P53 in acute respiratory distress syndrome

Barabutis, Nektarios

doi:10.1007/s00018-020-03629-1

Cited by 16 publications

(6 citation statements)

References 30 publications

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“…Hsp90 inhibitors suppress those events; exert anti‐inflammatory activities; and induce P53 and BiP expression (Figures 1‐2). Both proteins have been reported to strengthen the barrier integrity 59,60 . Future in vivo studies utilizing endothelial specific P53 knock‐out mice will delineate the association of Hsp90, P53 and UPR in the brain.…”

Section: Discussionmentioning

confidence: 94%

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Hsp90 inhibition protects brain endothelial cells against LPS‐induced injury

et al. 2022

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Dysfunction of the blood–brain barrier (BBB) endothelium increases infiltration of lymphocytes and innate immune cells in the brain, leading to the development of neurological disorders. Heat shock protein 90 (Hsp90) inhibitors are anti‐inflammatory agents and P53 inducers, which reduce the production of reactive oxygen species (ROS) in a diverse variety of human tissues. In this study, we investigate the effects of those compounds in LPS‐induced brain endothelial inflammation, by utilizing human cerebral microvascular endothelial cells (hCMEC/D3). Our results suggest that Hsp90 inhibitors suppress inflammation by inhibiting the LPS‐induced signal transducer and activator of transcription 3 (STAT3); and P38 activation. Moreover, those compounds reduce the P53 suppressors murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Immunoglobulin heavy chain binding protein/glucose‐regulated protein 78 (BiP/Grp78)—a key element of endothelial barrier integrity‐was also increased by Hsp90 inhibition. Hence, we conclude that application of Hsp90 inhibitors in diseases related to BBB dysfunction may deliver a novel therapeutic possibility in the affected population.

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Section: Discussionmentioning

confidence: 94%

“…Both proteins have been reported to strengthen the barrier integrity. 59,60 Future in vivo studies utilizing endothelial specific P53 knock-out mice will delineate the association of Hsp90, P53 and UPR in the brain.…”

Section: Auy-922 Induces Bip Expression In Hcmec/d3mentioning

confidence: 99%

Hsp90 inhibition protects brain endothelial cells against LPS‐induced injury

et al. 2022

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“…To explore the underlying mechanisms, we investigated the effect of UBA2 on p53 expression. As a transcription factor, p53 can activate the expression of hundreds of genes [ 18 ]. These p53 target genes are directly involved in the regulation of the cell cycle, repair of DNA damage, and the regulation of cell senescence, differentiation, and apoptosis [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of ubiquitin-like modifier-activating enzyme 2 promotes apoptosis of clear cell renal cell carcinoma cells

et al. 2021

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Small ubiquitin-related modifier (SUMO) proteins are involved in the development of tumors. Ubiquitin-like modifier-activating enzyme 2 (UBA2) is an important member of the SUMO modification system; however, its role in clear cell renal cell carcinoma (ccRCC) is unclear. Therefore, we investigated the expression and function of UBA2 in ccRCC. Both mRNA and protein expression levels of UBA2 were found to be higher in ccRCC than in normal renal tissues and significantly related to the tumor size, Fuhrman grade, and tumor stage. UBA2 knockdown inhibited ccRCC cell growth, promoted apoptosis in vitro and in vivo, and decreased the abundance of a p53 mutant, c-Myc, and key enzymes of the SUMO modification system. Meanwhile, overexpression of UBA2 had the opposite effects. Overexpression of the p53 mutant or c-Myc alleviated the effects of UBA2 knockdown on ccRCC cell proliferation and apoptosis. In conclusion, targeting UBA2 may have a therapeutic potential against ccRCC.

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“…The TP53 pathway was the most significant pathway identified (via both Network and Overlap approaches) and centers on the functional strong anti-inflammatory role of p53 as a tumor suppressor protein. Inflammation involving NFkB activation reduces p53 function and p53 activation is an inflammation-suppressing response to reduce unchecked vascular leakage 36 . In contrast, HDAC pathway 18 and TGF-β activation may increase endothelial permeability and play important role in lung fluid balance in ARDS 37 , 38 .…”

Section: Discussionmentioning

confidence: 99%

Identification of early and intermediate biomarkers for ARDS mortality by multi-omic approaches

Liao

Casanova

Bime

et al. 2021

Sci Rep

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The lack of successful clinical trials in acute respiratory distress syndrome (ARDS) has highlighted the unmet need for biomarkers predicting ARDS mortality and for novel therapeutics to reduce ARDS mortality. We utilized a systems biology multi-“omics” approach to identify predictive biomarkers for ARDS mortality. Integrating analyses were designed to differentiate ARDS non-survivors and survivors (568 subjects, 27% overall 28-day mortality) using datasets derived from multiple ‘omics’ studies in a multi-institution ARDS cohort (54% European descent, 40% African descent). ‘Omics’ data was available for each subject and included genome-wide association studies (GWAS, n = 297), RNA sequencing (n = 93), DNA methylation data (n = 61), and selective proteomic network analysis (n = 240). Integration of available “omic” data identified a 9-gene set (TNPO1, NUP214, HDAC1, HNRNPA1, GATAD2A, FOSB, DDX17, PHF20, CREBBP) that differentiated ARDS survivors/non-survivors, results that were validated utilizing a longitudinal transcription dataset. Pathway analysis identified TP53-, HDAC1-, TGF-β-, and IL-6-signaling pathways to be associated with ARDS mortality. Predictive biomarker discovery identified transcription levels of the 9-gene set (AUC-0.83) and Day 7 angiopoietin 2 protein levels as potential candidate predictors of ARDS mortality (AUC-0.70). These results underscore the value of utilizing integrated “multi-omics” approaches in underpowered datasets from racially diverse ARDS subjects.

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P53 in acute respiratory distress syndrome

Cited by 16 publications

References 30 publications

Hsp90 inhibition protects brain endothelial cells against LPS‐induced injury

Hsp90 inhibition protects brain endothelial cells against LPS‐induced injury

Knockdown of ubiquitin-like modifier-activating enzyme 2 promotes apoptosis of clear cell renal cell carcinoma cells

Identification of early and intermediate biomarkers for ARDS mortality by multi-omic approaches

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