Pub Date : 2024-08-01Epub Date: 2024-06-04DOI: 10.1007/s11064-024-04172-2
Robert Lalonde, Catherine Strazielle
The neurochemical anatomy underlying Cushing's syndrome is examined for regional brain metabolism as well as neurotransmitter levels and receptor binding of biogenic amines and amino acids. Preliminary studies generally indicate that glucose uptake, blood flow, and activation on fMRI scans decreased in neocortical areas and increased in subcortical areas of patients with Cushing's syndrome or disease. Glucocorticoid-mediated increases in hippocampal metabolism occurred despite in vitro evidence of glucocorticoid-induced decreases in glucose uptake or consumption, indicating that in vivo increases are the result of indirect, compensatory, or preliminary responses. In animal studies, glucocorticoid administration decreased 5HT levels and 5HT1A receptor binding in several brain regions while adrenalectomy increased such binding. Region-specific effects were also obtained in regard to the dopaminergic system, with predominant actions of glucocorticoid-induced potentiation of reuptake blockers and releasing agents. More in-depth neuroanatomical analyses are warranted of these and amino acid-related neurotransmission.
{"title":"Neurochemical Anatomy of Cushing's Syndrome.","authors":"Robert Lalonde, Catherine Strazielle","doi":"10.1007/s11064-024-04172-2","DOIUrl":"10.1007/s11064-024-04172-2","url":null,"abstract":"<p><p>The neurochemical anatomy underlying Cushing's syndrome is examined for regional brain metabolism as well as neurotransmitter levels and receptor binding of biogenic amines and amino acids. Preliminary studies generally indicate that glucose uptake, blood flow, and activation on fMRI scans decreased in neocortical areas and increased in subcortical areas of patients with Cushing's syndrome or disease. Glucocorticoid-mediated increases in hippocampal metabolism occurred despite in vitro evidence of glucocorticoid-induced decreases in glucose uptake or consumption, indicating that in vivo increases are the result of indirect, compensatory, or preliminary responses. In animal studies, glucocorticoid administration decreased 5HT levels and 5HT<sub>1A</sub> receptor binding in several brain regions while adrenalectomy increased such binding. Region-specific effects were also obtained in regard to the dopaminergic system, with predominant actions of glucocorticoid-induced potentiation of reuptake blockers and releasing agents. More in-depth neuroanatomical analyses are warranted of these and amino acid-related neurotransmission.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236260","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 : 2024-08-01Epub Date: 2024-06-01DOI: 10.1007/s11064-024-04177-x
Md Faysal, Zerrouki Dehbia, Mehrukh Zehravi, Sherouk Hussein Sweilam, M Akiful Haque, Kusuma Praveen Kumar, Rita D Chakole, Satish P Shelke, Swapna Sirikonda, Mohamed H Nafady, Sharuk L Khan, Firzan Nainu, Irfan Ahmad, Talha Bin Emran
Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca2+ stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant.
{"title":"Flavonoids as Potential Therapeutics Against Neurodegenerative Disorders: Unlocking the Prospects.","authors":"Md Faysal, Zerrouki Dehbia, Mehrukh Zehravi, Sherouk Hussein Sweilam, M Akiful Haque, Kusuma Praveen Kumar, Rita D Chakole, Satish P Shelke, Swapna Sirikonda, Mohamed H Nafady, Sharuk L Khan, Firzan Nainu, Irfan Ahmad, Talha Bin Emran","doi":"10.1007/s11064-024-04177-x","DOIUrl":"10.1007/s11064-024-04177-x","url":null,"abstract":"<p><p>Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca<sup>2+</sup> stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141185955","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}
Phosphodiesterase 8 (PDE8), as a member of PDE superfamily, specifically promotes the hydrolysis and degradation of intracellular cyclic adenosine monophosphate (cAMP), which may be associated with pathogenesis of Alzheimer's disease (AD). However, little is currently known about potential role in the central nervous system (CNS). Here we investigated the distribution and expression of PDE8 in brain of mouse, which we believe can provide evidence for studying the role of PDE8 in CNS and the relationship between PDE8 and AD. Here, C57BL/6J mice were used to observe the distribution patterns of two subtypes of PDE8, PDE8A and PDE8B, in different sexes in vivo by western blot (WB). Meanwhile, C57BL/6J mice were also used to demonstrate the distribution pattern of PDE8 in selected brain regions and localization in neural cells by WB and multiplex immunofluorescence staining. Furthermore, the triple transgenic (3×Tg-AD) mice and wild type (WT) mice of different ages were used to investigate the changes of PDE8 expression in the hippocampus and cerebral cortex during the progression of AD. PDE8 was found to be widely expressed in multiple tissues and organs including heart, kidney, stomach, brain, and liver, spleen, intestines, and uterus, with differences in expression levels between the two subtypes of PDE8A and PDE8B, as well as two sexes. Meanwhile, PDE8 was widely distributed in the brain, especially in areas closely related to cognitive function such as cerebellum, striatum, amygdala, cerebral cortex, and hippocampus, without differences between sexes. Furthermore, PDE8A was found to be expressed in neuronal cells, microglia and astrocytes, while PDE8B is only expressed in neuronal cells and microglia. PDE8A expression in the hippocampus of both female and male 3×Tg-AD mice was gradually increased with ages and PDE8B expression was upregulated only in cerebral cortex of female 3×Tg-AD mice with ages. However, the expression of PDE8A and PDE8B was apparently increased in both cerebral cortex and hippocampus in both female and male 10-month-old 3×Tg-AD mice compared WT mice. These results suggest that PDE8 may be associated with the progression of AD and is a potential target for its prevention and treatment in the future.
