Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression

Helenius, Iiro Taneli; Nair, Aisha; Bittar, Humberto E. Trejo; Sznajder, Jacob I.; Sporn, Peter H. S.; Beitel, Greg J.

doi:10.1177/1087057115624091

Cited by 4 publications

(2 citation statements)

References 30 publications

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“…Evoxine, however, did not inhibit all CO 2 ‐dependent responses, and thus the findings from this study suggest the potential existence of multiple CO 2 response pathways (Helenius et al . b ).…”

Section: Hypoxia‐responsive Transcriptional Regulationmentioning

confidence: 99%

Respiratory gases and the regulation of transcription

Cummins

Keogh

2016

Experimental Physiology

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Eoin obtained a bachelor's degree in Pharmacology (2002) and a PhD (2007) from University College Dublin (UCD). During his postdoctoral career, Eoin became interested in the potential role for carbon dioxide as a modulator of inflammatory and immune signalling, in particular in relation to nuclear factor-κB signalling. The first paper on this work was published in the Journal of Immunology in 2010. In 2013, Eoin obtained his first faculty position as a Lecturer/Assistant Professor in Physiology in the School of Medicine UCD, and he currently leads a research group focused on the effects of hypercapnia on inflammation and immunity. New Findings r What is the topic of this review? This review highlights the transcriptional consequences for decreased cellular O 2 levels (hypoxia) and increased cellular CO 2 levels (hypercapnia). r What advances does it highlight?We discuss recent advances in our understanding of the cellular response to hypoxia and consider the potential cross-talk between O 2 -and CO 2 -dependent transcriptional regulation.Oxygen and carbon dioxide are the substrate and product of aerobic metabolism, respectively. Thus, the levels of these physiological gases are inextricably linked in physiological and pathophysiological conditions. Increased mitochondrial consumption of O 2 (to produce ATP) will produce more CO 2 . Furthermore, in lung pathologies such as chronic obstructive pulmonary disease, sleep apnoea and central hypoventilation syndrome, hypoxia and hypercapnia are co-incident. Acute responses to hypoxia involve carotid body-mediated changes in the rate and depth of breathing. Chronic adaptation to hypoxia involves a multitude of changes on a transcriptional level, which simultaneously increases oxygen utilization (via hypoxia-inducible factor and others), while suppressing superfluous energy-demanding processes. Acute responses to CO 2 affect breathing primarily via central chemoreceptors. The nature of hypercapnia-dependent transcriptional regulation is an emerging area of research, but at present the mechanisms underpinning this response are not fully characterized and understood. Thus, given the juxtaposition of hypoxia and hypercapnia in health and disease, this manuscript reviews the current evidence for transcriptional responses to hypoxia and hypercapnia. Finally, we discuss the potential cross-talk between hypoxia and hypercapnia on a transcriptional level.

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Section: Hypoxia‐responsive Transcriptional Regulationmentioning

confidence: 99%

Respiratory gases and the regulation of transcription

Cummins

Keogh

2016

Experimental Physiology

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“…The finding that the plant alkaloid evoxine counteracts specific effects of hypercapnia in Drosophila and mammalian immune cells was also indicative of the evolutionary conservation of CO 2 response pathways regulating immune genes, such as the pathways controlling Na-K-ATPase endocytosis (25). Na-K-ATPase belongs to the P-type-ATPases.…”

Section: Discussionmentioning

confidence: 99%

Prediction and enrichment analyses of the Homo sapiens-Drosophila melanogaster COPD-related orthologs: potential for modeling of human COPD genomic responses with the fruit fly

Rouka

Gourgoulianni

Lüpold

et al. 2022

American Journal of Physiology-Regulatory, Integrative and Comp

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The significant similarities in airway epithelial cells between mammals and the fruit fly Drosophila melanogaster have rendered the latter an important model organism for studies of chronic inflammatory lung diseases. Focusing on the chronic obstructive pulmonary disease (COPD), we here mapped human gene orthologs associated with this disease in D. melanogaster to identify functionally equivalent genes for immediate, further screening with the fruit fly model. The DIOPT-DIST tool was accessed for the prediction of the COPD-associated orthologs between humans and Drosophila. Enrichment analyses with respect to pathways of the retrieved functional homologs were performed using the ToppFun and FlyMine tools, identifying 73 unique human genes as well as 438 fruit fly genes. The ToppFun analysis verified that the human gene list is associated with COPD phenotypes. Further, the FlyMine investigation highlighted that the Drosophila genes are functionally connected mainly with the 'ABC-family proteins mediated transport' and the 'beta-catenin independent WNT signaling pathway'. These results suggest an evolutionarily conserved role towards responses to inhaled toxicants and CO2 in both species. We reason that the predicted orthologous genes should be further studied in the Drosophila models of cigarette smoke-induced COPD.

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