Fasudil-Triggered Phagocytosis of Myelin Debris Promoted Meylin Regeneration via the Activation of TREM2/DAP12 Signaling Pathway in Cuprizone-Induced Mice

2021 ◽  
Author(s):  
Zhi-Bin Ding ◽  
Qing-Xian Han ◽  
Li-Juan Song ◽  
Qing Wang ◽  
Guang-Yuan Han ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Animal Experiments ◽  
Demyelinating Diseases ◽  
Phagocytic Capacity ◽  
Microglial Phagocytosis ◽  
M2 Polarization ◽  
M2 Microglia ◽  
Myelin Debris ◽  
The Central Nervous System

Abstract The inflammation and demyelination of the central nervous system (CNS) are mainly involved in multiple sclerosis (MS), in which the disorder of myelin regeneration leads to continual neurologic impairment. Fasudil, one of the ROCK inhibitors, has been shown protective functions in some models of demyelinating diseases. In this study, Fasudil treatment ameliorated the behavioral performance and myelin loss in CPZ-fed mice. Here, we demonstrated a new role of Fasudil, which triggered microglia to uptake myelin debris in both cell and animal experiments. This increased phagocytosis was associated with the polarization of M2 microglia. Furthermore, we found that Fasudil enhanced the expression of triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12), which regulated microglial phagocytosis and M2 polarization. The silence of TREM2 effectively blocked Fasudil-triggered phagocytic capacity, suggesting that Fasudil-triggered phagocytosis depends on TREM2 signaling pathway. Based on these evidences that TREM2 regulates microglial M2 polarization and phagocytosis, future studies targeted Fasudil as a therapy for demyelinating and neurodegenerative diseases are warranted.

scholarly journals LINC00467 Promotes Tumor Progression via Regulation of the NF-kb Signal Axis in Bladder Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiawei Xiao ◽  
Lian Gong ◽  
Mengqing Xiao ◽  
Dong He ◽  
Liang Xiang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Animal Experiments ◽  
Bioinformatic Analysis ◽  
New Strategy ◽  
Patient Prognosis

PurposeLong non-coding RNAs (lncRNAs) play an important role in the occurrence and development of bladder cancer, but the underlying molecular mechanisms remain largely unknown. In this study, we found that LINC00467 was significantly highly expressed in bladder cancer through bioinformatic analysis. The present study aimed to explore the role of LINC00467 in bladder cancer and its possible underlying molecular mechanisms.MethodsThe expression of LINC00467 was obtained from GEO (GSE31189), the TCGA database, and qRT-PCR. The role of LINC00467 in bladder cancer was assessed both in vitro and in vivo. RIP, RNA pulldown, and CO-IP were used to demonstrate the potential mechanism by which LINC00467 regulates the progression of bladder cancer.ResultsThrough the analysis of GEO (GSE133624) and the TCGA database, it was found that LINC00467 was highly expressed in bladder cancer tissues and that the expression of LINC00467 was significantly negatively correlated with patient prognosis. Cell and animal experiments suggest that LINC00467 promotes the proliferation and invasion of bladder cancer cells. On the one hand, LINC00467 can directly bind to NF-kb-p65 mRNA to stabilize its expression. On the other hand, LINC00467 can directly bind to NF-kb-p65 to promote its translocation into the nucleus to activate the NF-κB signaling pathway, which promotes the progression of bladder cancer.ConclusionsLINC00467 is highly expressed in bladder cancer and can promote the progression of bladder cancer by regulating the NF-κB signaling pathway. Therefore, targeting LINC00467 is very likely to provide a new strategy for the treatment of bladder cancer and for improving patient prognosis.

scholarly journals THE ROLE OF MAGNESIUM DEFICIENCY AND ITS SUPPLEMATION IN DISEASES OF CENTRAL NERVOUS SYSTEM. REVIEW

2018 ◽  
Vol 13 (3-4) ◽  
pp. 70-75
Author(s):  
M.V. Khaitovych
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Magnesium Deficiency ◽  
Close Association ◽  
Animal Experiments ◽  
Depression And Anxiety ◽  
Literary Sources ◽  
The Central Nervous System ◽  
System Review