{"title":"Phosphodiesterase 8 (PDE8): Distribution and Cellular Expression and Association with Alzheimer's Disease.","authors":"Nian-Zhuang Qiu, Hui-Mei Hou, Tian-Yang Guo, Yu-Li Lv, Yao Zhou, Fang-Fang Zhang, Feng Zhang, Xiao-Dan Wang, Wei Chen, Yong-Feng Gao, Mei-Hua Chen, Xue-Hui Zhang, Han-Ting Zhang, Hao Wang","doi":"10.1007/s11064-024-04156-2","DOIUrl":"10.1007/s11064-024-04156-2","url":null,"abstract":"<p><p>Phosphodiesterase 8 (PDE8), as a member of PDE superfamily, specifically promotes the hydrolysis and degradation of intracellular cyclic adenosine monophosphate (cAMP), which may be associated with pathogenesis of Alzheimer's disease (AD). However, little is currently known about potential role in the central nervous system (CNS). Here we investigated the distribution and expression of PDE8 in brain of mouse, which we believe can provide evidence for studying the role of PDE8 in CNS and the relationship between PDE8 and AD. Here, C57BL/6J mice were used to observe the distribution patterns of two subtypes of PDE8, PDE8A and PDE8B, in different sexes in vivo by western blot (WB). Meanwhile, C57BL/6J mice were also used to demonstrate the distribution pattern of PDE8 in selected brain regions and localization in neural cells by WB and multiplex immunofluorescence staining. Furthermore, the triple transgenic (3×Tg-AD) mice and wild type (WT) mice of different ages were used to investigate the changes of PDE8 expression in the hippocampus and cerebral cortex during the progression of AD. PDE8 was found to be widely expressed in multiple tissues and organs including heart, kidney, stomach, brain, and liver, spleen, intestines, and uterus, with differences in expression levels between the two subtypes of PDE8A and PDE8B, as well as two sexes. Meanwhile, PDE8 was widely distributed in the brain, especially in areas closely related to cognitive function such as cerebellum, striatum, amygdala, cerebral cortex, and hippocampus, without differences between sexes. Furthermore, PDE8A was found to be expressed in neuronal cells, microglia and astrocytes, while PDE8B is only expressed in neuronal cells and microglia. PDE8A expression in the hippocampus of both female and male 3×Tg-AD mice was gradually increased with ages and PDE8B expression was upregulated only in cerebral cortex of female 3×Tg-AD mice with ages. However, the expression of PDE8A and PDE8B was apparently increased in both cerebral cortex and hippocampus in both female and male 10-month-old 3×Tg-AD mice compared WT mice. These results suggest that PDE8 may be associated with the progression of AD and is a potential target for its prevention and treatment in the future.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086403","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 : 2024-07-27DOI: 10.1007/s11064-024-04214-9
Michael Aschner, Anatoly V Skalny, Abel Santamaria, Joao B T Rocha, Borhan Mansouri, Yousef Tizabi, Roberto Madeddu, Rongzu Lu, Eunsook Lee, Alexey A Tinkov
Aluminum (Al) is known to induce neurotoxic effects, potentially contributing to Alzheimer's disease (AD) pathogenesis. Recent studies suggest that epigenetic modification may contribute to Al neurotoxicity, although the mechanisms are still debatable. Therefore, the objective of the present study was to summarize existing data on the involvement of epigenetic mechanisms in Al-induced neurotoxicity, especially AD-type pathology. Existing data demonstrate that Al exposure induces disruption in DNA methylation, histone modifications, and non-coding RNA expression in brains. Alterations in DNA methylation following Al exposure were shown to be mediated by changes in expression and activity of DNA methyltransferases (DNMTs) and ten-eleven translocation proteins (TETs). Al exposure was shown to reduce histone acetylation by up-regulating expression of histone deacetylases (HDACs) and impair histone methylation, ultimately contributing to down-regulation of brain-derived neurotrophic factor (BDNF) expression and activation of nuclear factor κB (NF-κB) signaling. Neurotoxic effects of Al exposure were also associated with aberrant expression of non-coding RNAs, especially microRNAs (miR). Al-induced patterns of miR expression were involved in development of AD-type pathology by increasing amyloid β (Aβ) production through up-regulation of Aβ precursor protein (APP) and β secretase (BACE1) expression (down-regulation of miR-29a/b, miR-101, miR-124, and Let-7c expression), increasing in neuroinflammation through NF-κB signaling (up-regulation of miR-9, miR-125b, miR-128, and 146a), as well as modulating other signaling pathways. Furthermore, reduced global DNA methylation, altered histone modification, and aberrant miRNA expression were associated with cognitive decline in Al-exposed subjects. However, further studies are required to evaluate the contribution of epigenetic mechanisms to Al-induced neurotoxicity and/or AD development.
