Molecular mechanisms of oxidative tissue injury differ between multiple sclerosis and experimental disease models

AbstractAxon loss is a cardinal neuropathological feature of multiple sclerosis (MS). Axonal injury in MS and experimental disease models is most frequently detected in acutely demyelinating regions. Furthermore, acute axonal injury consistently correlates with the extent of inflammatory demyelination. Following lysolecithin-induced demyelination, we recently reported a compensatory response in neurons, where mitochondria move from the cell body to the acutely demyelinated axon and increase the mitochondrial content. We termed this energetics phenomenon, that is also evident in MS, the axonal response of mitochondria to demyelination (ARMD). In the present study, we assessed axonal mitochondrial content as well as axonal mitochondrial respiratory chain complex IV activity (COX) of axons and related these to axonal injury in nine different experimental disease models. We consistently found ARMD in all experimental disease models. However, the increase in mitochondrial content within demyelinated axons was not always accompanied by a proportionate increase in COX activity, particularly in experimental autoimmune encephalomyelitis (EAE). Axonal COX activity inversely correlated with the extent of axonal injury in experimental disease models. Our findings indicate that ARMD is a consistent and prominent finding and emphasises the need to preserve axonal mitochondrial COX activity in inflammatory demyelination, paving the way for the development of novel neuroprotective therapies.

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Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter

Acta Neuropathologica ◽

10.1007/s00401-021-02274-7 ◽

2021 ◽

Vol 141 (4) ◽

pp. 585-604 ◽

Cited By ~ 1

Author(s):

Carmen Picon ◽

Anusha Jayaraman ◽

Rachel James ◽

Catriona Beck ◽

Patricia Gallego ◽

...

Keyword(s):

Multiple Sclerosis ◽

Signaling Pathway ◽

Cortical Neurons ◽

Grey Matter ◽

Molecular Mechanisms ◽

Fold Increase ◽

Cell Types ◽

Meningeal Inflammation ◽

Cortical Grey Matter

AbstractSustained exposure to pro-inflammatory cytokines in the leptomeninges is thought to play a major role in the pathogenetic mechanisms leading to cortical pathology in multiple sclerosis (MS). Although the molecular mechanisms underlying neurodegeneration in the grey matter remain unclear, several lines of evidence suggest a prominent role for tumour necrosis factor (TNF). Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, we describe an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis, including the key proteins TNFR1, FADD, RIPK1, RIPK3 and MLKL. Activation of this pathway was indicated by the phosphorylation of RIPK3 and MLKL and the formation of protein oligomers characteristic of necrosomes. In contrast, caspase-8 dependent apoptotic signaling was decreased. Upregulation of necroptotic signaling occurred predominantly in macroneurons in cortical layers II–III, with little expression in other cell types. The presence of activated necroptotic proteins in neurons was increased in MS cases with prominent meningeal inflammation, with a 30-fold increase in phosphoMLKL+ neurons in layers I–III. The density of phosphoMLKL+ neurons correlated inversely with age at death, age at progression and disease duration. In vivo induction of chronically elevated TNF and INFγ levels in the CSF in a rat model via lentiviral transduction in the meninges, triggered inflammation and neurodegeneration in the underlying cortical grey matter that was associated with increased neuronal expression of TNFR1 and activated necroptotic signaling proteins. Exposure of cultured primary rat cortical neurons to TNF induced necroptosis when apoptosis was inhibited. Our data suggest that neurons in the MS cortex are dying via TNF/TNFR1 stimulated necroptosis rather than apoptosis, possibly initiated in part by chronic meningeal inflammation. Neuronal necroptosis represents a pathogenetic mechanism that is amenable to therapeutic intervention at several points in the signaling pathway.

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Scleroderma: from cell and molecular mechanisms to disease models

Trends in Immunology ◽

10.1016/j.it.2005.09.004 ◽

2005 ◽

Vol 26 (11) ◽

pp. 587-595 ◽

Cited By ~ 190

Author(s):

David J. Abraham ◽

John Varga

Keyword(s):

Molecular Mechanisms ◽

Disease Models

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The impact of Traditional Chinese Medicine on mitophagy in disease models

Current Pharmaceutical Design ◽

10.2174/1381612827666211006150410 ◽

2021 ◽

Vol 27 ◽

Author(s):

Li-Ping Yu ◽

Ting-Ting Shi ◽

Yan-Qin Li ◽

Jian-Kang Mu ◽

Ya-Qin Yang ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Molecular Mechanisms ◽

Human Diseases ◽

Regulatory Mechanisms ◽

Disease Models ◽

Relationship Of ◽

The Impact ◽

The Relationship

: Mitophagy plays an important role in maintaining mitochondrial quality and cell homeostasis through the degradation of damaged, aged, and dysfunctional mitochondria and misfolded proteins. Many human diseases, particularly neurodegenerative diseases, are related to disorders of mitochondrial phagocytosis. Exploring the regulatory mechanisms of mitophagy is of great significance for revealing the molecular mechanisms underlying the related diseases. Herein, we summarize the major mechanisms of mitophagy, the relationship of mitophagy with human diseases, and the role of traditional Chinese medicine (TCM) in mitophagy. These discussions enhance our knowledge of mitophagy and its potential therapeutic targets using TCM.