Relevance. Anti-depressant effects of NMDA receptor antagonists have been proven, a close association between low levels of magnesium in the blood and depression. Therefore, in recent years, antidepressant properties of magnesium are actively studied in animal experiments. Objective: To review modern literary sources about the role of magnesium deficiency in the pathogenesis of diseases of the central nervous system. Materials and methods. Searching for a depth of 12 years at Scopus, Google Scholar. Results. The results of experimental and clinical researches pointed out on association between low level of magnesium in hair, liquor, brain with higher risk of development dementia, depression and anxiety. An additional supplementation with magnesium in patients associates with decreasing risk of ischemic stroke and dementia, in pregnancy – provides neuroprotection of fetus, in case of depression increases effectiveness of antidepressants, in brain injury associates with faster recovery of cognitive functions, in migraines - with decreasing in the frequency of attacks and improvement of the quality patients’ lives, in case of neuroleptic therapy - with the possibility of delayed appearance or absence of manifestations of drug parkinsonism. These changes are explained by antagonistic effects of magnesium on glutamate receptors, decreasing oxidative stress intensity as well as neural cell  apoptosis. Conclusion. Magnesium plays an important neuroprotective role.

scholarly journals The Role of Extracellular Vesicles in Demyelination of the Central Nervous System

2020 ◽  
Vol 21 (23) ◽  
pp. 9111
Author(s):  
José Antonio López-Guerrero ◽  
Inés Ripa ◽  
Sabina Andreu ◽  
Raquel Bello-Morales
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Extracellular Vesicles ◽  
Viral Infections ◽  
Membrane Vesicles ◽  
Synaptic Activity ◽  
Demyelinating Diseases ◽  
Parkinson’S Diseases ◽  
The Central Nervous System

It is being increasingly demonstrated that extracellular vesicles (EVs) are deeply involved in the physiology of the central nervous system (CNS). Processes such as synaptic activity, neuron-glia communication, myelination and immune response are modulated by EVs. Likewise, these vesicles may participate in many pathological processes, both as triggers of disease or, on the contrary, as mechanisms of repair. EVs play relevant roles in neurodegenerative disorders such as Alzheimer’s or Parkinson’s diseases, in viral infections of the CNS and in demyelinating pathologies such as multiple sclerosis (MS). This review describes the involvement of these membrane vesicles in major demyelinating diseases, including MS, neuromyelitis optica, progressive multifocal leukoencephalopathy and demyelination associated to herpesviruses.

scholarly journals High-Molecular-Weight Hyaluronic Acid Inhibits IL-1β-Induced Synovial Inflammation and Macrophage Polarization through the GRP78-NF-κB Signaling Pathway

2021 ◽  
Vol 22 (21) ◽  
pp. 11917
Author(s):  
Chien-Hsing Lee ◽  
Chi-Fu Chiang ◽  
Feng-Chih Kuo ◽  
Sheng-Chiang Su ◽  
Chia-Luen Huang ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Hyaluronic Acid ◽  
High Molecular Weight ◽  
Signaling Pathway ◽  
Macrophage Polarization ◽  
Synovial Inflammation ◽  
Synovial Cells ◽  
Additive Effects ◽  
M2 Polarization

Recent evidence has suggested that synovial inflammation and macrophage polarization were involved in the pathogenesis of osteoarthritis (OA). Additionally, high-molecular-weight hyaluronic acid (HMW-HA) was often used clinically to treat OA. GRP78, an endoplasmic reticulum (ER) stress chaperone, was suggested to contribute to the hyperplasia of synovial cells in OA. However, it was still unclear whether HMW-HA affected macrophage polarization through GRP78. Therefore, we aimed to identify the effect of HMW-HA in primary synovial cells and macrophage polarization and to investigate the role of GRP78 signaling. We used IL-1β to treat primary synoviocytes to mimic OA, and then treated them with HMW-HA. We also collected conditioned medium (CM) to culture THP-1 macrophages and examine the changes in the phenotype. IL-1β increased the expression of GRP78, NF-κB (p65 phosphorylation), IL-6, and PGE2 in primary synoviocytes, accompanied by an increased macrophage M1/M2 polarization. GRP78 knockdown significantly reversed the expression of IL-1β-induced GRP78-related downstream molecules and macrophage polarization. HMW-HA with GRP78 knockdown had additive effects in an IL-1β culture. Finally, the synovial fluid from OA patients revealed significantly decreased IL-6 and PGE2 levels after the HMW-HA treatment. Our study elucidated a new form of signal transduction for HMW-HA-mediated protection against synovial inflammation and macrophage polarization and highlighted the involvement of the GRP78-NF-κB signaling pathway.