众所周知,铝(Al)具有神经毒性作用,可能导致阿尔茨海默病(AD)的发病。最近的研究表明,表观遗传修饰可能有助于铝的神经毒性,但其机制仍有待商榷。因此,本研究旨在总结表观遗传机制参与铝诱导的神经毒性,尤其是 AD 型病理学的现有数据。现有数据表明,铝暴露会诱导大脑中DNA甲基化、组蛋白修饰和非编码RNA表达的破坏。研究表明,暴露于铝后DNA甲基化的改变是由DNA甲基转移酶(DNMTs)和十-十一转位蛋白(TETs)的表达和活性变化介导的。研究表明,接触铝会通过上调组蛋白去乙酰化酶(HDACs)的表达来减少组蛋白乙酰化,并损害组蛋白甲基化,最终导致脑源性神经营养因子(BDNF)表达下调和核因子κB(NF-κB)信号的激活。铝暴露的神经毒性效应还与非编码 RNA,特别是微 RNA(miR)的异常表达有关。铝诱导的 miR 表达模式通过上调 Aβ 前体蛋白(APP)和 β 分泌酶(BACE1)的表达(下调 miR-29a/b、miR-101、miR-124 和 Let-7c 的表达),通过 NF-κB 信号转导增加神经炎症(上调 miR-9、miR-125b、miR-128 和 146a),以及调节其他信号通路。此外,全局 DNA 甲基化的减少、组蛋白修饰的改变和 miRNA 表达的异常与暴露于铝的受试者认知能力的下降有关。然而,要评估表观遗传机制对铝诱导的神经毒性和/或注意力缺失症发展的贡献,还需要进一步的研究。
{"title":"Epigenetic Mechanisms of Aluminum-Induced Neurotoxicity and Alzheimer's Disease: A Focus on Non-Coding RNAs.","authors":"Michael Aschner, Anatoly V Skalny, Abel Santamaria, Joao B T Rocha, Borhan Mansouri, Yousef Tizabi, Roberto Madeddu, Rongzu Lu, Eunsook Lee, Alexey A Tinkov","doi":"10.1007/s11064-024-04214-9","DOIUrl":"https://doi.org/10.1007/s11064-024-04214-9","url":null,"abstract":"<p><p>Aluminum (Al) is known to induce neurotoxic effects, potentially contributing to Alzheimer's disease (AD) pathogenesis. Recent studies suggest that epigenetic modification may contribute to Al neurotoxicity, although the mechanisms are still debatable. Therefore, the objective of the present study was to summarize existing data on the involvement of epigenetic mechanisms in Al-induced neurotoxicity, especially AD-type pathology. Existing data demonstrate that Al exposure induces disruption in DNA methylation, histone modifications, and non-coding RNA expression in brains. Alterations in DNA methylation following Al exposure were shown to be mediated by changes in expression and activity of DNA methyltransferases (DNMTs) and ten-eleven translocation proteins (TETs). Al exposure was shown to reduce histone acetylation by up-regulating expression of histone deacetylases (HDACs) and impair histone methylation, ultimately contributing to down-regulation of brain-derived neurotrophic factor (BDNF) expression and activation of nuclear factor κB (NF-κB) signaling. Neurotoxic effects of Al exposure were also associated with aberrant expression of non-coding RNAs, especially microRNAs (miR). Al-induced patterns of miR expression were involved in development of AD-type pathology by increasing amyloid β (Aβ) production through up-regulation of Aβ precursor protein (APP) and β secretase (BACE1) expression (down-regulation of miR-29a/b, miR-101, miR-124, and Let-7c expression), increasing in neuroinflammation through NF-κB signaling (up-regulation of miR-9, miR-125b, miR-128, and 146a), as well as modulating other signaling pathways. Furthermore, reduced global DNA methylation, altered histone modification, and aberrant miRNA expression were associated with cognitive decline in Al-exposed subjects. However, further studies are required to evaluate the contribution of epigenetic mechanisms to Al-induced neurotoxicity and/or AD development.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764722","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 : 2024-07-26DOI: 10.1007/s11064-024-04219-4
Iqraa Shaikh, Lokesh Kumar Bhatt
