented by Memophenol™ intake. Hippocampal mRNA sequencing analysis revealed significant downregulation in regulatory pathways of neurodegeneration with Memophenol™ intake. These findings may indicate a novel protective role of the (poly)phenol-rich grape and blueberry extract on the endothelial tight junction component ZO-1, acting through modulation of gut microbial metabolism.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-08DOI: 10.1016/j.neuint.2024.105877
Neuropathic pain (NP) is a complex disorder caused by lesions or diseases affecting the somatosensory nervous system, severely impacting patients' quality of life. Recent studies suggest ferroptosis may be involved in NP induction, but its precise mechanisms remain unclear. We used GO and KEGG pathway enrichment analyses to functionally annotate ferroptosis-related differentially expressed genes (FRDs). Through STRING and the maximum cluster centrality (MCC) algorithm, we identified five hub FRDs (Jun, Timp1, Egfr, Cdkn1a, Cdkn2a). Single-cell analysis revealed significant expression of Jun and Timp1 in neurons. Our study confirmed the association between ferroptosis and endoplasmic reticulum stress (ERS) in NP and validated changes in hub FRD expression across various NP animal models. In vitro experiments demonstrated that Jun regulates neuronal ferroptosis and ERS, particularly by modulating Timp1 expression. Transcription factor prediction and JASPAR binding site analysis elucidated the regulatory network involving Jun. ROC curve analysis of external datasets highlighted the diagnostic potential of hub FRDs and ERS-related differentially expressed genes (ERSRDs) in NP. Using the Comparative Toxicogenomics Database (CTD), we identified estradiol (E2) as a potential therapeutic drug targeting hub FRDs and ERSRDs. Molecular docking predicted its binding sites with Jun and Timp1, and in vivo experiments confirmed that E2 alleviated NP and reversed the expression of Jun and Timp1. This study underscores the crucial role of Jun and Timp1 in the interplay between ferroptosis and ERS, offering new insights and promising avenues for NP treatment.
神经性疼痛（NP）是一种复杂的疾病，由影响躯体感觉神经系统的病变或疾病引起，严重影响患者的生活质量。最近的研究表明，铁变态反应可能参与了 NP 的诱导，但其确切机制仍不清楚。我们利用 GO 和 KEGG 通路富集分析对与铁突变相关的差异表达基因（FRDs）进行了功能注释。通过 STRING 和最大聚类中心性（MCC）算法，我们确定了五个中心 FRDs（Jun、Timp1、Egfr、Cdkn1a、Cdkn2a）。单细胞分析显示，Jun和Timp1在神经元中有显著表达。我们的研究证实了 NP 中铁质氧化与内质网应激（ERS）之间的关联，并验证了各种 NP 动物模型中枢 FRD 表达的变化。体外实验证明，Jun 特别是通过调节 Timp1 的表达来调控神经元的铁突变和 ERS。转录因子预测和 JASPAR 结合位点分析阐明了涉及 Jun 的调控网络。外部数据集的 ROC 曲线分析凸显了 NP 中枢 FRDs 和 ERS 相关差异表达基因（ERSRDs）的诊断潜力。通过比较毒物基因组学数据库（CTD），我们发现雌二醇（E2）是一种针对中枢FRD和ERSRD的潜在治疗药物。分子对接预测了其与 Jun 和 Timp1 的结合位点，体内实验证实 E2 可减轻 NP 并逆转 Jun 和 Timp1 的表达。这项研究强调了 Jun 和 Timp1 在铁突变和 ERS 之间相互作用中的关键作用，为治疗 NP 提供了新的见解和前景广阔的途径。
{"title":"Jun modulates endoplasmic reticulum stress-associated ferroptosis in dorsal root ganglia neurons during neuropathic pain by regulating Timp1","authors":"","doi":"10.1016/j.neuint.2024.105877","DOIUrl":"10.1016/j.neuint.2024.105877","url":null,"abstract":"<div><div>Neuropathic pain (NP) is a complex disorder caused by lesions or diseases affecting the somatosensory nervous system, severely impacting patients' quality of life. Recent studies suggest ferroptosis may be involved in NP induction, but its precise mechanisms remain unclear. We used GO and KEGG pathway enrichment analyses to functionally annotate ferroptosis-related