Activation of Thousands of Genes in the Lungs and Kidneys by Sepsis is Countered by the Selective Nuclear Blockade
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA999188 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25436700_1.fastq.gz | Fastqsanger.gz | |||
| SRR25436700_2.fastq.gz | Fastqsanger.gz | |||
| SRR25436701_1.fastq.gz | Fastqsanger.gz | |||
| SRR25436701_2.fastq.gz | Fastqsanger.gz | |||
| SRR25436702_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 144 |
Similar Datasets
Project description:The steady rise of sepsis globally has reached almost 49 million cases in 2017, and 11 million sepsis-related deaths. The genomic response to sepsis comprising multi-system stage of raging microbial inflammation has been reported in the whole blood, while effective treatment is lacking besides anti-microbial therapy and supportive measures. Here we show that, astoundingly, 6,237 significantly expressed genes in sepsis are increased or decreased in the lungs, the site of acute respiratory distress syndrome (ARDS). Moreover, 5,483 significantly expressed genes in sepsis are increased or decreased in the kidneys, the site of acute injury (AKI). This massive genomic response to polymicrobial sepsis is countered by the selective nuclear blockade with the cell-penetrating Nuclear Transport Checkpoint Inhibitor (NTCI). It controlled 3,735 sepsis-induced genes in the lungs and 1,951 sepsis-induced genes in the kidneys. The NTCI also reduced without antimicrobial therapy the bacterial dissemination: 18-fold in the blood, 11-fold in the lungs, and 9-fold in the spleen. This enhancement of bacterial clearance was not significant in the kidneys. Cumulatively, identification of the sepsis-responsive host’s genes and their control by the selective nuclear blockade advances a better understanding of the multi-system mechanism of sepsis. Moreover, it spurs much-needed new diagnostic, therapeutic, and preventive approaches.
2023-08-14 | GSE239388 | GEO
Project description:The steady rise of sepsis globally has reached almost 49 million cases in 2017, and 11 million sepsis-related deaths. The genomic response to sepsis comprising multi-system stage of raging microbial inflammation has been reported in the whole blood, while effective treatment is lacking besides anti-microbial therapy and supportive measures. Here we show that, astoundingly, 6,237 significantly expressed genes in sepsis are increased or decreased in the lungs, the site of acute respiratory distress syndrome (ARDS). Moreover, 5,483 significantly expressed genes in sepsis are increased or decreased in the kidneys, the site of acute injury (AKI). This massive genomic response to polymicrobial sepsis is countered by the selective nuclear blockade with the cell-penetrating Nuclear Transport Checkpoint Inhibitor (NTCI). It controlled 3,735 sepsis-induced genes in the lungs and 1,951 sepsis-induced genes in the kidneys. The NTCI also reduced without antimicrobial therapy the bacterial dissemination: 18-fold in the blood, 11-fold in the lungs, and 9-fold in the spleen. This enhancement of bacterial clearance was not significant in the kidneys. Cumulatively, identification of the sepsis-responsive host's genes and their control by the selective nuclear blockade advances a better understanding of the multi-system mechanism of sepsis. Moreover, it spurs much-needed new diagnostic, therapeutic, and preventive approaches.
| S-EPMC10450963 | biostudies-literature
Project description:Expression data from Total RNA extracted from murine spleen, liver, lungs, kidneys and hearts. Sepsis was induced in C57Bl/6J mice by cecal ligation and puncture (CLP), followed 6 hours later by an intravenous injection of Mesenchymal Stem Cell (MSC) or saline. Twenty-eight hours after CLP, plasma, bronchoalveolar lavage (BAL) fluid and tissues were collected for analyses. Total RNA was extracted using Trizol (as per manufactures' instruction) followed by clean-up procedure using Qiagen RNA easy Prep (as per manufactures instructions) In the following study we hypothesized that mesenchymal stem cells (MSCs), which have documented immunomodulatory properties, would reduce sepsis-associated inflammation and organ injury in a clinically relevant model of sepsis. To identify the molecular changes associated with decreased inflammation in CLP-injured mice treated with MSCs, we analyzed the gene expression profiles from spleens, liver, lungs, kidneys and heart collected at 28 hours from 4 animals per group: sham/saline, CLP/saline, and CLP/MSCs.