LINC01956 Promotes Metastasis and M2 Polarization of Tumor-Associated Macrophages in Glioblastoma Via The FUS/β-Catenin Signaling Pathway

2021 ◽  
Author(s):  
fengfei lu ◽  
fa jin
Keyword(s):  
Signaling Pathway ◽  
Cancer Progression ◽  
Nuclear Translocation ◽  
Hypoxic Conditions ◽  
M2 Polarization ◽  
Rna Immunoprecipitation ◽  
First Time

Abstract Background:Long noncoding RNAs (lncRNAs) can drive cancer progression. Here, we studied the role of a novel lncRNA, LINC01956, in glioblastoma (GBM). Methods:RT-PCR assay was used to examine LINC01956 expression levels. Colony-formation, MTT, cell-cycle and in-vivo tumorigenesis assays were used to examine the role of LINC01956 in cell growth in vitro and in vivo. Boyden assay was used to examine cell invasion ability in vitro. RNA immunoprecipitation and RNA-protein pull-down assays were used to examine the interaction between LINC01956 and FUS protein.ChIP assay was used to examine HIF1-binding sites in the LINC01956 promoter.Results:The level of LINC01956 was elevated in GBM cell lines and tissues. LINC01956 downregulation suppressed the migration and proliferation of GBM cells. M2 polarization of macrophages induced by exosomes derived from glioma cells overexpressing LINC01956 further accelerated GBM progression. Mechanistically, we found that FUS interacted with both LINC01956 and β-catenin. LINC01956 bound to FUS and reduced its ubiquitination. LINC01956 evoked nuclear translocation of phosphorylated (p)-β-catenin by recruiting FUS. Furthermore, under hypoxic conditions, LINC01956 was regulated by HIF-1α. Conclusion:Taken together, our data revealed for the first time that LINC01956 exerts protumor effects via FUS-dependent activation of the WNT/β-catenin signaling pathway.

scholarly journals Linc00514 promotes breast cancer metastasis and M2 polarization of tumor-associated macrophages via Jagged1-mediated notch signaling pathway

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Sifeng Tao ◽  
Qiang Chen ◽  
Chen Lin ◽  
Haiying Dong
Keyword(s):  
Breast Cancer ◽  
Notch Signaling ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Notch Signaling Pathway ◽  
M2 Macrophage ◽  
M2 Polarization

Abstract Background Tumor-associated macrophages (TAMs) and tumor cells are important components of the tumor microenvironment. M2 polarization of TAMs, which is a major actor in breast cancer malignancy and metastasis, can be induced by breast cancer cells. However, the potential mechanisms of the interaction between breast cancer cells and TAMs remain unclear. Methods The candidate breast cancer-associated long non-coding RNAs (lncRNAs) were analyzed using the GEO database. Functional assays, including MTT assay, Transwell assay, and EdU labeling detection, were performed to investigate the oncogenic role of linc00514 in breast cancer progression. The co-culture and ELISA assays were used to assess the role of linc00514 in macrophage recruitment and M2 polarization. RNA immunoprecipitation, RNA pull-down, and luciferase reporter assays were applied to determine the mechanism of linc00514 in breast cancer metastasis. Mouse xenograft models, mouse pulmonary metastatic models, and mouse primary tumor models were used to assess the role of linc00514 in M2 macrophage polarization and breast cancer tumorigenicity. Results Linc00514 was highly expressed in clinical breast cancer tissues and breast cancer cell lines. Overexpression of linc00514 promoted the proliferation and invasion of breast cancer cells and increased xenograft tumor volumes and pulmonary metastatic nodules. Overexpression of linc00514 also increased the percentage of macrophages expressing M2 markers CD206 and CD163. Mechanistically, linc00514 promoted Jagged1 expression in a transcriptional manner by increasing the phosphorylation of a transcription factor STAT3. Subsequently, Jagged1-mediated Notch signaling pathway promoted IL-4 and IL-6 secretions in breast cancer cells and ultimately inducing M2 polarization of macrophages. Conclusion Linc00514 plays an important role in regulating breast cancer tumorigenicity and M2 macrophage polarization via Jagged1-mediated Notch signaling pathway.

