Identification of Potential Sepsis Therapeutic Drugs Using a Zebrafish Rapid Screening Approach DOI Creative Commons
Mark W. Widder,

Chance Carbaugh,

William van der Schalie

et al.

Life, Journal Year: 2024, Volume and Issue: 14(12), P. 1689 - 1689

Published: Dec. 20, 2024

In the military, combat wound infections can progress rapidly to life-threatening sepsis. The discovery of effective small-molecule drugs prevent and/or treat sepsis is a priority. To identify potential drug candidates, we used an optimized larval zebrafish model endotoxicity/sepsis screen commercial libraries approved by U.S. Food and Drug Administration (FDA) other active pharmaceutical ingredients (APIs) known affect pathways implicated in initiation progression humans (i.e., inflammation, mitochondrial dysfunction, coagulation, apoptosis). We induced endotoxicity 3- 5-day post fertilization (characterized mortality tail fin edema (vascular leakage)) immersion exposure 60 µg/mL Pseudomonas aeruginosa lipopolysaccharide (LPS) for 24 h, then screened rescue 644 selected at 10 µM through simultaneous LPS. After LPS exposure, neurobehavioral assay (light-dark test) further evaluate from determine possible off-target side effects. identified 29 with > 60% mortality. Three (Ketanserin, Tegaserod, Brexpiprazole) produced 100% did not differ controls light-dark test, suggesting lack Further testing these three nearly lethal concentration Klebsiella pneumoniae (45 µg/mL) showed 88–100% mitigation against edema. success warrants evaluation mammalian models.

Language: Английский

Harnessing artificial intelligence in sepsis care: advances in early detection, personalized treatment, and real-time monitoring DOI Creative Commons
Fang Li, Shengguo Wang, Zhi Gao

et al.

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 11

Published: Jan. 6, 2025

Sepsis remains a leading cause of morbidity and mortality worldwide due to its rapid progression heterogeneous nature. This review explores the potential Artificial Intelligence (AI) transform sepsis management, from early detection personalized treatment real-time monitoring. AI, particularly through machine learning (ML) techniques such as random forest models deep algorithms, has shown promise in analyzing electronic health record (EHR) data identify patterns that enable detection. For instance, have demonstrated high accuracy predicting onset intensive care unit (ICU) patients, while approaches been applied recognize complications sepsis-associated acute respiratory distress syndrome (ARDS). Personalized plans developed AI algorithms predict patient-specific responses therapies, optimizing therapeutic efficacy minimizing adverse effects. AI-driven continuous monitoring systems, including wearable devices, provide predictions sepsis-related complications, enabling timely interventions. Beyond these advancements, enhances diagnostic accuracy, predicts long-term outcomes, supports dynamic risk assessment clinical settings. However, ethical challenges, privacy concerns algorithmic biases, must be addressed ensure fair effective implementation. The significance this lies addressing current limitations management highlighting how can overcome hurdles. By leveraging healthcare providers significantly enhance optimize protocols, improve overall patient outcomes. Future research should focus on refining with diverse datasets, integrating emerging technologies, fostering interdisciplinary collaboration address challenges realize AI's transformative care.

Language: Английский

Citations

6
Neutrophil-derived heparin-binding protein increases endothelial permeability in acute lung injury by promoting TRIM21 and the ubiquitination of P65 DOI Creative Commons
Jian Zhang, Yong Cao,

Wenqi Shu

et al.

Cell Biology and Toxicology, Journal Year: 2025, Volume and Issue: 41(1)

Published: March 5, 2025

Acute lung injury (ALI), which poses a significant public health threat, is commonly caused by sepsis. ALI associated with permeability and glycolysis changes in pulmonary microvascular endothelial cells. Our study demonstrates that heparin-binding protein (HBP), released from neutrophils during sepsis, exacerbates glycolysis, thereby triggering ALI. Through coimmunoprecipitation mass spectrometry, TRIM21 was identified as HBP interaction partner. Notably, enhances the stability of inhibiting K48 ubiquitination. binds to promotes K63-linked ubiquitination P65, facilitating its nuclear translocation. regulates HPMEC manner dependent on P65 stabilizes interactions P65. Rescue experiments conducted vivo vitro demonstrate modulation predominantly mediated through TRIM21-P65 axis. results suggest targeting HBP/TRIM21/P65 axis novel therapeutic strategy ameliorate

Language: Английский

Citations

1
Hospital Acquired Sepsis, Disease Prevalence, and Recent Advances in Sepsis Mitigation DOI Creative Commons
Mary Garvey