Epilepsy affects 65 million people globally and causes neurobehavioral, cognitive, and psychological defects. Although research on the disease is progressing and a wide range of treatments are available, approximately 30% of people have refractory epilepsy that cannot be managed with conventional medications. This underlines the importance of further understanding the condition and exploring cutting-edge targets for treatment. Adipokines are peptides secreted by adipocyte's white adipose tissue, involved in controlling food intake and metabolism. Their regulatory functions in the central nervous system (CNS) are multifaceted and identified in several physiology and pathologies. Adipokines play a role in oxidative stress and neuroinflammation which are associated with brain degeneration and connected neurological diseases. This review aims to highlight the potential impacts of leptin, adiponectin, apelin, vaspin, visfatin, and chimerin in the pathogenesis of epilepsy.
{"title":"Targeting Adipokines: A Promising Therapeutic Strategy for Epilepsy.","authors":"Iqraa Shaikh, Lokesh Kumar Bhatt","doi":"10.1007/s11064-024-04219-4","DOIUrl":"10.1007/s11064-024-04219-4","url":null,"abstract":"<p><p>Epilepsy affects 65 million people globally and causes neurobehavioral, cognitive, and psychological defects. Although research on the disease is progressing and a wide range of treatments are available, approximately 30% of people have refractory epilepsy that cannot be managed with conventional medications. This underlines the importance of further understanding the condition and exploring cutting-edge targets for treatment. Adipokines are peptides secreted by adipocyte's white adipose tissue, involved in controlling food intake and metabolism. Their regulatory functions in the central nervous system (CNS) are multifaceted and identified in several physiology and pathologies. Adipokines play a role in oxidative stress and neuroinflammation which are associated with brain degeneration and connected neurological diseases. This review aims to highlight the potential impacts of leptin, adiponectin, apelin, vaspin, visfatin, and chimerin in the pathogenesis of epilepsy.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764724","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 : 2024-07-01Epub Date: 2024-05-24DOI: 10.1007/s11064-024-04152-6
Anand Thirupathi, Luis Felipe Marqueze, Tiago F Outeiro, Zsolt Radak, Ricardo A Pinho
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Ferroptosis, an iron-dependent form of regulated cell death, may contribute to the progression of PD owing to an unbalanced brain redox status. Physical exercise is a complementary therapy that can modulate ferroptosis in PD by regulating the redox system through the activation of nuclear factor (erythroid-derived 2)-like 2 (NRF2) and brain-derived neurotrophic factor (BDNF) signaling. However, the precise effects of physical exercise on ferroptosis in PD remain unclear. In this review, we explored how physical exercise influences NRF2 and BDNF signaling and affects ferroptosis in PD. We further investigated relevant publications over the past two decades by searching the PubMed, Web of Science, and Google Scholar databases using keywords related to physical exercise, PD, ferroptosis, and neurotrophic factor antioxidant signaling. This review provides insights into current research gaps and demonstrates the necessity for future research to elucidate the specific mechanisms by which exercise regulates ferroptosis in PD, including the assessment of different exercise protocols and their long-term effects. Ultimately, exploring these aspects may lead to the development of improved exercise interventions for the better management of patients with PD.
