The pathophysiology of sepsis and precision-medicine-based immunotherapy

Nature Immunology, Journal Year: 2024, Volume and Issue: 25(1), P. 19 - 28

Published: Jan. 1, 2024

Language: Английский

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METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury

Clinical and Translational Medicine, Journal Year: 2023, Volume and Issue: 13(9)

Published: Sept. 1, 2023

Neutrophil extracellular traps (NETs), released by polymorphonuclear neutrophils (PMNs), exert a robust antimicrobial function in infectious diseases such as sepsis. NETs also contribute to the pathogenesis and exacerbation of Although lung is highly vulnerable infections, few studies have explored role sepsis-induced acute injury (SI-ALI). We demonstrate that induce SI-ALI via enhanced ferroptosis alveolar epithelial cells. Our findings reveal excessive release patients mice with accompanied upregulation depending on METTL3-induced m6A modification hypoxia-inducible factor-1α (HIF-1α) subsequent mitochondrial metabolic reprogramming. In addition conducting METTL3 overexpression knockdown experiments vitro, we investigated impact caused caecum ligation puncture (CLP)-induced model using condition knockout (CKO) wild-type mice. results indicate crucial progression NET-activated m6A-IGF2BP2-dependent HIF-1α, which further contributes reprogramming

Language: Английский

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Surviving Sepsis Campaign Research Priorities 2023

Critical Care Medicine, Journal Year: 2024, Volume and Issue: 52(2), P. 268 - 296

Published: Jan. 19, 2024

OBJECTIVES: To identify research priorities in the management, epidemiology, outcome, and pathophysiology of sepsis septic shock. DESIGN: Shortly after publication most recent Surviving Sepsis Campaign Guidelines, Research Committee, a multiprofessional group 16 international experts representing European Society Intensive Care Medicine Critical Medicine, convened virtually iteratively developed article recommendations, which represents an update from 2018 Priorities. METHODS: Each task force member submitted five questions on any sepsis-related subject. Committee members then independently ranked their top three list generated. The highest rated clinical basic science were into current article. RESULTS: A total 81 submitted. After merging similar questions, there 34 ten for voting. as follows: 1) what is best strategy screening identification patients with sepsis, can predictive modeling assist real-time recognition sepsis? 2) causes organ injury dysfunction how should it be defined, detected? 3) fluid resuscitation individualized initially beyond? 4) vasopressor approach treating different phases shock? 5) personalized/precision medicine optimal therapies to improve patient outcomes? How we animal models so that they more closely resemble humans? What outcome variables maximize correlations between human are therefore appropriate use both? does affect brain, do sepsis-induced brain alterations contribute dysfunction? interactions neural, endocrine, immune systems? microbiome pathobiology? genetics epigenetics influence development course response treatments CONCLUSIONS: Knowledge advances multiple domains have been incorporated progressive iterations guidelines, allowing evidence-based recommendations short- long-term management sepsis. However, strength existing evidence modest significant knowledge gaps mortality remains high. identified represent roadmap

Language: Английский

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Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury

Redox Biology, Journal Year: 2024, Volume and Issue: 74, P. 103194 - 103194

Published: May 16, 2024

Elevated lactate levels are a significant biomarker of sepsis and positively associated with sepsis-related mortality. Sepsis-associated lung injury (ALI) is leading cause poor prognosis in clinical patients. However, the underlying mechanisms lactate's involvement sepsis-associated ALI remain unclear. In this study, we demonstrate that regulates N6-methyladenosine (m6A) modification by facilitating p300-mediated H3K18la binding to METTL3 promoter site. The METTL3-mediated m6A enriched ACSL4, its mRNA stability regulated through YTHDC1-dependent pathway. Furthermore, short-term stimulation upregulates which promotes mitochondria-associated ferroptosis. Inhibition knockdown or targeted inhibition effectively suppresses septic hyper-lactate-induced ferroptosis alveolar epithelial cells mitigates mice. Our findings suggest induces via GPR81/H3K18la/METTL3/ACSL4 axis during ALI. These results reveal histone lactylation-driven mechanism inducing modification. Targeting represents promising therapeutic strategy for patients

Language: Английский

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High-throughput sequencing: a breakthrough in molecular diagnosis for precision medicine

Functional & Integrative Genomics, Journal Year: 2025, Volume and Issue: 25(1)

Published: Jan. 22, 2025

Language: Английский

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Deciphering sepsis: transforming diagnosis and treatment through systems immunology