scholarly journals Functional Role of SIL1 in Neurodevelopment and Learning

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Shilian Xu ◽  
Jia Zhu ◽  
Kai Mi ◽  
Yan Shen ◽  
Xiaomin Zhang
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Western Blot ◽  
Signaling Pathway ◽  
Spatial Learning ◽  
Cortical Neurons ◽  
Developmental Expression ◽  
The Central Nervous System ◽  
Reelin Signaling

Background. Sil1 is the causative gene of Marinesco-Sjӧgren Syndrome (MSS). The mutated Sil1 generates shortened SIL1 protein which will form aggregation and be degraded rapidly. Mental retardation is a major symptom of MSS which suggests a role of SIL1 in the development of the central nervous system, but how SIL1 functions remains unclear. Objectives. The aim of this study is to explore the role of SIL1 in regulating cerebral development and its underlying molecular mechanism. Methods. The basic expression pattern of SIL1 in tissues and cultured cortical neurons is measured by immunostaining and Western blot. The expression of SIL1 is reduced in vitro and in vivo through RNA interference delivered by a lentivirus. The expression of NMDA receptor subunits and the function of the Reelin signaling pathway are then examined by surface biotinylation and Western blot subsequently. Finally, the spatial learning of young mice was assessed by the Barnes maze task. Results. SIL1 deficiency caused a diminished expression of both Reelin receptors and therefore impaired the Reelin signaling pathway. It then inhibited the developmental expression of GluN2A and impaired the spatial learning of 5-week-old mice. Conclusions. These results suggested that SIL1 is required for the development of the central nervous system which is associated with its role in Reelin signaling.

scholarly journals The Role of Microglial Phagocytosis in Ischemic Stroke

2022 ◽  
Vol 12 ◽  
Author(s):  
Junqiu Jia ◽  
Lixuan Yang ◽  
Yan Chen ◽  
Lili Zheng ◽  
Yanting Chen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Apoptotic Cell ◽  
Neurological Deficits ◽  
Specific Cell ◽  
Microglial Polarization ◽  
Microglial Phagocytosis ◽  
Injured Brain ◽  
Tissue Reconstruction ◽  
The Central Nervous System

Microglia are the resident immune cells of the central nervous system that exert diverse roles in the pathogenesis of ischemic stroke. During the past decades, microglial polarization and chemotactic properties have been well-studied, whereas less attention has been paid to phagocytic phenotypes of microglia in stroke. Generally, whether phagocytosis mediated by microglia plays a beneficial or detrimental role in stroke remains controversial, which calls for further investigations. Most researchers are in favor of the former proposal currently since efficient clearance of tissue debris promotes tissue reconstruction and neuronal network reorganization in part. Other scholars propose that excessively activated microglia engulf live or stressed neuronal cells, which results in neurological deficits and brain atrophy. Upon ischemia challenge, the microglia infiltrate injured brain tissue and engulf live/dead neurons, myelin debris, apoptotic cell debris, endothelial cells, and leukocytes. Cell phagocytosis is provoked by the exposure of “eat-me” signals or the loss of “don’t eat-me” signals. We supposed that microglial phagocytosis could be initiated by the specific “eat-me” signal and its corresponding receptor on the specific cell type under pathological circumstances. In this review, we will summarize phagocytic characterizations of microglia after stroke and the potential receptors responsible for this programmed biological progress. Understanding these questions precisely may help to develop appropriate phagocytic regulatory molecules, which are promoting self-limiting inflammation without damaging functional cells.

Sign in / Sign up

Export Citation Format

Share Document