帕金森病(PD)是一种进行性神经退行性疾病,其特征是黑质中多巴胺能神经元的丧失。由于大脑氧化还原状态失衡,铁中毒(一种依赖铁的调节性细胞死亡形式)可能会导致帕金森病的进展。体育锻炼是一种辅助疗法,可通过激活核因子(红细胞衍生 2)-类 2(NRF2)和脑源性神经营养因子(BDNF)信号来调节氧化还原系统,从而调节帕金森病的铁氧化。然而,体育锻炼对帕金森病铁氧化的确切影响仍不清楚。在这篇综述中,我们探讨了体育锻炼如何影响 NRF2 和 BDNF 信号传导,以及如何影响帕金森病的铁蛋白沉积。我们使用与体育锻炼、帕金森病、铁突变和神经营养因子抗氧化信号转导相关的关键词搜索了 PubMed、Web of Science 和 Google Scholar 数据库,进一步研究了过去二十年中的相关文献。本综述深入探讨了目前的研究空白,并表明未来研究有必要阐明运动调节帕金森病铁蛋白沉积的具体机制,包括评估不同的运动方案及其长期影响。最终,对这些方面的探索可能会开发出更好的运动干预措施,从而更好地管理帕金森病患者。
{"title":"Physical Exercise-Induced Activation of NRF2 and BDNF as a Promising Strategy for Ferroptosis Regulation in Parkinson's Disease.","authors":"Anand Thirupathi, Luis Felipe Marqueze, Tiago F Outeiro, Zsolt Radak, Ricardo A Pinho","doi":"10.1007/s11064-024-04152-6","DOIUrl":"10.1007/s11064-024-04152-6","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Ferroptosis, an iron-dependent form of regulated cell death, may contribute to the progression of PD owing to an unbalanced brain redox status. Physical exercise is a complementary therapy that can modulate ferroptosis in PD by regulating the redox system through the activation of nuclear factor (erythroid-derived 2)-like 2 (NRF2) and brain-derived neurotrophic factor (BDNF) signaling. However, the precise effects of physical exercise on ferroptosis in PD remain unclear. In this review, we explored how physical exercise influences NRF2 and BDNF signaling and affects ferroptosis in PD. We further investigated relevant publications over the past two decades by searching the PubMed, Web of Science, and Google Scholar databases using keywords related to physical exercise, PD, ferroptosis, and neurotrophic factor antioxidant signaling. This review provides insights into current research gaps and demonstrates the necessity for future research to elucidate the specific mechanisms by which exercise regulates ferroptosis in PD, including the assessment of different exercise protocols and their long-term effects. Ultimately, exploring these aspects may lead to the development of improved exercise interventions for the better management of patients with PD.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086405","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 : 2024-07-01Epub Date: 2024-05-17DOI: 10.1007/s11064-024-04147-3
Miriam Ulloa, Fernando Macías, Carmen Clapp, Gonzalo Martínez de la Escalera, Edith Arnold
Oxidative stress-induced death of neurons and astrocytes contributes to the pathogenesis of numerous neurodegenerative diseases. While significant progress has been made in identifying neuroprotective molecules against neuronal oxidative damage, little is known about their counterparts for astrocytes. Prolactin (PRL), a hormone known to stimulate astroglial proliferation, viability, and cytokine expression, exhibits antioxidant effects in neurons. However, its role in protecting astrocytes from oxidative stress remains unexplored. Here, we investigated the effect of PRL against hydrogen peroxide (H2O2)-induced oxidative insult in primary cortical astrocyte cultures. Incubation of astrocytes with PRL led to increased enzymatic activity of superoxide dismutase (SOD) and glutathione peroxidase (GPX), resulting in higher total antioxidant capacity. Concomitantly, PRL prevented H2O2-induced cell death, reactive oxygen species accumulation, and protein and lipid oxidation. The protective effect of PRL upon H2O2-induced cell death can be explained by the activation of both signal transducer and activator of transcription 3 (STAT3) and NFE2 like bZIP transcription factor 2 (NRF2) transduction cascades. We demonstrated that PRL induced nuclear translocation and transcriptional upregulation of Nrf2, concurrently with the transcriptional upregulation of the NRF2-dependent genes heme oxygenase 1, Sod1, Sod2, and Gpx1. Pharmacological blockade of STAT3 suppressed PRL-induced transcriptional upregulation of Nrf2, Sod1 and Gpx1 mRNA, and SOD and GPX activities. Furthermore, genetic ablation of the PRL receptor increased astroglial susceptibility to H2O2-induced cell death and superoxide accumulation, while diminishing their intrinsic antioxidant capacity. Overall, these findings unveil PRL as a potent antioxidant hormone that protects astrocytes from oxidative insult, which may contribute to brain neuroprotection.
