Decitabine Reactivation of FoxM1-Dependent Endothelial Regeneration and Vascular Repair for Potential Treatment of Elderly ARDS and COVID-19 Patients

Mutlu, Gökhan M.; Fang, Yun; Wu, David

doi:10.1101/2021.04.29.442061

Cited by 4 publications

(4 citation statements)

References 51 publications

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“…We also demonstrated GCN2 activation in MCT-induced rat PAH model and in IPAH patients. Employing endothelium-targeted nanoparticles to deliver the CRISPR/Cas9 system 35,50 to knockout Gcn2 selectively in ECs, we also observed attenuated PH in these ECspecific knockout mice, demonstrating the important role of hypoxia-activated GCN2 in ECs in mediating pulmonary vascular remodeling and pulmonary hypertension development. Since we also observed GCN2 hyperphosphorylation in pulmonary vascular SMCs and interstitial tissues in MCT rats and IPAH patients, it is possible that GCN2 can also be activated by other PAHcausing factors such as growth factors or inflammatory mediators 51 EDN1, an EC-derived factor, plays an important role in the pathogenesis of PAH in increasing vasoconstriction and cell proliferation.…”

Section: Discussionmentioning

confidence: 71%

The Unexpected Role of GCN2 Kinase Activation in Mediating Pulmonary Arterial Hypertension

Zhu,

Dai,

Dai

et al. 2023

Preprint

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Background: Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart hypertrophy and failure. Published studies show that recessive mutations of EIF2AK4 gene (encoding GCN2, General control nonderepressibe 2 kinase) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients and EIF2AK4 mutations were also found in PAH patients although very rare. However, the role of GCN2 kinase in the pathogenesis of PAH remains unclear. Methods: Eif2ak4-/- mice with genetic disruption of the kinase domain and GCN2 kinase inhibitor A-92 were employed in animal models of PH including chronic hypoxia-exposed mice and monocrotaline-challenged rats. Human lung endothelial cells (HLMVECs) were used for mechanistic studies. Endothelium-targeted nanoparticles were employed to deliver plasmid DNA to adult mice to knockout Eif2ak4 or overexpress Endothelin-1 (Edn1) selectively in ECs. Results: Here we show that loss of GCN2 induced neither spontaneous PVOD nor PH in Eif2ak4-/- mice but inhibited hypoxia-induced PH evident by reduced right ventricular systolic pressure, right ventricle hypertrophy and pulmonary vascular remodeling. RNA sequencing analysis suggested Edn1 as the downstream target of GCN2. In cultured HLMVECs, GCN2 was phosphorylated and activated in response to hypoxia, mediating hypoxia-induced Edn1 expression via HIF-2?. Restored Edn1 expression in ECs in Gcn2-deficient mice reversed the reduced phenotype of hypoxia-induced PH. Furthermore, loss of endothelial Eif2ak4 in mice attenuated hypoxia-induced PH. Monocrotaline-induced PH and pulmonary vascular remodeling in rats were inhibited by GCN2 inhibitor A-92 treatment. The clinical relevance of the observation was validated by GCN2 hyperphosphorylation indicative of activation in ECs of pulmonary vascular lesions of PAH patients. Conclusion: These studies demonstrate that GCN2 activation by hypoxia mediates pulmonary vascular remodeling and PAH through Edn1. Thus, targeting GCN2 signaling is a promising therapeutic strategy for treatment of PAH in patients without EIF2AK4 loss of function mutations.

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Section: Discussionmentioning

confidence: 71%

The Unexpected Role of GCN2 Kinase Activation in Mediating Pulmonary Arterial Hypertension

Zhu,

Dai,

Dai

et al. 2023

Preprint

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“…It is highly expressed in the PBMCs of COVID-19 patients [ 45 ]. Studies have shown that the expression of CCNB1 markedly increases during the recovery period of patients, which is related to the endothelial regeneration and vascular repair during the recovery process of ARDS; therefore, CCNB1 may have different expression levels in patients with different states of ARDS [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Transcriptome Biomarkers for Severe COVID-19 with Machine Learning Methods

