scholarly journals Epigenetic Regulations of Microglia/Macrophage Polarization in Ischemic Stroke

2021 ◽  
Vol 14 ◽  
Author(s):  
Meiqian Qiu ◽  
En Xu ◽  
Lixuan Zhan
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Neuronal Damage ◽  
Macrophage Polarization ◽  
Pathological Process ◽  
Non Coding Rna ◽  
Inflammatory Phenotype ◽  
The Central Nervous System ◽  
Epigenetic Regulations ◽  
Underlying Mechanisms

Ischemic stroke is one of the leading causes of death and disability worldwide. Microglia/macrophages (MMs)-mediated neuroinflammation contributes significantly to the pathological process of ischemic brain injury. Microglia, serving as resident innate immune cells in the central nervous system, undergo pro-inflammatory phenotype or anti-inflammatory phenotype in response to the microenvironmental changes after cerebral ischemia. Emerging evidence suggests that epigenetics modifications, reversible modifications of the phenotype without changing the DNA sequence, could play a pivotal role in regulation of MM polarization. However, the knowledge of the mechanism of epigenetic regulations of MM polarization after cerebral ischemia is still limited. In this review, we present the recent advances in the mechanisms of epigenetics involved in regulating MM polarization, including histone modification, non-coding RNA, and DNA methylation. In addition, we discuss the potential of epigenetic-mediated MM polarization as diagnostic and therapeutic targets for ischemic stroke. It is valuable to identify the underlying mechanisms between epigenetics and MM polarization, which may provide a promising treatment strategy for neuronal damage after cerebral ischemia.

scholarly journals Proteomic Assessment of iTRAQ-Based NaoMaiTong in the Treatment of Ischemic Stroke in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Kening Li ◽  
Minghua Xian ◽  
Chi Chen ◽  
Shengwang Liang ◽  
Lei Chen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Cerebral Infarction ◽  
Western Blot ◽  
Stress Responses ◽  
Neuronal Damage ◽  
Interaction Analysis ◽  
Protective Effects ◽  
Cellular Mechanisms ◽  
Altered Expression

Background. NaoMaiTong (NMT) is widely used in the treatment of cerebral ischemia but the molecular details of its beneficial effects remain poorly characterized. Materials and Methods. In this study, we used iTRAQ using 2D LC-MS/MS technology to investigate the cellular mechanisms governing the protective effects of NMT. The transient middle cerebral artery occlusion (MCAO) rat model was established and evaluated. The degree of cerebral ischemia was assessed through scoring for nerve injury symptoms and through the assessment of the areas of cerebral infarction. Brain tissues were subjected to analysis by iTRAQ. High-pH HPLC and RSLC-MS/MS analysis were performed to detect differentially expressed proteins (DEPs) between the treatment groups (Sham, MCAO, and NMT). Bioinformatics were employed for data analysis and DEPs were validated by western blot. Results. The results showed that NMT offers protection to the neurological damage caused by MCAO and was found to reduce the areas of cerebral infarction. We detected 3216 DEPs via mass spectrometry. Of these proteins, 21 displayed altered expression following NMT intervention. These included DEPs involved in translation, cell cycle regulation, cellular nitrogen metabolism, and stress responses. Pathway analysis revealed seven key DEPs that were enriched in ribosomal synthesis pathways, tight junction formation, and regulation of the actin cytoskeleton. According to protein-protein interaction analysis, RPL17, Tuba, and Rac1 were affected by NMT treatment, which was validated by western blot analysis. Discussion. We therefore identify new pharmacodynamic mechanisms of NMT for the prevention and treatment of ischemic stroke. These DEPs reveal new targets to prevent ischemic stroke induced neuronal damage.

scholarly journals Persistent DNA damage promotes microglial dysfunction in Ataxia-telangiectasia

2021 ◽  
Author(s):  
Julie Bourseguin ◽  
Wen Cheng ◽  
Emily Talbot ◽  
Liana Hardy ◽  
Svetlana V. Khoronenkova
Keyword(s):  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Genome Instability ◽  
Neuronal Damage ◽  
Common Mechanism ◽  
Atm Kinase ◽  
Human Microglia ◽  
Neuronal Processes ◽  
The Central Nervous System ◽  
Underlying Mechanisms

The autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterised by the progressive loss of cerebellar neurons. We find that DNA damage associated with ATM loss results in dysfunctional behaviour of human microglia, immune cells of the central nervous system. Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-κB transcriptional pathway and leads to excessive phagocytic clearance of neurites. Pathological phagocytosis of neuronal processes by microglia has also been observed in multiple sclerosis, Alzheimer′s and progranulin deficiency, suggesting a common mechanism that promotes neuronal damage. Activation of the RELB/p52 pathway in ATM-deficient microglia is driven by persistent DNA damage and is dependent on the NIK kinase. These results provide insights into the underlying mechanisms of aberrant microglial behaviour in Ataxia telangiectasia, potentially contributing to neurodegeneration.

scholarly journals The Role of Ubiquitin-Proteasome Pathway and Autophagy-Lysosome Pathway in Cerebral Ischemia

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Chunli Chen ◽  
Haiyun Qin ◽  
Jieqiong Tan ◽  
Zhiping Hu ◽  
Liuwang Zeng
Keyword(s):  
Cerebral Ischemia ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Current Knowledge ◽  
Pathological Process ◽  
Neuronal Necrosis ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Novel Therapeutic Strategies

The ubiquitin-proteasome pathway and autophagy-lysosome pathway are two major routes for clearance of aberrant cellular components to maintain protein homeostasis and normal cellular functions. Accumulating evidence shows that these two pathways are impaired during cerebral ischemia, which contributes to ischemic-induced neuronal necrosis and apoptosis. This review aims to critically discuss current knowledge and controversies on these two pathways in response to cerebral ischemic stress. We also discuss molecular mechanisms underlying the impairments of these protein degradation pathways and how such impairments lead to neuronal damage after cerebral ischemia. Further, we review the recent advance on the understanding of the involvement of these two pathways in the pathological process during many therapeutic approaches against cerebral ischemia. Despite recent advances, the exact role and molecular mechanisms of these two pathways following cerebral ischemia are complex and not completely understood, of which better understanding will provide avenues to develop novel therapeutic strategies for ischemic stroke.

scholarly journals A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer’s disease

2019 ◽  
Author(s):  
Dhanya Krishnan ◽  
Ramsekhar N Menon ◽  
Mathuranath PS ◽  
Srinivas Gopala
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Cell ◽  
Macrophage Polarization ◽  
Amyloid Β ◽  
The Novel ◽  
Inflammatory Phenotype ◽  
Underlying Mechanisms

AbstractINTRODUCTIONDefective immune cell-mediated clearance of amyloid-beta (Aβ) and Aβ-associated inflammatory activation of immune cells are key contributors of Aβ accumulation and neurodegeneration in Alzheimer’s disease (AD), however, the underlying mechanisms remain elusive.METHODSDifferentiated THP-1 cells treated with Aβ and AD patient-derived macrophages were used as in-vitro model. The role of SHARPIN was analysed in differentiated THP-1 cells using siRNA-mediated knockdown followed by immunoblotting, ELISA, real-time PCR, immunoprecipitation and flow cytometry. Differentiated SHSY5Y cells were used to study inflammation-mediated apoptosis.RESULTSSHARPIN was found to regulate Aβ-phagocytosis and NLRP3 expression in THP-1 derived macrophages. Further, it was found to promote macrophage polarization to an M1 (pro-inflammatory) phenotype resulting in enhanced inflammation and associated neuronal death, demonstrated using in-vitro culture systems. SHARPIN expression by blood-derived macrophages was further found to be higher in the early stages of AD, which correlates with Aβ40/42 concentration in the plasma and age of the study subjects.DISCUSSIONThe novel protein, SHARPIN has been shown to play critical roles in regulation of Aβ-phagocytosis and inflammation in AD and the mechanism by which SHARPIN is activated by Aβ in macrophages has been elucidated.

scholarly journals On the Question of the Reflexotherapy Action Mechanisms in the Ischemic Stroke Acute Period (Literature Review)

