ArticlePloS one2014
The "genomic storm" induced by bacterial endotoxin is calmed by a nuclear transport modifier that attenuates localized and systemic inflammation.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 21 citations in OpenAlex.
- The peptide genomic therapy increases antibacterial immunity and survival in sepsis by reprograming the gene orthologs of human immunodeficiencies in the spleen and lungs.Frontiers in immunology · 2025Article
- Beyond Transduction: Anti-Inflammatory Effects of Cell Penetrating Peptides.Molecules (Basel, Switzerland) · 2024Review
- Anti-inflammatory control of human skin keratinocytes by targeting nuclear transport checkpoint.Skin health and disease · 2024Article
- Advances and transgressions of nuclear transport checkpoint inhibitors.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Activation of thousands of genes in the lungs and kidneys by sepsis is countered by the selective nuclear blockade.Frontiers in immunology · 2023Article
- Genomic control of inflammation in experimental atopic dermatitis.Scientific reports · 2022Article
- Challenging molecular dogmas in human sepsis using mathematical reasoning.EBioMedicine · 2022Review
- Adjunctive granisetron therapy in patients with sepsis or septic shock (GRANTISS): A single-center, single-blinded, randomized, controlled clinical trial.Frontiers in pharmacology · 2022Article
- Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors.Journal of clinical medicine · 2021Article
- Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles.Scientific reports · 2021Article
- COVID-19 and Hypertension: The What, the Why, and the How.Frontiers in physiology · 2021Review
- COVID-19 Sepsis and Microcirculation Dysfunction.Frontiers in physiology · 2020Review
- Decoding inflammation, its causes, genomic responses, and emerging countermeasures.Scandinavian journal of immunology · 2019Review
- Protection from Endotoxin Shock by Selective Targeting of Proinflammatory Signaling to the Nucleus Mediated by Importin Alpha 5.ImmunoHorizons · 2019Article
- Chronic Critical Illness and the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome.Frontiers in immunology · 2018Review
- Survival, bacterial clearance and thrombocytopenia are improved in polymicrobial sepsis by targeting nuclear transport shuttles.PloS one · 2017Article
- Analysis of differentially expressed proteins in Yersinia enterocolitica-infected HeLa cells.Biochimica et biophysica acta · 2016Article
- New paradigms in sepsis: from prevention to protection of failing microcirculation.Journal of thrombosis and haemostasis : JTH · 2015Review
- Innate immunity gene expression changes in critically ill patients with sepsis and disease-related malnutrition.Central-European journal of immunology · 2015Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Lipopolysaccharide (LPS) is a potent microbial virulence factor that can trigger production of proinflammatory mediators involved in the pathogenesis of localized and systemic inflammation. Importantly, the role of nuclear transport of stress responsive transcription factors in this LPS-generated "genomic storm" remains largely undefined. We developed a new nuclear transport modifier (NTM) peptide, cell-penetrating cSN50.1, which targets nuclear transport shuttles importin α5 and importin β1, to analyze its effect in LPS-induced localized (acute lung injury) and systemic (lethal endotoxic shock) murine inflammation models. We analyzed a human genome database to match 46 genes that encode cytokines, chemokines and their receptors with transcription factors whose nuclear transport is known to be modulated by NTM. We then tested the effect of cSN50.1 peptide on proinflammatory gene expression in murine bone marrow-derived macrophages stimulated with LPS. This NTM suppressed a proinflammatory transcriptome of 37 out of 84 genes analyzed, without altering expression of housekeeping genes or being cytotoxic. Consistent with gene expression analysis in primary macrophages, plasma levels of 23 out of 26 LPS-induced proinflammatory cytokines, chemokines, and growth factors were significantly attenuated in a murine model of LPS-induced systemic inflammation (lethal endotoxic shock) while the anti-inflammatory cytokine, interleukin 10, was enhanced. This anti-inflammatory reprogramming of the endotoxin-induced genomic response was accompanied by complete protection against lethal endotoxic shock with prophylactic NTM treatment, and 75% protection when NTM was first administered after LPS exposure. In a murine model of localized lung inflammation caused by direct airway exposure to LPS, expression of cytokines and chemokines in the bronchoalveolar space was suppressed with a concomitant reduction of neutrophil trafficking. Thus, calming the LPS-triggered "genomic storm" by modulating nuclear transport with cSN50.1 peptide attenuates the systemic inflammatory response associated with lethal shock as well as localized lung inflammation.
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