Zhou

Ding

et al. 2022

Biomolecules

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The rapid spread of COVID-19 has become a major concern for people’s lives and health all around the world. COVID-19 patients in various phases and severity require individualized treatment given that different patients may develop different symptoms. We employed machine learning methods to discover biomarkers that may accurately classify COVID-19 in various disease states and severities in this study. The blood gene expression profiles from 50 COVID-19 patients without intensive care, 50 COVID-19 patients with intensive care, 10 non-COVID-19 individuals without intensive care, and 16 non-COVID-19 individuals with intensive care were analyzed. Boruta was first used to remove irrelevant gene features in the expression profiles, and then, the minimum redundancy maximum relevance was applied to sort the remaining features. The generated feature-ranked list was fed into the incremental feature selection method to discover the essential genes and build powerful classifiers. The molecular mechanism of some biomarker genes was addressed using recent studies, and biological functions enriched by essential genes were examined. Our findings imply that genes including UBE2C, PCLAF, CDK1, CCNB1, MND1, APOBEC3G, TRAF3IP3, CD48, and GZMA play key roles in defining the different states and severity of COVID-19. Thus, a new point of reference is provided for understanding the disease’s etiology and facilitating a precise therapy.

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“…In COVID-19 studies, CMPK2 was highly upregulated in severe cases related to ARDS [202,203]. Moreover, FOXM1-dependent tissue regeneration is impaired in severe COVID-19 cases, causing sustained lung injury and a high fatality rate [204]. RRM2, a cell cycle regulator, had an increased expression in lung adenocarcinoma with a poor prognosis [205].…”

Section: Important Immune-related Proteins With the Ranking Scoresmentioning

confidence: 99%

“…Decitabine is a pyrimidine nucleoside antimetabolite used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [222,223]. A study in the mice model showed that decitabine improved FOXM1-dependent endothelial regeneration and vascular repair [204]. As mentioned above, lung tissue degeneration can cause worsening lung injury.…”

Section: Potential Drugs To Cure Severe Covid-19 Patientsmentioning

confidence: 99%

Analysis of protein-protein interaction network from leukocyte transcriptomic profiles in severe COVID -19 patients

Sagulkoo

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Coronavirus disease 2019 (COVID-19) still provides global public health issues although several vaccines and antiviral agents have been developed. Some patients experience severe conditions needed medical intensive care, and some are dead due to the failure of treatments. Therefore, identifying the key genes and underlying molecular mechanisms is necessary to discover precisely targeted drugs. Analysis of protein-protein interaction (PPI) networks provides invaluable information to find disease mechanisms and effective alternative drugs. Hence, PPI network analysis based on leukocyte transcriptomic profiles of severe COVID-19 collected from Gene Expression Omnibus (GEO) DataSets was proposed for this study. A network diffusion method called Laplacian heat diffusion (LHD) algorithm was performed to construct an immune-related PPI network (IPIN). Furthermore, several network centrality measurements can identify 23 key genes from the IPIN. Subsequently, drug-gene interaction networks were constructed using database searching based on the key genes. There were 5 candidate drugs having the potential effect of interacting with the key genes. To find additional key genes and candidate drugs, two different leukocyte transcriptomic datasets were combined for the common PPI network construction. Centrality measurement and survival analysis were used to find and validate the further key genes. The analysis revealed 4 common key genes. The drug-gene interaction and molecular docking technique provided 2 further candidate drugs that interacted with the key genes. Additionally, miRNA-mRNA regulatory networks were built based on the PPI network to recognize 5 novel biomarkers for severe COVID-19 prediction. In conclusion, PPI network analysis can discover candidate biomarkers and drugs to predict�and treat severe COVID-19 patients.�

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Decitabine Reactivation of FoxM1-Dependent Endothelial Regeneration and Vascular Repair for Potential Treatment of Elderly ARDS and COVID-19 Patients

Cited by 4 publications

References 51 publications

The Unexpected Role of GCN2 Kinase Activation in Mediating Pulmonary Arterial Hypertension

The Unexpected Role of GCN2 Kinase Activation in Mediating Pulmonary Arterial Hypertension

Identification of Transcriptome Biomarkers for Severe COVID-19 with Machine Learning Methods

Analysis of protein-protein interaction network from leukocyte transcriptomic profiles in severe COVID -19 patients

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