differentially expressed genes (FRDs). Through STRING and the maximum cluster centrality (MCC) algorithm, we identified five hub FRDs (Jun, Timp1, Egfr, Cdkn1a, Cdkn2a). Single-cell analysis revealed significant expression of Jun and Timp1 in neurons. Our study confirmed the association between ferroptosis and endoplasmic reticulum stress (ERS) in NP and validated changes in hub FRD expression across various NP animal models. In vitro experiments demonstrated that Jun regulates neuronal ferroptosis and ERS, particularly by modulating Timp1 expression. Transcription factor prediction and JASPAR binding site analysis elucidated the regulatory network involving Jun. ROC curve analysis of external datasets highlighted the diagnostic potential of hub FRDs and ERS-related differentially expressed genes (ERSRDs) in NP. Using the Comparative Toxicogenomics Database (CTD), we identified estradiol (E2) as a potential therapeutic drug targeting hub FRDs and ERSRDs. Molecular docking predicted its binding sites with Jun and Timp1, and in vivo experiments confirmed that E2 alleviated NP and reversed the expression of Jun and Timp1. This study underscores the crucial role of Jun and Timp1 in the interplay between ferroptosis and ERS, offering new insights and promising avenues for NP treatment.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.neuint.2024.105866
Type C hepatic encephalopathy (Type C HE) is a major and complex neurological condition that occurs following chronic liver failure. The molecular basis of Type C HE remains elusive. Type C HE is characterized by mental confusion, cognitive and motor disturbances. The presence of Alzheimer type II astrocytes (AT2A) is the key histopathological finding observed in Type C HE. However, nothing is currently known regarding AT2A development and its involvement in cognitive, and motor deficits in Type C HE. We, therefore, examined in rats the mechanisms by which liver failure contributes to the progression of AT2A, and its role in the development of cognitive and motor deficits in thioacetamide (TAA) model of Type C HE. We and others earlier reported increased oxidative/nitrosative stress (ONS), JNK1/2, and cMyc activation in ammonia-treated astrocyte cultures, as well as in brains from chronic liver failure. We now found increased levels of astrocytic glia maturation factor (GMF, a factor strongly implicated in neuroinflammation), as well as various inflammatory factors (IL-1β, TNF-α, IL-6, MMP-3, COX2, CXCL1, and PGE2), and reduced levels of GFAP and increased levels of aggregated nuclear protein Lamin A/C in rat brain cortex post-chronic liver failure. We also found increased levels of GMF and inflammatory factors (MMP-3, COX2, CXCL1, and PGE2) in astrocytes post-ammonia treatment in vitro. Additionally, pharmacological inhibition of upstream signaling of GMF (ONS, JNK1/2, and cMyc) or GMF inhibitors W-7 and trifluoperazine significantly reduced the levels of inflammatory factors, the number of AT2A cells, as well as the cognitive and motor deficits in TAA-treated rats. Increased levels of GMF were also identified in human post-mortem brain sections. These findings strongly suggest that increased levels of astrocytic GMF due to elevated levels of ONS, JNK1/2, and cMyc and the subsequent inflammation contribute to the development of AT2A and the consequent cognitive, and motor deficits in chronic liver failure.