Frontiers in Science, Journal Year: 2025, Volume and Issue: 2

Published: Jan. 30, 2025

Sepsis is an abnormal, life-threatening response to infection that leads (multi-)organ dysfunction and failure. It causes ~20% of deaths worldwide each year, most related severe COVID-19 share various molecular features with sepsis. Current treatment approaches (antimicrobials supportive care) do not address the complexity sepsis or its mechanistic heterogeneity between within patients over time. Systems immunology methods, including multiomics (notably RNA sequencing transcriptomics), machine learning, network biology analysis, have potential transform management paradigm toward precision approaches. Immune dysfunctions evident very early in drive development novel diagnostic gene expression signatures (e.g., cellular reprogramming) could inform therapy. can now be categorized into “endotypes” based on unique immune mechanisms corresponding varying severity mortality rates, raising prospect endotype-specific diagnostics patient-specific immune-directed Longitudinal within-patient analyses also reveal (including epigenetics) differential trajectories time, enabling disease stage-specific therapy during after hospitalization, for post-sepsis long COVID syndromes. Achieving this transformation will require addressing barriers systems research, cost resource-intensiveness, relatively low volume available data, lack suitable animal models; it a change mindset healthcare providers This should prioritized multistakeholder collaborations involving research communities, providers/systems, patients, governments reduce current high burden from mitigate against future pandemics.

Language: Английский

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Leveraging non-enzymatic functions of LSD1 for novel therapeutics

Trends in Pharmacological Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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The potential immunological mechanisms of sepsis

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: July 8, 2024

Sepsis is described as a life-threatening organ dysfunction and heterogeneous syndrome that leading cause of morbidity mortality in intensive care settings. Severe sepsis could incite an uncontrollable surge inflammatory cytokines, the host immune system's immunosuppression respond to counter excessive responses, characterized by accumulated anti-inflammatory impaired function cells, over-proliferation myeloid-derived suppressor cells regulatory T depletion effector different means death, etc. In this review, we delve into underlying pathological mechanisms sepsis, emphasizing both hyperinflammatory phase associated immunosuppression. We offer in-depth exploration critical spanning from individual holistic perspective, further down epigenetic metabolic reprogramming. Furthermore, outline strengths artificial intelligence analyzing extensive datasets pertaining septic patients, showcasing how classifiers trained on various clinical data sources can identify distinct phenotypes thus guide personalized therapy strategies for management sepsis. Additionally, provide comprehensive summary recent, reliable biomarkers immunosuppressive states, facilitating more precise expedited diagnosis

Language: Английский

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Ferritin-mediated neutrophil extracellular traps formation and cytokine storm via macrophage scavenger receptor in sepsis-associated lung injury

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 2, 2024

Abstract Background Sepsis is a severe systemic inflammatory disorder manifested by dysregulated immune response to infection and multi-organ failure. Numerous studies have shown that elevated ferritin levels exist as an essential feature during sepsis are able suggest patients’ prognoses. At the same time, specific mechanism of ferritin-induced injury remains unclear. Methods Hyper-ferritin state inflammation was performed injecting into mouse model demonstrated injection could induce increase neutrophil extracellular trap (NET) formation.Padi4 −/− , Elane Cybb mice were used for NETs formation experiment. Western blot, immunofluorescence, ELISA, flow cytometry examined changes in NETs, inflammation, related signaling pathways. Results Ferritin induces NET peptidylarginine deiminase 4 (PAD4), elastase (NE), reactive oxygen species (ROS)-dependent manner, thereby exacerbating response. Mechanistically, expression macrophage scavenger receptor (MSR), which promotes NETs. Clinically, high patients with correlate NETs-mediated cytokines storm proportional severity sepsis-induced lung injury. Conclusions In conclusion, we hyper-ferritin can MSR-dependent manner. This process relies on PAD4, NE, ROS, further aggravating acute clinic, serum associated worse injury, suggests poor prognosis sepsis. Our study indicated targeting or MSR be potential treatment alleviate damage

Language: Английский

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The histone lactylation of AIM2 influences the suppression of ferroptosis by ACSL4 through STAT5B and promotes the progression of lung cancer

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(1)

Published: Jan. 10, 2025

Lung cancer progression is characterized by intricate epigenetic changes that impact critical metabolic processes and cell death pathways. In this study, we investigate the role of histone lactylation at AIM2 locus its downstream effects on ferroptosis regulation lung progression. We utilized a combination biochemical assays, including chromatin immunoprecipitation (ChIP), quantitative real-time PCR (qRT-PCR), western blotting to assess levels gene expression. To evaluate functional consequences, employed gain- loss-of-function approaches using shikonin treatment siRNA knockdowns in lines. Additionally, assessed these interventions markers viability. Our results reveal increased correlates with enhanced transcriptional activity AIM2, leading reduced through modulation ACSL4 STAT5B. Furthermore, demonstrate shikonin, natural naphthoquinone derivative, effectively downregulates PKM2 expression, thereby inhibiting counteracting These findings highlight importance regulating expression cells. They also suggest targeting particularly use could be promising strategy for developing novel therapies against cancer.

Language: Английский

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