2021 ◽  
Vol 20 (6) ◽  
pp. 67-75
Author(s):  
Elena E. Molchanova ◽  
Victoria V. Polunina ◽  
Boris A. Polyaev ◽  
Valery P. Plotnikov ◽  
Andrey N. Lobov ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Economic Losses ◽  
Stroke Patients ◽  
Cerebrovascular Reserve ◽  
Acute Period ◽  
Mediators Of Inflammation ◽  
Acute Cerebral Ischemia ◽  
Degree Of Disability ◽  
Underlying Mechanisms

A high degree of disability in stroke patients, along with severe social and economic losses, determine the enduring urgency of the problem of early rehabilitation for post-stroke patients. Despite the proven effectiveness of the various reflexotherapy techniques in rehabilitation of patients with ischemic stroke, the underlying mechanisms remain unclear. The aim of the review was to analyze the mechanisms of the acupuncture intervention effect on the main links of the ischemic stroke pathogenesis, on neurological deficit and the volume of cerebral infarction (based on publications in international databases). The use of acupuncture in the acute period of ischemic stroke can improve the ability to cerebrovascular reserve, reduce the severity of arterial stiffness and endothelial dysfunction, induce neuroprotection, inhibit cell apoptosis and stimulate neuroplasticity, alleviate the inflammatory response in acute cerebral ischemia, regulate mediators of inflammation and oxidative stress etc., thus improving cerebral blood flow. The analysis of literature data has shown that acupuncture induces multilevel regulation through complex mechanisms, and one factor may not be enough to explain the positive effect against cerebral ischemia.

scholarly journals Astrogliopathy in Tauopathies

Neuroglia ◽  
2018 ◽  
Vol 1 (1) ◽  
pp. 126-150 ◽  
Author(s):  
Isidro Ferrer
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glial Cells ◽  
Neuronal Damage ◽  
Pathological Process ◽  
Loss Of Function ◽  
System Integrity ◽  
The Central Nervous System ◽  
Astrocytic Plaques ◽  
Complex Scenario

Astrocytes are involved in many diseases of the central nervous system, not only as reactive cells to neuronal damage but also as primary actors in the pathological process. Astrogliopathy is a term used to designate the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Astrocytopathy is utilized to name non-reactive astrogliosis covering hypertrophy, atrophy and astroglial degeneration with loss of function in astrocytes and pathological remodeling, as well as senescent changes. Astrogliopathy and astrocytopathy are hallmarks of tauopathies—neurodegenerative diseases with abnormal hyper-phosphorylated tau aggregates in neurons and glial cells. The involvement of astrocytes covers different disease-specific types such as tufted astrocytes, astrocytic plaques, thorn-shaped astrocytes, granular/fuzzy astrocytes, ramified astrocytes and astrocytes with globular inclusions, as well as others which are unnamed but not uncommon in familial frontotemporal degeneration linked to mutations in the tau gene. Knowledge of molecular differences among tau-containing astrocytes is only beginning, and their distinct functional implications remain rather poorly understood. However, tau-containing astrocytes in certain conditions have deleterious effects on neuronal function and nervous system integrity. Moreover, recent studies have shown that tau-containing astrocytes obtained from human brain tauopathies have a capacity for abnormal tau seeding and spreading in wild type mice. Inclusive conceptions include a complex scenario involving neurons, glial cells and local environmental factors that potentiate each other and promote disease progression in tauopathies.

scholarly journals Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti‐inflammatory phenotype through STAT3 pathway

2019 ◽  
Vol 25 (12) ◽  
pp. 1353-1362 ◽  
Author(s):  
Zong‐Jian Liu ◽  
Yuan‐Yuan Ran ◽  
Shu‐Yan Qie ◽  
Wei‐Jun Gong ◽  
Fu‐Hai Gao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Macrophage Polarization ◽  
Stat3 Pathway ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory

scholarly journals Recent advances in understanding neuropathic pain: glia, sex differences, and epigenetics

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2743 ◽  
Author(s):  
Halina Machelska ◽  
Melih Ö. Celik
Keyword(s):  
Nervous System ◽  
Neuropathic Pain ◽  
Neuronal Damage ◽  
G Protein Coupled Receptors ◽  
The Central Nervous System ◽  
Non Coding Rnas ◽  
Underlying Mechanisms ◽  
G Protein Coupled ◽  
Epigenetic Processes

