Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 19, 2025

Abstract Nucleic acids from both self- and non-self-sources act as vital danger signals that trigger immune responses. Critical illnesses such acute respiratory distress syndrome, sepsis, trauma ischemia lead to the aberrant cytosolic accumulation massive release of nucleic are detected by antiviral innate receptors in endosome or cytosol. Activation for deoxyribonucleic ribonucleic triggers inflammation, a major contributor morbidity mortality critically ill patients. In past decade, there has been growing recognition therapeutic potential targeting acid sensing critical care. This review summarizes current knowledge ischemia. Given extensive research on common pathological conditions like cancer, autoimmune disorders, metabolic disorders aging, we provide comprehensive summary beyond illness offer insights may inform its role conditions. Additionally, discuss strategies specifically target sensing. By examining sources, sensor activation function, well impact regulating these pathways across various diseases, highlight driving illness.

Language: Английский

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Identifying potential drug targets for sepsis-related adult respiratory distress syndrome through comprehensive genetic analysis and druggability assessment

Journal of Global Health, Journal Year: 2025, Volume and Issue: 15

Published: March 21, 2025

Abstract Background Sepsis-related adult respiratory distress syndrome (ARDS) is a life-threatening condition characterised by high mortality rate. This underscores the pressing requirement to identify and develop potential therapeutic targets for severe condition. study investigated genetic predisposition sepsis-related ARDS in this study. Methods We utilised summary-based Mendelian randomisation (SMR), two-sample MR (TSMR), mediating MR, multivariate (MVMR) analysis explore susceptibility of integrating over 10 000 cis-expression quantitative trait loci (cis-eQTLs) 100 participants. Subsequently, we performed drug target potentially druggable cis-eQTL genes. Results The SMR identified 677 genes associated with sepsis. Further TSMR validation filtered 72 causally Sepsis was (beta = 1.80, standard error (SE) 0.36, P < 0.001). After conducting MVMR analysis, 50 were reported be ARDS. Subsequent confirmed role four (PSMA4, PDK2, RPS18, NDUFV3) as Conclusions Through an extensive Additional research imperative substantiate our discoveries pave way development novel pharmaceuticals aimed at these specific targets.

Language: Английский

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Molecular basis of sepsis: A New insight into the role of mitochondrial DNA as a damage-associated molecular pattern

Mitochondrion, Journal Year: 2024, Volume and Issue: unknown, P. 101967 - 101967

Published: Sept. 1, 2024

Language: Английский

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The effect of therapeutic plasma exchange on the inflammatory response in septic shock: a secondary analysis of the EXCHANGE-1 trial

Intensive Care Medicine Experimental, Journal Year: 2025, Volume and Issue: 13(1)

Published: Feb. 14, 2025

Abstract Background Sepsis and septic shock, defined by a profound immune dysregulation, are among the leading causes of death in intensive care unit (ICU). Despite advances understanding underlying pathophysiology, evidence for specific immunomodulatory treatment does not exist to date. Therapeutic plasma exchange (TPE) represents an adjunctive approach rebalance homeostasis. In EXCHANGE-1 trial, we recently demonstrated rapid hemodynamic improvement, possibly caused removal harmful mediators replacement protective proteins. The aim this secondary analysis is further characterize effects identify biomarkers that may predict response. Methods This included patients early shock (< 24 h duration) norepinephrine (NE) dose ≥ 0.4 μg/kg/min. Patients were randomized 1:1 receive standard (SOC) or SOC + one single TPE samples collected before after TPE. Within-group between group circulating levels acute-phase proteins [CRP Pentraxin3 (PTX3)], inflammatory (IL-4, IL-6, IL-8, IL-10, TNF-α, IL-2Rα/CD25) damage-associated molecular pattern (DAMP) [cell-free DNA (cfDNA)] analyzed via paired t test Wilcoxon signed-rank mixed-effects model. Multivariate mixed‐effects modeling NE lactate reduction was performed investigate if cfDNA could be associated with response Results led significant protein (CRP p = 0.00976, PTX3 0.0001). Pro-inflammatory cytokines, such as TNF-α-, IL-6- und IL-8-levels, significantly reduced both groups no difference except IL-2Rα/CD25 ( ≤ multivariate model, rising over first 6 indicated refractoriness regarding 0.004) 0.001), whereas those receiving sustained reductions parameters. Conclusions trial IL-2Rα/CD25, however pro-inflammatory cytokines. phenomenon contribute observed enhancement hemodynamics shock. Furthermore, particularly beneficial who exhibit cfDNA.

Language: Английский

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Associations between prenatal distress, mitochondrial health, and gestational age: findings from two pregnancy studies in the USA and Turkey

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 16, 2024

Pregnancy outcomes are influenced by maternal distress but the pathways underlying these effects still unknown. Mitochondria, crucial for stress adaptation and energy production, may link psychosocial to its biological effects, especially during pregnancy when demands significantly increase. This study explores two mitochondrial markers-circulating cell-free DNA (cf-mtDNA) Growth Differentiation Factor-15 (GDF15)-as potential health indicators linking in longitudinal studies from USA Turkey.

Language: Английский

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