P53 in RhoA regulation

Barabutis, Nektarios

doi:10.1002/cm.21604

Cited by 15 publications

(6 citation statements)

References 46 publications

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“…In a similar fashion, P53 can kill the cells upon intense environmental and extracellular factors ( 36 , 63 ), but its mild induction delivers protective effects against lung hyperpermeability ( 58 ). An increased production of reactive oxygen species may either promote lung pathologies or kill the cancer cells ( 64 ).…”

Section: Discussionmentioning

confidence: 99%

Unfolded Protein Response in Lung Health and Disease

Barabutis

2020

Front. Med.

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The unfolded protein response (UPR) is a complex element, destined to protect the cells against a diverse variety of extracellular and intracellular challenges. UPR activation devises highly efficient responses to counteract cellular threats. If those activities fail, it will dictate cellular execution. The current work focuses on the role of UPR in pulmonary function, by immersing into the highly interrelated network that operates toward the endothelial barrier function. A highly sophisticated UPR manipulation shall reveal new therapeutic possibilities against inflammatory lung disease, such as acute lung injury and acute respiratory distress syndrome.

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Section: Discussionmentioning

confidence: 99%

Unfolded Protein Response in Lung Health and Disease

Barabutis

2020

Front. Med.

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“…▶Fig. 1d suggests that MIA-602 blocks the activation of the inflammatory RhoA [12], whereas GHRH delivers the opposite effects.…”

Section: Resultsmentioning

confidence: 99%

“…ver, MIA-602 suppresses the inflammatory RhoA, which in turn induces the formation of the F-actin fibers, thus it increases cellular permeability [11]. This small GTPase (RhoA) has been previously shown to be suppressed by P53 [12], and to be induced by the production of ROS [13]. Moreover, we reveal that this antagonist counteracts the deteriorating effects of H 2 O 2 towards the integrity of the brain microvascular endothelium, as reflected in measurements of transendothelial resistance.…”

Section: Introductionmentioning

confidence: 98%

GHRH Antagonists Protect Against Hydrogen Peroxide-Induced Breakdown of Brain Microvascular Endothelium Integrity

et al. 2020

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Growth hormone releasing hormone is a hypothalamic neuropeptide, which regulates the release of growth hormone from the anterior pituitary gland. Growth hormone releasing hormone antagonists are anticancer agents, associated with strong anti-inflammatory activities. In the present study, we investigated the effects of the GHRH antagonist MIA-602 in the integrity of the brain microvascular endothelium in vitro. Our observations suggest that MIA-602 protects against the H2O2-induced breakdown of the brain endothelium and enhances its integrity by inducing P53, deactivating cofilin, and suppressing the RhoA inflammatory pathway. Thus, GHRH antagonists may offer an exciting possibility for the treatment of pathologies related to the blood brain barrier dysfunction, including the Parkinson’s and Alzheimer’s diseases.

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“…P53 functions as an orchestrator of anti-inflammatory signaling. It suppresses the redox regulator APE1/Ref1 [22,44,45], inhibits the RhoA/MLC2 pathway [46] and deactivates the actin severing activity of cofilin in endothelial cells [47,48]. P53 is subjected to phosphorylation and subsequent degradation by bacterial toxins such as lipopolysaccharide [49] and lipoteichoic acid [50].…”

Section: Discussionmentioning

confidence: 99%

Elucidation of the Molecular Pathways Involved in the Protective Effects of AUY-922 in LPS-Induced Inflammation in Mouse Lungs

et al. 2021

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) cause thousands of deaths every year and are associated with high mortality rates (~40%) due to the lack of efficient therapies. Understanding the molecular mechanisms associated with those diseases will most probably lead to novel therapeutics. In the present study, we investigated the effects of the Hsp90 inhibitor AUY-922 in the major inflammatory pathways of mouse lungs. Mice were treated with LPS (1.6 mg/kg) via intratracheal instillation for 24 h and were then post-treated intraperitoneally with AUY-922 (10 mg/kg). The animals were examined 48 h after AUY-922 injection. LPS activated the TLR4-mediated signaling pathways, which in turn induced the release of different inflammatory cytokines and chemokines. AUY-922 suppressed the LPS-induced inflammation by inhibiting major pro-inflammatory pathways (e.g., JAK2/STAT3, MAPKs), and downregulated the IL-1β, IL-6, MCP-1 and TNFα. The expression levels of the redox regulator APE1/Ref1, as well as the DNA-damage inducible kinases ATM and ATR, were also increased after LPS treatment. Those effects were counteracted by AUY-922. Interestingly, this Hsp90 inhibitor abolished the LPS-induced pIRE1α suppression, a major component of the unfolded protein response. Our study elucidates the molecular pathways involved in the progression of murine inflammation and supports our efforts on the development of new therapeutics against lung inflammatory diseases and sepsis.

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P53 in RhoA regulation

Cited by 15 publications

References 46 publications

Unfolded Protein Response in Lung Health and Disease

Unfolded Protein Response in Lung Health and Disease

GHRH Antagonists Protect Against Hydrogen Peroxide-Induced Breakdown of Brain Microvascular Endothelium Integrity

Elucidation of the Molecular Pathways Involved in the Protective Effects of AUY-922 in LPS-Induced Inflammation in Mouse Lungs

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