Neuropathic pain results from diseases or trauma affecting the nervous system. This pain can be devastating and is poorly controlled. The pathophysiology is complex, and it is essential to understand the underlying mechanisms in order to identify the relevant targets for therapeutic intervention. In this article, we focus on the recent research investigating neuro-immune communication and epigenetic processes, which gain particular attention in the context of neuropathic pain. Specifically, we analyze the role of glial cells, including microglia, astrocytes, and oligodendrocytes, in the modulation of the central nervous system inflammation triggered by neuropathy. Considering epigenetics, we address DNA methylation, histone modifications, and the non-coding RNAs in the regulation of ion channels, G-protein-coupled receptors, and transmitters following neuronal damage. The goal was not only to highlight the emerging concepts but also to discuss controversies, methodological complications, and intriguing opinions.

Minocycline inhibits mTOR signaling activation and alleviates behavioral deficits in the Wistar rats with acute ischemia stroke

2020 ◽  
Vol 19 ◽  
Author(s):  
Shengyuan Wang ◽  
Chuanling Wang ◽  
Lihua Wang ◽  
Zhiyou Cai
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Acute Ischemia ◽  
Intragastric Administration ◽  
Underlying Mechanisms ◽  
Signaling Activation ◽  
The Brain ◽  
Minocycline Therapy

Background: Mammalian target of rapamycin (mTOR) has been evidenced as a multimodal therapy in the path-ophysiological process of acute ischemic stroke (AIS). However, the pathway that minocycline targets mTOR signaling is not fully defined in the AIS pathogenesis. This study is to aim at the effects of minocycline on the mTOR signaling in the AIS process and further discover the underlying mechanisms of minocycline involved in the following change of mTOR signaling-autophagy. Methods: Cerebral ischemia/reperfusion (CIR) rat animal models were established with the transient suture occlusion into middle cerebral artery. Minocycline (50mg/kg) was given by intragastric administration. The Morris water maze was used to test the cognitive function of animals. Immunohistochemistry and immunofluorescence were introduced for testing the lev-els of synaptophysin and PSD-95. Western blot was conducted for investigating the levels of mTOR, p-mTOR (Ser2448), p70S6, p-p70S6 (Thr389), eEF2k, p-eEF2k (Ser366), p-eIF4B (Ser406), LC3, p62, synaptophysin and PSD-95. Results: Minocycline prevents cognitive decline of the MCAO stroke rats. Minocycline limits the expression of p-mTOR (Ser2448) and the downstream targets of mTOR [p70S6, p-p70S6 (Thr389), eEF2k, p-eEF2k (Ser366) and p-eIF4B (Ser406)] (P<0.01), while minocycline has no influence on mTOR. LC3-II abundance and the LC3-II/I ratio were upregu-lated in the hippocampus of the MCAO stroke rats by the minocycline therapy (P<0.01). p62 was downregulated in the hippocampus from the MCAO stroke rats administrated with minocycline therapy(P<0.01). The levels of SYP and PSD-95 were up-regulated in the brain of the MCAO stroke rats administrated with minocycline therapy. Conclusion: Minocycline prevents cognitive deficits via inhibiting mTOR signaling and enhancing autophagy process, and promoting the expression of pre-and postsynaptic proteins (synaptophysin and PSD-95) in the brain of the MCAO stroke rats. The potential neuroprotective role of minocycline in the process of cerebral ischemia may be related to mitigating is-chemia-induced synapse injury via inhibiting activation of mTOR signaling.

scholarly journals SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms

2020 ◽  
Vol 21 (15) ◽  
pp. 5475 ◽  
Author(s):  
Manuela Pennisi ◽  
Giuseppe Lanza ◽  
Luca Falzone ◽  
Francesco Fisicaro ◽  
Raffaele Ferri ◽  
...  
Keyword(s):  
Nervous System ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Neurological Complications ◽  
Neurological Manifestations ◽  
Wide Range ◽  
Inflammatory State ◽  
Acute Polyneuropathy ◽  
The Central Nervous System ◽  
The Impact

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called “cytokine storm”), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.

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