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Lost in the Translation Trap: Quest for a Research Reporting Culture That More Carefully Weighs Clinical Applicability in Experimental Disease Models

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.800207 ◽

2021 ◽

Vol 15 ◽

Author(s):

Dirk M. Hermann

Keyword(s):

Disease Models ◽

Research Reporting ◽

Clinical Applicability ◽

Experimental Disease

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The Role of Complement in Experimental Disease Models

Complement ◽

10.1007/978-3-642-82416-6_19 ◽

1985 ◽

pp. 421-428 ◽

Cited By ~ 1

Author(s):

Charles G. Cochrane

Keyword(s):

Disease Models ◽

Experimental Disease

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Cyclophilin a as a Mediator of Tissue Injure and Nephrotoxicity

Nephrology Research & Reviews ◽

10.4081/nr.2012.e9 ◽

2012 ◽

Vol 4 (2) ◽

pp. 42-44

Author(s):

Grace Moscoso-Solorzano ◽

Gianna Mastroianni-Kirsztajn

Keyword(s):

Molecular Mechanisms ◽

Tissue Injury ◽

Cyclophilin A ◽

Common Mechanism ◽

Ppiase Activity ◽

Expression Of Genes ◽

Inflammatory Stimuli ◽

Genes Encoding ◽

Inflammatory Processes

Cyclophilin A (CypA) belongs to the peptidyl-prolil isomerase (PPlase) family of proteins and it is also known as the cellular receptor for cyclosporine A (CsA). CsA binds to CypA and inhibits the PPIase activity, but the CypA-CsA complex also binds to calcineurin that promotes the expression of genes encoding cytokines and other proteins required for immune response. In addition, the polymorphism variation of CypA promoter seems to have an influence on the expression of CypA in in vitro studies. CypA was also implicated in inflammatory processes (such as, among others, those observed in rheumatoid arthritis, atherosclerotic disease, nephrotoxicity) and it can be secreted by cells in response to inflammatory stimuli. CypA can also have a role in the molecular mechanisms by which CsA induces nephroxicity but these remain poorly understood. Recent studies suggest that CsA inhibition of CypA PPlase activity is a possible mechanism of this drug toxicity. In addition, CypA overexpression could be protective against CsA nephrotoxicity. Finally, the putative common mechanism by which CypA could be involved in CsA nephrotoxicity and tissue injury is related to its proinflammatory effects in cells.

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Adhesion of flowing monocytes to hypoxia-reoxygenation-exposed endothelial cells: role of Rac1, ROS, and VCAM-1

AJP Cell Physiology ◽

10.1152/ajpcell.00301.2001 ◽

2002 ◽

Vol 283 (1) ◽

pp. C93-C102 ◽

Cited By ~ 30

Author(s):

C. K. Domingos Ng ◽

Shailesh S. Deshpande ◽

Kaikobad Irani ◽

B. Rita Alevriadou

Keyword(s):

Endothelial Cells ◽

Molecular Mechanisms ◽

Tissue Injury ◽

Umbilical Vein ◽

Ischemia Reperfusion ◽

Small Gtpase ◽

Dominant Negative ◽

Pyrrolidine Dithiocarbamate ◽

U937 Cells ◽

Hypoxia Reoxygenation

Production of reactive oxygen species (ROS) by ischemic tissue after ischemia-reperfusion (I/RP) is an important factor that contributes to tissue injury. The small GTPase Rac1 mediates the oxidative burst, and ROS act on signaling pathways involved in expression of inflammatory genes. Because there is evidence implicating monocytes in the pathogenesis of I/RP injury, our objective was to determine the molecular mechanisms that regulate adhesive interactions between monocytes and hypoxia-reoxygenation (H/RO)-exposed cultured endothelial cells (ECs). When U937 cells were perfused over human umbilical vein ECs at 1 dyn/cm2, H (1 h at 1% O2)/RO (13 h) significantly increased the fluxes of rolling and stably adherent U937 cells. Either EC treatment with the antioxidant pyrrolidine dithiocarbamate (PDTC) or infection with AdRac1N17, which results in expression of the dominant-negative form of Rac1, abolished H/RO-induced ROS production, attenuated rolling, and abolished stable adhesion of U937 cells to H/RO-exposed ECs. Infection with AdRac1N17 also abolished H/RO-induced upregulation of vascular cell adhesion molecule (VCAM)-1. In turn, blocking VCAM-1 abolished U937 cell stable adhesion and slightly increased rolling. We concluded that the Rac1-dependent ROS partially regulate rolling and exclusively regulate stable adhesion of monocytic cells to ECs after H/RO and that stable adhesion, but not rolling, is mediated by ROS-induced expression of VCAM-1.

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