2012-12-31 | E-GEOD-40180 | biostudies-arrayexpress
Project description:Expression data from Total RNA extracted from murine spleen, liver, lungs, kidneys and hearts. Sepsis was induced in C57Bl/6J mice by cecal ligation and puncture (CLP), followed 6 hours later by an intravenous injection of Mesenchymal Stem Cell (MSC) or saline. Twenty-eight hours after CLP, plasma, bronchoalveolar lavage (BAL) fluid and tissues were collected for analyses. Total RNA was extracted using Trizol (as per manufactures' instruction) followed by clean-up procedure using Qiagen RNA easy Prep (as per manufactures instructions) In the following study we hypothesized that mesenchymal stem cells (MSCs), which have documented immunomodulatory properties, would reduce sepsis-associated inflammation and organ injury in a clinically relevant model of sepsis.
2012-12-31 | GSE40180 | GEO
Project description:Background: COVID-19 and sepsis represent formidable public health challenges, characterized by incompletely elucidated molecular mechanisms. Elucidating the interplay between COVID-19 and sepsis, particularly in geriatric patients suffering from sepsis-induced acute respiratory distress syndrome (ARDS), is of paramount importance for identifying potential therapeutic interventions to mitigate hospitalization and mortality risks.We employed bioinformatics and systems biology approaches to identify hub genes, shared pathways, molecular biomarkers, and candidate therapeutics for managing COVID-19, sepsis, and sepsis-induced ARDS. We corroborated these hub genes utilizing murine sepsis-ARDS models and blood samples derived from geriatric patients afflicted by sepsis-induced ARDS.Results: Our investigation revealed 189 differentially expressed genes (DEGs) shared among COVID-19 and sepsis datasets. We constructed a protein-protein interaction network, unearthing pivotal hub genes and modules. Notably, nine hub genes displayed significant alterations and correlations with critical inflammatory mediators of pulmonary injury in murine septic lungs. Simultaneously, 12 displayed significant changes and correlations with a neutrophil-recruiting chemokine in geriatric patients with sepsis-induced ARDS. Of these, six hub genes (CD247, CD2, CD40LG, KLRB1, LCN2, RETN) showed significant alterations across COVID-19, sepsis, and geriatric sepsis-induced ARDS. Our single-cell RNA sequencing analysis of hub genes across 3 diverse immune cell types furnished insights into disease pathogenesis. Functional analysis underscored the interconnection between sepsis/sepsis-ARDS and COVID-19, enabling us to pinpoint potential therapeutic targets, transcription factor-gene interactions, DEG-microRNA co-regulatory networks, and prospective drug and chemical compound interactions involving hub genes.Our investigation offers potential therapeutic targets/biomarkers, sheds light on the immune response in geriatric patients with sepsis-induced ARDS, emphasizes the association between sepsis/sepsis-ARDS and COVID-19, and proposes novel avenues for targeted therapies.
2023-09-01 | GSE242127 | GEO
Project description:Background: Septic shock is a life-threatening clinical condition characterized by a robust immune inflammatory response to disseminated infection. Little is known about its impact on the transcriptome of distinct human organs. Objective and Methods: To address this, we performed RNA sequencing of samples from the prefrontal cortex, hippocampus, heart, lung, kidney and colon of seven individuals who succumbed to sepsis and seven uninfected controls. Main Results: We identified that the lungs and colon were the most affected organs. While gene activation dominated, strong inhibitory signals were also detected, particularly in the lungs. Principal Conclusions: We found that septic shock is an extremely heterogeneous disease, not only when different individuals are investigated, but also when comparing different tissues of the same patient. However, several pathways, such as respiratory electron transport and other metabolic functions, revealed distinctive alterations, providing evidence that tissue specificity is a hallmark of sepsis. Strikingly, we found evident signals of accelerated ageing in our sepsis population.
