Vimentin participates in microglia activation and neurotoxicity in cerebral ischemia

Jiang, Shuxian; Slinn, Jacqueline; Aylsworth, Amy; Hou, Sheng T.

doi:10.1111/j.1471-4159.2012.07823.x

Cited by 50 publications

(47 citation statements)

References 37 publications

(46 reference statements)

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“…Two of the significantly dysregulated proteins, namely vimentin and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP) were chosen for further validation using Western blotting, as changes of both vimentin and CNP have been previously reported in rodent models of ischemic stroke232425. Vimentin expression was markedly up-regulated in the ipsilateral (Ipsi) region of the brain compared to that of the contralateral part.…”

Section: Resultsmentioning

confidence: 99%

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Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy

Zhang

Sun

et al. 2016

Sci Rep

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TBN, a novel tetramethylpyrazine derivative armed with a powerful free radical-scavenging nitrone moiety, has been reported to reduce cerebral infarction in rats through multi-functional mechanisms of action. Here we study the therapeutic effects of TBN on non-human primate model of stroke. Thirty male Cynomolgus macaques were subjected to stroke with 4 hours ischemia and then reperfusion. TBN were injected intravenously at 3 or 6 hours after the onset of ischemia. Cerebral infarction was examined by magnetic resonance imaging at 1 and 4 weeks post ischemia. Neurological severity scores were evaluated during 4 weeks observation. At the end of experiment, protein markers associated with the stroke injury and TBN treatment were screened by quantitative proteomics. We found that TBN readily penetrated the blood brain barrier and reached effective therapeutic concentration after intravenous administration. It significantly reduced brain infarction and modestly preserved the neurological function of stroke-affected arm. TBN suppressed over-expression of neuroinflammatory marker vimentin and decreased the numbers of GFAP-positive cells, while reversed down-regulation of myelination-associated protein 2′, 3′-cyclic-nucleotide 3′-phosphodiesterase and increased the numbers of NeuN-positive cells in the ipsilateral peri-infarct area. TBN may serve as a promising new clinical candidate for the treatment of ischemic stroke.

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Section: Resultsmentioning

confidence: 99%

“…S2). Vimentin is a component of the intermediate filament system and a prominent marker of microglia and reactive astrocytes23. Up-regulation of vimentin demonstrates that microglia and reactive astrocytes are activated and/or are proliferating in response to the presence of injured neural tissues (Fig.…”

Section: Resultsmentioning

confidence: 99%

Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy

Zhang

Sun

et al. 2016

Sci Rep

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“…Vimentin can activate microglia and astrocytes to aggravate neurotoxicity and impairment. Deleted vimentin can alleviate microglia activation and neuron damage [45,46]. In this study, a high-level of vimentin increase was observed in the APP/PS1-ShDbn1 mice.…”

Section: Discussionmentioning

confidence: 53%

Down-Regulated Drebrin Aggravates Cognitive Impairments in a Mouse Model of Alzheimer’s Disease

Liu

Zhang

et al. 2017

IJMS

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The developmentally regulated brain protein drebrin (Dbn) is a functional protein involved with long-term memory formation and is widely distributed in brain neurons, especially in the dendritic spines. A noticeable decline of this protein has been found in the hippocampus and cortex of patients with Alzheimer’s disease (AD), yet the relationship between Dbn and AD has not been fully understood. In the present study, we examined how down-regulation of Dbn impacts the progression of AD in experimental animals. Accordingly, we injected Dbn interference vector (rAAV-mDbn1 ShRNA) into the hippocampus of three-month old APP(swe)/PS1(ΔE9) mice (APP/PS1 mice) and then successfully down-regulated Dbn expression in this brain region. Behavioral tests, including the Morris water maze test, the open field test, and the novel object test were conducted when the animals were nine months old. Subsequently, MicroPET/CT imaging to monitor glucose metabolism was done. We then investigated Aβ, GFAP, PSD-95, MAP2, vimentin, Cox43, and Syn1 expressions in the brain of the experimental animals via immunohistochemical or immunofluorescence methods. We found that AD mice with a low expression of Dbn performed poorly in the behavioral tests and showed decreased glucose utilization. In the brains of these animals, we detected a slight increase of Aβ, GFAP and vimentin and a significant decline of PSD-95. Altogether our data warrant further studies to elucidate the effect of Dbn on the development and progression of AD.