氧化应激引起的神经元和星形胶质细胞死亡是多种神经退行性疾病的发病机制之一。尽管在确定神经元氧化损伤的神经保护分子方面取得了重大进展,但人们对星形胶质细胞的相应分子却知之甚少。催乳素(PRL)是一种已知能刺激星形胶质细胞增殖、活力和细胞因子表达的激素,在神经元中具有抗氧化作用。然而,它在保护星形胶质细胞免受氧化应激方面的作用仍有待探索。在这里,我们研究了 PRL 对原代皮质星形胶质细胞培养物中过氧化氢(H2O2)诱导的氧化损伤的影响。用 PRL 培养星形胶质细胞可提高超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GPX)的酶活性,从而提高总抗氧化能力。同时,PRL 还能防止 H2O2 诱导的细胞死亡、活性氧积累以及蛋白质和脂质氧化。PRL对H2O2诱导的细胞死亡的保护作用可通过激活信号转导子和转录激活子3(STAT3)以及类似于bZIP转录因子2(NRF2)的NFE2转导级联来解释。我们证实,PRL诱导Nrf2的核转位和转录上调,同时NRF2依赖基因血红素加氧酶1、Sod1、Sod2和Gpx1也转录上调。药物阻断 STAT3 可抑制 PRL 诱导的 Nrf2、Sod1 和 Gpx1 mRNA 转录上调以及 SOD 和 GPX 活性。此外,PRL 受体的遗传消减增加了星形胶质细胞对 H2O2 诱导的细胞死亡和超氧化物积累的敏感性,同时降低了其内在的抗氧化能力。总之,这些研究结果揭示了 PRL 是一种有效的抗氧化激素,它能保护星形胶质细胞免受氧化损伤,这可能有助于脑神经保护。
{"title":"Prolactin is an Endogenous Antioxidant Factor in Astrocytes That Limits Oxidative Stress-Induced Astrocytic Cell Death via the STAT3/NRF2 Signaling Pathway.","authors":"Miriam Ulloa, Fernando Macías, Carmen Clapp, Gonzalo Martínez de la Escalera, Edith Arnold","doi":"10.1007/s11064-024-04147-3","DOIUrl":"10.1007/s11064-024-04147-3","url":null,"abstract":"<p><p>Oxidative stress-induced death of neurons and astrocytes contributes to the pathogenesis of numerous neurodegenerative diseases. While significant progress has been made in identifying neuroprotective molecules against neuronal oxidative damage, little is known about their counterparts for astrocytes. Prolactin (PRL), a hormone known to stimulate astroglial proliferation, viability, and cytokine expression, exhibits antioxidant effects in neurons. However, its role in protecting astrocytes from oxidative stress remains unexplored. Here, we investigated the effect of PRL against hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>)-induced oxidative insult in primary cortical astrocyte cultures. Incubation of astrocytes with PRL led to increased enzymatic activity of superoxide dismutase (SOD) and glutathione peroxidase (GPX), resulting in higher total antioxidant capacity. Concomitantly, PRL prevented H<sub>2</sub>O<sub>2</sub>-induced cell death, reactive oxygen species accumulation, and protein and lipid oxidation. The protective effect of PRL upon H<sub>2</sub>O<sub>2</sub>-induced cell death can be explained by the activation of both signal transducer and activator of transcription 3 (STAT3) and NFE2 like bZIP transcription factor 2 (NRF2) transduction cascades. We demonstrated that PRL induced nuclear translocation and transcriptional upregulation of Nrf2, concurrently with the transcriptional upregulation of the NRF2-dependent genes heme oxygenase 1, Sod1, Sod2, and Gpx1. Pharmacological blockade of STAT3 suppressed PRL-induced transcriptional upregulation of Nrf2, Sod1 and Gpx1 mRNA, and SOD and GPX activities. Furthermore, genetic ablation of the PRL receptor increased astroglial susceptibility to H<sub>2</sub>O<sub>2</sub>-induced cell death and superoxide accumulation, while diminishing their intrinsic antioxidant capacity. Overall, these findings unveil PRL as a potent antioxidant hormone that protects astrocytes from oxidative insult, which may contribute to brain neuroprotection.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11144156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955674","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}
Methylglyoxal (MG) is considered a classical biomarker of diabetes mellitus and its comorbidities. However, a role for this compound in exacerbated immune responses, such as septicemia, is being increasingly observed and requires clarification, particularly in the context of neuroinflammatory responses. Herein, we used two different approaches (in vivo and acute hippocampal slice models) to investigate MG as a biomarker of neuroinflammation and the neuroimmunometabolic shift to glycolysis in lipopolysaccharide (LPS) inflammation models. Our data reinforce the hypothesis that LPS-induced neuroinflammation stimulates the cerebral innate immune response by increasing IL-1β, a classical pro-inflammatory cytokine, and the astrocyte reactive response, via elevating S100B secretion and GFAP levels. Acute neuroinflammation promotes an early neuroimmunometabolic shift to glycolysis by elevating glucose uptake, lactate release, PFK1, and PK activities. We observed high serum and cerebral MG levels, in association with a reduction in glyoxalase 1 detoxification activity, and a close correlation between serum and hippocampus MG levels with the systemic and neuroinflammatory responses to LPS. Findings strongly suggest a role for MG in immune responses.