{"title":"Mechanism of Alzheimer type II astrocyte development in hepatic encephalopathy","authors":"","doi":"10.1016/j.neuint.2024.105866","DOIUrl":"10.1016/j.neuint.2024.105866","url":null,"abstract":"<div><div>Type C hepatic encephalopathy (Type C HE) is a major and complex neurological condition that occurs following chronic liver failure. The molecular basis of Type C HE remains elusive. Type C HE is characterized by mental confusion, cognitive and motor disturbances. The presence of Alzheimer type II astrocytes (AT2A) is the key histopathological finding observed in Type C HE. However, nothing is currently known regarding AT2A development and its involvement in cognitive, and motor deficits in Type C HE. We, therefore, examined in rats the mechanisms by which liver failure contributes to the progression of AT2A, and its role in the development of cognitive and motor deficits in thioacetamide (TAA) model of Type C HE. We and others earlier reported increased oxidative/nitrosative stress (ONS), JNK1/2, and cMyc activation in ammonia-treated astrocyte cultures, as well as in brains from chronic liver failure. We now found increased levels of astrocytic glia maturation factor (GMF, a factor strongly implicated in neuroinflammation), as well as various inflammatory factors (IL-1β, TNF-α, IL-6, MMP-3, COX2, CXCL1, and PGE2), and reduced levels of GFAP and increased levels of aggregated nuclear protein Lamin A/C in rat brain cortex post-chronic liver failure. We also found increased levels of GMF and inflammatory factors (MMP-3, COX2, CXCL1, and PGE2) in astrocytes post-ammonia treatment <em>in vitro</em>. Additionally, pharmacological inhibition of upstream signaling of GMF (ONS, JNK1/2, and cMyc) or GMF inhibitors W-7 and trifluoperazine significantly reduced the levels of inflammatory factors, the number of AT2A cells, as well as the cognitive and motor deficits in TAA-treated rats. Increased levels of GMF were also identified in human post-mortem brain sections. These findings strongly suggest that increased levels of astrocytic GMF due to elevated levels of ONS, JNK1/2, and cMyc and the subsequent inflammation contribute to the development of AT2A and the consequent cognitive, and motor deficits in chronic liver failure.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-03DOI: 10.1016/j.neuint.2024.105876
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that gradually deteriorates motor neurons, leading to demyelination, muscle weakness, and eventually respiratory failure. The disease involves several pathological processes, such as increased glutamate levels, mitochondrial dysfunction, and persistent neuroinflammation, often exacerbated by environmental toxins like mercury. This study explores the therapeutic potential of Olea europaea active phytoconstituents oleanolic acid (OLA) against ALS by targeting the overactivated PI3K/Akt/mTOR/STAT-3/GSK-3β signalling pathways. Methods involved in-silico studies, in vitro and in vivo experiments in which varying doses of methylmercury 5 mg/kg, p.o. and OLA (100 and 200 mg/kg, i.p.) were administered to rats for 42 days. Behavioural assessments, gross morphological, histopathological, and neurochemical parameters were measured in cerebrospinal fluid (CSF), blood plasma, and brain homogenates (cerebral cortex, hippocampus, striatum, midbrain, cerebellum) along with complete blood count (CBC) analysis. Results revealed OLA's significant neuroprotective properties. OLA effectively modulated targeted pathways, reducing pro-inflammatory cytokines, restoring normal levels of myelin basic protein (MBP) and neurofilament light chain (NEFL), and reducing histopathological changes. Gross pathological studies indicated less tissue damage, while CBC analysis showed improved hematology parameters. Additionally, the combination of OLA and edaravone (10 mg/kg, i.p.) demonstrated enhanced efficacy, improving motor functions and extending survival in ALS model rats. In conclusion, OLA exhibits significant therapeutic potential for ALS, acting as a potent modulator of key pathological signaling pathways. The findings suggest the feasibility of integrating OLA into existing treatment regimens, potentially improving clinical outcomes for ALS patients. However, further research must validate these findings in human clinical trials.