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“…Additionally, by treating KPV +/+ mice with WFA following tumor development, we show that the delayed tumor growth and metastasis observed in KPV −/− mice in Figure 1 is not due solely to delayed onset of tumor growth, but rather to attenuated growth kinetics in tumor cells that lack an intact vimentin network. Although vimentin-null mice were first reported to display no obvious phenotype, these data and others suggest that loss of vimentin is protective against a range of challenges including lung cancer, lipopolysaccharides, bleomycin, asbestos, bacterial meningitis, cerebral ischemia, and acute colitis (26, 38, 62–64). While this study adds to the body of knowledge on the phenotype of the vimentin-null mouse, the global knockout model presents limitations.…”

Section: Discussionmentioning

confidence: 95%

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

Berr¹,

Wiese²,

Santos³

et al. 2020

Preprint

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1Vimentin, a type III intermediate filament, is highly expressed in aggressive epithelial 2 cancers and is associated with increased rates of metastasis. We show that vimentin is causally 3 required for lung cancer metastasis using a genetic mouse model of lung adenocarcinoma (LSL-4 Kras G12D ;Tp53 fl/fl , termed KPV +/+ ) crossed with vimentin-null mice (thereby creating KPV −/− mice). 5Both KPV +/+ and KPV −/− mice developed lung tumors, yet KPV −/− mice had delayed tumorigenesis 6 and prolonged survival. KPV +/+ cells implanted in the flank metastasized to the lung while KPV −/− 7 cells did not, providing additional evidence that vimentin is required for metastasis. Differential 8 expression analysis of RNA-seq data demonstrated that KPV −/− cells had suppressed expression 9 of genes that drive epithelial-to-mesenchymal transition, migration, and invasion, processes that 10 are critical to the metastatic cascade. Integrative metabolomic and transcriptomic analysis 11 revealed altered glutaminolysis, with KPV −/− cells accumulating glutathione, leading to impaired 12 cell motility in response to oxidative stress. Together, these results show that loss of vimentin 13 impairs epithelial-to-mesenchymal transition and regulation of the oxidative stress response, 14 resulting in decreased metastasis in murine lung adenocarcinoma. 15 16 17 18Non-small-cell lung cancers (NSCLCs) represent 80% of all lung cancers and are often 20 diagnosed at more advanced stages of the disease resulting in high rates of mortality (1). 21Adenocarcinoma is the most common subtype of NSCLC and is characterized by activating 22 mutations in the Kras proto-oncogene in up to 30% of diagnoses and by inactivating mutations in 23 the tumor suppressor gene Tp53 in up to 60% of diagnoses (2)(3)(4)(5). Despite the prevalence of lung 24 adenocarcinoma, the metastatic mechanisms that drive lung cancer progression are incompletely 25 understood. 26The type III intermediate filament vimentin is associated with increased metastatic spread 27 and lower rates of survival in patients with NSCLC (6-8). Vimentin is a canonical marker of 28 epithelial-to-mesenchymal transition (EMT), an initiating event of the metastatic cascade (9). EMT 29 is the process by which epithelial cells remodel cell-cell and cell-extracellular-matrix (ECM) 30 contacts, lose their apical-basal polarity, and adopt the spindle-shaped morphology associated 31 with a mesenchymal cell phenotype (10). During EMT, cells undergo a downregulation of 32 epithelial cell associated genes, including E-cadherin and cytokeratins, and an upregulation of 33 mesenchymal cell associated genes, including N-cadherin and vimentin. In addition to acting as 34 a marker of EMT, vimentin is functionally involved in EMT. Structurally, vimentin intermediate 35 filaments control cell shape, and thus facilitate the transition toward a mesenchymal phenotype 36(11). Twist1, a transcription factor critical to EMT, upregulates vimentin expression (12). Vimentin 37 also serves as a scaffold for Slug, another transc...

show abstract

Vimentin participates in microglia activation and neurotoxicity in cerebral ischemia

Cited by 50 publications

References 37 publications

Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy

Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy

Down-Regulated Drebrin Aggravates Cognitive Impairments in a Mouse Model of Alzheimer’s Disease

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

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