{"title":"Is Methylglyoxal a Potential Biomarker for the Warburg Effect Induced by the Lipopolysaccharide Neuroinflammation Model?","authors":"Adriana Fernanda Kuckartz Vizuete, Carlos-Alberto Gonçalves","doi":"10.1007/s11064-024-04142-8","DOIUrl":"10.1007/s11064-024-04142-8","url":null,"abstract":"<p><p>Methylglyoxal (MG) is considered a classical biomarker of diabetes mellitus and its comorbidities. However, a role for this compound in exacerbated immune responses, such as septicemia, is being increasingly observed and requires clarification, particularly in the context of neuroinflammatory responses. Herein, we used two different approaches (in vivo and acute hippocampal slice models) to investigate MG as a biomarker of neuroinflammation and the neuroimmunometabolic shift to glycolysis in lipopolysaccharide (LPS) inflammation models. Our data reinforce the hypothesis that LPS-induced neuroinflammation stimulates the cerebral innate immune response by increasing IL-1β, a classical pro-inflammatory cytokine, and the astrocyte reactive response, via elevating S100B secretion and GFAP levels. Acute neuroinflammation promotes an early neuroimmunometabolic shift to glycolysis by elevating glucose uptake, lactate release, PFK1, and PK activities. We observed high serum and cerebral MG levels, in association with a reduction in glyoxalase 1 detoxification activity, and a close correlation between serum and hippocampus MG levels with the systemic and neuroinflammatory responses to LPS. Findings strongly suggest a role for MG in immune responses.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896843","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 : 2024-07-01Epub Date: 2024-03-30DOI: 10.1007/s11064-024-04131-x
Ming Wang, Binyuan Xu, Yangmei Xie, Ge Yao, Yinghui Chen
Convulsive status epilepticus (CSE) is a common critical neurological condition that can lead to irreversible hippocampal neuron damage and cognitive dysfunction. Multiple studies have demonstrated the critical roles that long non-coding RNA Mir155hg plays in a variety of diseases. However, less is known about the function and mechanism of Mir155hg in CSE. Here we investigate and elucidate the mechanism underlying the contribution of Mir155hg to CSE-induced hippocampal neuron injury. By applying high-throughput sequencing, we examined the expression of differentially expressed genes in normal and CSE rats. Subsequent RT-qPCR enabled us to measure the level of Mir155hg in rat hippocampal tissue. Targeted knockdown of Mir155hg was achieved by the AAV9 virus. Additionally, we utilized HE and Tunel staining to evaluate neuronal injury. Immunofluorescence (IF), Golgi staining, and brain path clamping were also used to detect the synaptic plasticity of hippocampal neurons. Finally, through IF staining and Sholl analysis, we assessed the degree of microglial phagocytic function. It was found that the expression of Mir155hg was elevated in CSE rats. HE and Tunel staining results showed that Mir155hg knockdown suppressed the hippocampal neuron loss and apoptosis followed CSE. IF, Golgi staining and brain path clamp data found that Mir155hg knockdown enhanced neuronal synaptic plasticity. The results from IF staining and Sholl analysis showed that Mir155hg knockdown enhanced microglial phagocytosis. Our findings suggest that Mir155hg promotes CSE-induced hippocampal neuron injury by inhibiting microglial phagocytosis.
