Cardiotoxicity of anthracycline: Novel approach through down regulation of TLR-3 via TRAF/MAPK signaling pathway

Cardiotoxicity is one of the most important complications doxorubicin (DOX) and its pathomechanisms are not completely elucidated. We hypothesize that signaling via toll-like receptor (TLR)-3, a receptor that is activated upon binding of double-stranded nucleotides, might play a crucial role in the pathogenesis of cardiac-toxicity following DOX treatment. Male adult C57BL6 wild-type mice and TLR-3 knock-out (-/-) mice were subjected to 20 mg/kg; administered intraperitoneally. TLR-3 down-stream signaling was activated in WT mice lead to strong pro-inflammatory response with significant monocyte cells invasion. In contrast, this effect was attenuated in TLR-3-/- mice. Moreover, the TLR-3 activation resulted in cardiac damage that was associated with significantly reduced LV function and increased monocyte chemoattractant protein-1 (MCP)-1 expression in WT mice. This finding was confirmed by increased MAPK and TRIF protein expression in WT mice. This study confirmed that the absence of TLR-3 is associated with lower heart injury and maintained LV function. Thus, we conclude that TLR-3 seems to participate in the pathogenesis of cardiotoxicity of DOX.

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Cardiotoxicity of anthracycline: Novel approach through down regulation of TLR-3 via TRAF/MAPK signaling pathway

American Journal of BioMedicine ◽

10.18081/2333-5106/015-02/413-422 ◽

2015 ◽

Vol 2 (3) ◽

pp. 423-432

Author(s):

Robyn Wonder ◽

Steliana Penzkofer ◽

Evelyn G Hazen

Keyword(s):

Mapk Signaling ◽

Lv Function ◽

Toll Like Receptor ◽

Cardiac Damage ◽

Male Adult ◽

Knock Out ◽

Monocyte Chemoattractant Protein 1 ◽

Novel Approach ◽

Heart Injury ◽

Knock Out Mice

Cardiotoxicity is one of the most important complications doxorubicin (DOX) and its pathomechanisms are not completely elucidated. We hypothesize that signaling via toll-like receptor (TLR)-3, a receptor that is activated upon binding of double-stranded nucleotides, might play a crucial role in the pathogenesis of cardiac-toxicity following DOX treatment. Male adult C57BL6 wild-type mice and TLR-3 knock-out (-/-) mice were subjected to 20 mg/kg; administered intraperitoneally. TLR-3 down-stream signaling was activated in WT mice lead to strong pro-inflammatory response with significant monocyte cells invasion. In contrast, this effect was attenuated in TLR-3-/- mice. Moreover, the TLR-3 activation resulted in cardiac damage that was associated with significantly reduced LV function and increased monocyte chemoattractant protein-1 (MCP)-1 expression in WT mice. This finding was confirmed by increased MAPK and TRIF protein expression in WT mice. This study confirmed that the absence of TLR-3 is associated with lower heart injury and maintained LV function. Thus, we conclude that TLR-3 seems to participate in the pathogenesis of cardiotoxicity of DOX.

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Toll-like receptor 5 knock-out mice exhibit a specific low level of anxiety

Brain Behavior and Immunity ◽

10.1016/j.bbi.2021.01.020 ◽

2021 ◽

Author(s):

A.M. Hamieh ◽

G. Mallaret ◽

M. Meleine ◽

A. Lashermes ◽

S. Roumeau ◽

...

Keyword(s):

Toll Like Receptor ◽

Knock Out ◽

Low Level ◽

Knock Out Mice ◽

Toll Like Receptor 5

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Cortical excitation:inhibition imbalance causes abnormal brain network dynamics as observed in neurodevelopmental disorders

10.1101/492108 ◽

2018 ◽

Cited By ~ 3

Author(s):

Marija Markicevic ◽

Ben D. Fulcher ◽

Christopher Lewis ◽

Fritjof Helmchen ◽

Markus Rudin ◽

...

Keyword(s):

Neurodevelopmental Disorders ◽

Spatial Scales ◽

Brain Network ◽

Cellular Level ◽

Network Activity ◽

Knock Out ◽

Novel Approach ◽

Knock Out Mice ◽

Abnormal Brain ◽

Parvalbumin Neurons

AbstractAbnormal brain development manifests itself at different spatial scales. However, whether abnormalities at the cellular level can be diagnosed from network activity measured withfunctional magnetic resonance imaging (fMRI) is largely unknown, yet of high clinical relevance. Here we applied fMRI while using chemogenetics to increase the excitation-to-inhibition ratio (E:I) within cortical microcircuits of the mouse brain, thereby mimicking a putative mechanism of neurodevelopmental disorders including autism. Increased E:I caused a significant reduction of long-range connectivity, irrespective of whether excitatory neurons were facilitated or inhibitory Parvalbumin interneurons were suppressed. Training a classifier on fMRI signals, we were able to accurately classify cortical areas exhibiting increased E:I. This classifier was validated in an independent cohort of Fmr1y/- knock-out mice, a model for autism with well-documented loss of Parvalbumin neurons and chronic alterations of E:I. Our findings demonstrate a promising novel approach towards inferring microcircuit abnormalities from macroscopic fMRI measurements.

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