肌萎缩性脊髓侧索硬化症（ALS）是一种进行性神经退行性疾病，会使运动神经元逐渐退化，导致脱髓鞘、肌肉无力，最终导致呼吸衰竭。这种疾病涉及多个病理过程，如谷氨酸水平升高、线粒体功能障碍和持续性神经炎症，而汞等环境毒素往往会加重病情。本研究探讨了油橄榄活性植物成分齐墩果酸（OLA）通过靶向过度激活的 PI3K/Akt/mTOR/STAT-3/GSK-3β 信号通路对 ALS 的治疗潜力。实验方法包括室内研究、体外和体内实验，在这些实验中，给大鼠注射不同剂量的甲基汞（5 毫克/千克，口服）和 OLA（100 和 200 毫克/千克，静脉注射），共 42 天。对大鼠的脑脊液（CSF）、血浆、脑匀浆（大脑皮层、海马、纹状体、中脑、小脑）以及全血细胞计数（CBC）进行了行为评估、大体形态学、组织病理学和神经化学参数测定。结果显示，OLA 具有显著的神经保护特性。OLA 有效调节了目标通路，减少了促炎细胞因子，恢复了髓鞘碱性蛋白 (MBP) 和神经丝轻链 (NEFL) 的正常水平，并减少了组织病理学变化。大体病理研究显示组织损伤减少，而 CBC 分析显示血液学参数有所改善。此外，OLA 和依达拉奉（10 毫克/千克，静注）的联合用药还能增强疗效，改善 ALS 模型大鼠的运动功能并延长存活时间。总之，OLA 作为关键病理信号通路的强效调节剂，对 ALS 具有显著的治疗潜力。研究结果表明，将 OLA 纳入现有治疗方案是可行的，有可能改善 ALS 患者的临床疗效。不过，进一步的研究必须在人体临床试验中验证这些发现。
{"title":"Therapeutic potential of oleanolic acid in modulation of PI3K/Akt/mTOR/STAT-3/GSK-3β signaling pathways and neuroprotection against methylmercury-induced neurodegeneration","authors":"","doi":"10.1016/j.neuint.2024.105876","DOIUrl":"10.1016/j.neuint.2024.105876","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that gradually deteriorates motor neurons, leading to demyelination, muscle weakness, and eventually respiratory failure. The disease involves several pathological processes, such as increased glutamate levels, mitochondrial dysfunction, and persistent neuroinflammation, often exacerbated by environmental toxins like mercury. This study explores the therapeutic potential of Olea europaea active phytoconstituents oleanolic acid (OLA) against ALS by targeting the overactivated PI3K/Akt/mTOR/STAT-3/GSK-3β signalling pathways. Methods involved in-silico studies, in vitro and in vivo experiments in which varying doses of methylmercury 5 mg/kg, <em>p.o.</em> and OLA (100 and 200 mg/kg, <em>i.p.</em>) were administered to rats for 42 days. Behavioural assessments, gross morphological, histopathological, and neurochemical parameters were measured in cerebrospinal fluid (CSF), blood plasma, and brain homogenates (cerebral cortex, hippocampus, striatum, midbrain, cerebellum) along with complete blood count (CBC) analysis. Results revealed OLA's significant neuroprotective properties. OLA effectively modulated targeted pathways, reducing pro-inflammatory cytokines, restoring normal levels of myelin basic protein (MBP) and neurofilament light chain (NEFL), and reducing histopathological changes. Gross pathological studies indicated less tissue damage, while CBC analysis showed improved hematology parameters. Additionally, the combination of OLA and edaravone (10 mg/kg, <em>i.p.</em>) demonstrated enhanced efficacy, improving motor functions and extending survival in ALS model rats. In conclusion, OLA exhibits significant therapeutic potential for ALS, acting as a potent modulator of key pathological signaling pathways. The findings suggest the feasibility of integrating OLA into existing treatment regimens, potentially improving clinical outcomes for ALS patients. However, further research must validate these findings in human clinical trials.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-02DOI: 10.1016/j.neuint.2024.105874
Several clinical and experimental studies have demonstrated that traumatic brain injury (TBI) activates cascades of biochemical, molecular, structural, and pathological changes in the brain. These changes combine to contribute to the various outcomes observed after TBI. Given the breadth and complexity of changes, combination treatments may be an effective approach for targeting multiple detrimental pathways to yield meaningful improvements. In order to identify targets for therapy development, the temporally evolving pathophysiology of TBI needs to be elucidated in detail at both the cellular and molecular levels, as it has been shown that the mechanisms contributing to cognitive dysfunction change over time. Thus, a combination of individual mechanism-based therapies is likely to be effective when maintained based on the time courses of the cellular and molecular changes being targeted. In this review, we will discuss the temporal changes of some of the key clinical pathologies of human TBI, the underlying cellular and molecular mechanisms, and the results from preclinical and clinical studies aimed at mitigating their consequences. As most of the pathological events that occur after TBI are likely to have subsided in the chronic stage of the disease, combination treatments aimed at attenuating chronic conditions such as cognitive dysfunction may not require the initiation of individual treatments at a specific time. We propose that a combination of acute, subacute, and chronic interventions may be necessary to maximally improve health-related quality of life (HRQoL) for persons who have sustained a TBI.