{"title":"Mir155hg Accelerates Hippocampal Neuron Injury in Convulsive Status Epilepticus by Inhibiting Microglial Phagocytosis.","authors":"Ming Wang, Binyuan Xu, Yangmei Xie, Ge Yao, Yinghui Chen","doi":"10.1007/s11064-024-04131-x","DOIUrl":"10.1007/s11064-024-04131-x","url":null,"abstract":"<p><p>Convulsive status epilepticus (CSE) is a common critical neurological condition that can lead to irreversible hippocampal neuron damage and cognitive dysfunction. Multiple studies have demonstrated the critical roles that long non-coding RNA Mir155hg plays in a variety of diseases. However, less is known about the function and mechanism of Mir155hg in CSE. Here we investigate and elucidate the mechanism underlying the contribution of Mir155hg to CSE-induced hippocampal neuron injury. By applying high-throughput sequencing, we examined the expression of differentially expressed genes in normal and CSE rats. Subsequent RT-qPCR enabled us to measure the level of Mir155hg in rat hippocampal tissue. Targeted knockdown of Mir155hg was achieved by the AAV9 virus. Additionally, we utilized HE and Tunel staining to evaluate neuronal injury. Immunofluorescence (IF), Golgi staining, and brain path clamping were also used to detect the synaptic plasticity of hippocampal neurons. Finally, through IF staining and Sholl analysis, we assessed the degree of microglial phagocytic function. It was found that the expression of Mir155hg was elevated in CSE rats. HE and Tunel staining results showed that Mir155hg knockdown suppressed the hippocampal neuron loss and apoptosis followed CSE. IF, Golgi staining and brain path clamp data found that Mir155hg knockdown enhanced neuronal synaptic plasticity. The results from IF staining and Sholl analysis showed that Mir155hg knockdown enhanced microglial phagocytosis. Our findings suggest that Mir155hg promotes CSE-induced hippocampal neuron injury by inhibiting microglial phagocytosis.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140329467","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 : 2024-07-01Epub Date: 2024-03-21DOI: 10.1007/s11064-024-04128-6
Ling Liu, Wen Gao, Shun Yang, Fei Yang, Shangyingying Li, Yaqiong Tian, Li Yang, Qianyu Deng, Zhengwei Gan, Shengfen Tu
Propofol is a clinically common intravenous general anesthetic and is widely used for anesthesia induction, maintenance and intensive care unit (ICU) sedation in children. Hypoxemia is a common perioperative complication. In clinical work, we found that children with hypoxemia who received propofol anesthesia experienced significant postoperative cognitive changes. To explore the causes of this phenomenon, we conducted the study. In this study, our in vivo experiments found that immature rats exposed to hypoxia combined with propofol (HCWP) could develop cognitive impairment. We performed the RNA-seq analysis of its hippocampal tissues and found that autophagy and ferroptosis may play a role in our model. Next, we verified the participation of the two modes of death by detecting the expression of autophagy-related indexes Sequestosome 1 (SQSTM1) and Beclin1, and ferroptosis-related indicators Fe2+, reactive oxygen species (ROS) and glutathione peroxidase 4 (GPX4). Meanwhile, we found that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, could improve cognitive impairment in immature rats caused by HCWP. In addition, we found that nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy, which acted as a key junction between autophagy and ferroptosis, was also involved. Finally, our in vitro experiments concluded that autophagy activation was an upstream factor in HCWP-induced hippocampus ferroptosis through the intervention of autophagy inhibitor 3-methyladenine (3-MA). Our study was expected to provide an attractive therapeutic target for cognitive impairment that occurred after HCWP exposures.
{"title":"Ferritinophagy-Mediated Hippocampus Ferroptosis is Involved in Cognitive Impairment in Immature Rats Induced by Hypoxia Combined with Propofol.","authors":"Ling Liu, Wen Gao, Shun Yang, Fei Yang, Shangyingying Li, Yaqiong Tian, Li Yang, Qianyu Deng, Zhengwei Gan, Shengfen Tu","doi":"10.1007/s11064-024-04128-6","DOIUrl":"10.1007/s11064-024-04128-6","url":null,"abstract":"<p><p>Propofol is a clinically common intravenous general anesthetic and is widely used for anesthesia induction, maintenance and intensive care unit (ICU) sedation in children. Hypoxemia is a common perioperative complication. In clinical work, we found that children with hypoxemia who received propofol anesthesia experienced significant postoperative cognitive changes. To explore the causes of this phenomenon, we conducted the study. In this study, our in vivo experiments found that immature rats exposed to hypoxia combined with propofol (HCWP) could develop cognitive impairment. We performed the RNA-seq analysis of its hippocampal tissues and found that autophagy and ferroptosis may play a role in our model. Next, we verified the participation of the two modes of death by detecting the expression of autophagy-related indexes Sequestosome 1 (SQSTM1) and Beclin1, and ferroptosis-related indicators Fe<sup>2+</sup>, reactive oxygen species (ROS) and glutathione peroxidase 4 (GPX4). Meanwhile, we found that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, could improve cognitive impairment in immature rats caused by HCWP. In addition, we found that nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy, which acted as a key junction between autophagy and ferroptosis, was also involved. Finally, our in vitro experiments concluded that autophagy activation was an upstream factor in HCWP-induced hippocampus ferroptosis through the intervention of autophagy inhibitor 3-methyladenine (3-MA). Our study was expected to provide an attractive therapeutic target for cognitive impairment that occurred after HCWP exposures.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140183445","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}