2023-09-21 | GSE237861 | GEO
Project description:Rationale: Sepsis is a leading cause of morbidity and mortality; early diagnosis and prediction of progression is difficult to determine. The integration of metabolomic and transcriptomic data in an experimental model of sepsis may be a novel method to identify molecular signatures of clinical sepsis. Objectives: Develop a biomarker panel for earlier diagnosis and prognostic characterization of sepsis patients to inform personalized clinical management and improve understanding of the pathophysiology of sepsis progression. Methods: Mild to severe sepsis, lung injury and death was recapitulated in Macaca fascicularis by intravenous inoculation of Escherichia coli. Plasma samples were obtained at time of challenge and at one, three, and five days later or time of euthanasia. Necropsy was performed and blood, lung, kidney and spleen samples were obtained. An integrative analysis of comprehensive metabolomic and transcriptomic datasets was performed to identify and parameterize a biomarker panel. Measurements and Main Results: Pathogen invasion, respiratory distress, lethargy and mortality was dose dependent. Severe infection and death were associated with metabolomic and transcriptomic changes indicative of mitochondrial, peroxisomal and liver dysfunction. Analysis of reciprocal pulmonary transcriptome and plasma metabolome data revealed an integrated host response that suggested dysregulated fatty acid catabolism resulting from peroxisome-proliferator activated receptor signaling. A representative 4-metabolite model effectively diagnosed sepsis in primates (AUC 0.966) and in two human sepsis cohorts (AUC=0.78 and 0.82). Conclusion: A model to guide early management of patients with sepsis was developed by analysis of reciprocal metabolomic and transcriptomic data in primates that diagnosed sepsis in humans. Transcriptomic analysis of lungs from Cynomolgus macaques challenged with E. coli
2015-07-03 | E-GEOD-59075 | biostudies-arrayexpress
Project description:The temporal evolution of sepsis was monitored by transcriptional profiling of five critically ill children with meningococcal sepsis and sepsis-induced multiple organ failure. Blood was sampled at 6 time points during the first 48 hours of their admission to pediatric intensive care, where the children received standard clinical treatment including organ support and antimicrobial therapy. Striking transcript instability was observed over the 48 hours, with increasing numbers of regulated genes over time. Most notably, proposed biomarkers for sepsis risk stratification also showed expression instability, with varied expression levels over 48 hours. This study demonstrates the extent of the complexity of temporal changes in gene expression that occur during the evolution of sepsis-induced multiple organ failure. Importantly, stratification tools that propose expression of biomarkers must take into account the temporal changes, over the use of single snapshots that may be less informative.
2013-04-03 | E-MEXP-3850 | biostudies-arrayexpress
Project description:The peripheral whole-blood transcriptome analysis has been used to the identification of biomarkers in different clinical syndromes. The ability to simultaneously measure the gene expression levels of the whole transcriptome is providing a broader view of clinical syndromes such as sepsis. The aim of this study was to assess the gene expression profiles of post-surgical patients with septic shock compared with patients without sepsis.
2014-03-15 | E-MTAB-1548 | biostudies-arrayexpress
Project description:Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events are unclear. This has resulted in ineffective development of sepsis-specific biomarkers and therapies, and suboptimal treatment regimens in preventing and reversing organ damage. Here, we used pharmacoproteomics to score treatment effects in a preclinical Escherichia coli sepsis model based on changes in the organ, cell, and plasma proteome landscapes. A combination of pathophysiological read-outs and time-resolved proteome maps of organs and blood enabled the definition of time-dependent and organotypic proteotypes of dysfunction and damage that was used to guide the administration of several combinations of beta-lactam antibiotic meropenem and immunomodulatory glucocorticoid methylprednisolone. The proteome-based scoring strategy revealed three distinct response patterns defined as intervention-specific reversions, non-reversions, and specific intervention-induced effects, revealing that the intervention effects depended on the underlying proteotype and varied significantly between organs. In the later stages of the disease, administration of glucocorticoids accentuated some of the positive effects exerted by Mem leading to superior reduction of the inflammatory response in the kidneys and partial restoration of the metabolic dysfunction instigated by sepsis. Unexpectedly, antibiotics introduced sepsis-independent perturbations in the mitochondrial proteome that was to some degree counteracted by glucocorticoids. In summary, this study provides a pharmacoproteomic resource describing the time-resolved septic organ failure landscape across organs and the blood compartment, and a novel scoring strategy that captures unintended secondary drug effects as an important criterion to consider while assessing therapeutic efficacy. Such information is critically important to enable a quantitative, objective and organotypic assessment of treatment benefits and unintended effects, drug synergies of candidate treatments as well as the effect of dose and time in murine sepsis models.
2023-05-10 | PXD036832 | Pride