{"title":"The evolving pathophysiology of TBI and the advantages of temporally-guided combination therapies","authors":"","doi":"10.1016/j.neuint.2024.105874","DOIUrl":"10.1016/j.neuint.2024.105874","url":null,"abstract":"<div><div>Several clinical and experimental studies have demonstrated that traumatic brain injury (TBI) activates cascades of biochemical, molecular, structural, and pathological changes in the brain. These changes combine to contribute to the various outcomes observed after TBI. Given the breadth and complexity of changes, combination treatments may be an effective approach for targeting multiple detrimental pathways to yield meaningful improvements. In order to identify targets for therapy development, the temporally evolving pathophysiology of TBI needs to be elucidated in detail at both the cellular and molecular levels, as it has been shown that the mechanisms contributing to cognitive dysfunction change over time. Thus, a combination of individual mechanism-based therapies is likely to be effective when maintained based on the time courses of the cellular and molecular changes being targeted. In this review, we will discuss the temporal changes of some of the key clinical pathologies of human TBI, the underlying cellular and molecular mechanisms, and the results from preclinical and clinical studies aimed at mitigating their consequences. As most of the pathological events that occur after TBI are likely to have subsided in the chronic stage of the disease, combination treatments aimed at attenuating chronic conditions such as cognitive dysfunction may not require the initiation of individual treatments at a specific time. We propose that a combination of acute, subacute, and chronic interventions may be necessary to maximally improve health-related quality of life (HRQoL) for persons who have sustained a TBI.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neuint.2024.105872
A growing body of evidence supports the link between peripheral inflammation and impairment of neurologic functions, including mood and cognitive abilities. The pathogenic event connecting peripheral inflammation and brain dysfunction is represented by neuroinflammation, a pathogenic phenomenon that provides an important contribution to neurodegeneration and cognitive decline also in Alzheimer's, Parkinson's, Huntington's diseases, as well as in Multiple Sclerosis. It is driven by resident brain immune cells, microglia and astrocytes, that acquire an activated phenotype in response to proinflammatory molecules moving from the periphery to the brain parenchyma. Although a huge progress has been made in clarifying cellular and molecular mechanisms bridging peripheral and central inflammation, a clear picture has not been achieved so far. Therefore, experimental models are of crucial relevance to clarify knowledge gaps in this regard. Many findings demonstrate that systemic inflammation induced by pathogen-associated molecular patterns, such as lipopolysaccharide (LPS), is able to trigger neuroinflammation. Therefore, LPS-administration is widely considered a useful tool to study this phenomenon. On this basis, the present review will focus on in vivo studies based on acute and subacute effects of systemic administration of LPS, with special attention on the state of art of microglia and astrocyte response to peripheral challenge.
{"title":"Crosstalk between peripheral inflammation and brain: Focus on the responses of microglia and astrocytes to peripheral challenge","authors":"","doi":"10.1016/j.neuint.2024.105872","DOIUrl":"10.1016/j.neuint.2024.105872","url":null,"abstract":"<div><div>A growing body of evidence supports the link between peripheral inflammation and impairment of neurologic functions, including mood and cognitive abilities. The pathogenic event connecting peripheral inflammation and brain dysfunction is represented by neuroinflammation, a pathogenic phenomenon that provides an important contribution to neurodegeneration and cognitive decline also in Alzheimer's, Parkinson's, Huntington's diseases, as well as in Multiple Sclerosis. It is driven by resident brain immune cells, microglia and astrocytes, that acquire an activated phenotype in response to proinflammatory molecules moving from the periphery to the brain parenchyma. Although a huge progress has been made in clarifying cellular and molecular mechanisms bridging peripheral and central inflammation, a clear picture has not been achieved so far. Therefore, experimental models are of crucial relevance to clarify knowledge gaps in this regard. Many findings demonstrate that systemic inflammation induced by pathogen-associated molecular patterns, such as lipopolysaccharide (LPS), is able to trigger neuroinflammation. Therefore, LPS-administration is widely considered a useful tool to study this phenomenon. On this basis, the present review will focus on <em>in vivo</em> studies based on acute and subacute effects of systemic administration of LPS, with special attention on the state of art of microglia and astrocyte response to peripheral challenge.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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