Pathogens, Journal Year: 2024, Volume and Issue: 13(6), P. 461 - 461

Published: May 30, 2024

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, commonly associated with nosocomial transmission. Gram-negative bacterial species are particularly problematic due the release of lipopolysaccharide toxins upon cell death. The toxin E. coli has greater immunogenic potential than that other bacteria. resultant dysregulation immune system failure and mortality, pregnant women, ICU patients, neonates being vulnerable. Additionally, sepsis recovery patients have an increased risk re-hospitalisation, chronic illness, co-morbidities, damage/failure, reduced life expectancy. emergence increasing prevalence antimicrobial resistance in fungal impacted treatment leading mortality rates. Multidrug resistant pathogens including vancomycin-resistant Enterococcus, beta lactam-resistant Klebsiella, carbapenem-resistant Acinetobacter mortality. To improve prognosis predominantly high-risk neonates, advances must be made early diagnosis, triage, control sepsis. identification suitable biomarkers biomarker combinations, coupled machine learning artificial intelligence, show promise detection protocols. Rapid diagnosis essential inform on clinical treatment, especially infectious agents. This timely review aims discuss prevalence, aetiology, recent towards disease mitigation control.

Language: Английский

Citations

6
Distinct functional neutrophil phenotypes in sepsis patients correlate with disease severity DOI Creative Commons
Qingliang Yang, Jordan C. Langston,

Roman Prosniak

et al.

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

Published: March 8, 2024

Purpose Sepsis is a clinical syndrome defined as life-threatening organ dysfunction caused by dysregulated host response to infection. highly heterogeneous with distinct phenotypes that impact immune function and To develop targeted therapeutics, immunophenotyping needed identify functional of cells. In this study, we utilized our Organ-on-Chip assay categorize sepsis patients into using patient data, neutrophil analysis, proteomics. Methods Following informed consent, neutrophils plasma were isolated from in the Temple University Hospital ICU (n=45) healthy control donors (n=7). Human lung microvascular endothelial cells (HLMVEC) cultured treated buffer or cytomix ((TNF/IL-1β/IFNγ). Neutrophil adhesion migration across HLMVEC used phenotypes. Quantitative label-free global proteomics was performed on differentially expressed proteins. Plasma levels biomarkers extracellular traps (NETs) determined ELISA. Results We identified three critically ill based ex vivo patterns. The classified as: Hyperimmune characterized enhanced migration, Hypoimmune unresponsive stimulation, Hybrid increased but blunted migration. These associated proteomic signatures differentiated important parameters related disease severity. group demonstrated higher oxygen requirements, mechanical ventilation, longer length stay compared groups. Patients phenotype had significantly circulating elevated NETs. Conclusion Neutrophils NETs play critical role vascular barrier may be key biomarker identifying group. Our results establish significant associations between specific severity pathophysiology provide new approach classify for therapeutic interventions.

Language: Английский

Citations

3
Neutrophils, Fast and Strong 2.0: Heterogeneity of Neutrophil Parameters in Health and in Disease DOI Creative Commons
Galina F. Sud’ina

Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 436 - 436

Published: Feb. 11, 2025

Neutrophils are very important cells of the immune system, and every year, new nuances their functional activity in body participation various pathological processes discovered [...].

Language: Английский

Citations

0
Neutrophils: a Central Point of Interaction Between Immune Cells and Nonimmune Cells in Rheumatoid Arthritis DOI
Zhaoran Wang, Yi Jiao,

Wenya Diao

et al.

Clinical Reviews in Allergy & Immunology, Journal Year: 2025, Volume and Issue: 68(1)

Published: March 28, 2025

Language: Английский

Citations

0
Value of animal sepsis research in navigating the translational labyrinth DOI Creative Commons
Haichao Wang, Alfred Ayala, Monowar Aziz

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 15, 2025

Language: Английский

Citations

0
Identification of Potential Sepsis Therapeutic Drugs Using a Zebrafish Rapid Screening Approach DOI Creative Commons
Mark W. Widder,

Chance Carbaugh,

William van der Schalie

et al.

Life, Journal Year: 2024, Volume and Issue: 14(12), P. 1689 - 1689

Published: Dec. 20, 2024

In the military, combat wound infections can progress rapidly to life-threatening sepsis. The discovery of effective small-molecule drugs prevent and/or treat sepsis is a priority. To identify potential drug candidates, we used an optimized larval zebrafish model endotoxicity/sepsis screen commercial libraries approved by U.S. Food and Drug Administration (FDA) other active pharmaceutical ingredients (APIs) known affect pathways implicated in initiation progression humans (i.e., inflammation, mitochondrial dysfunction, coagulation, apoptosis). We induced endotoxicity 3- 5-day post fertilization (characterized mortality tail fin edema (vascular leakage)) immersion exposure 60 µg/mL Pseudomonas aeruginosa lipopolysaccharide (LPS) for 24 h, then screened rescue 644 selected at 10 µM through simultaneous LPS. After LPS exposure, neurobehavioral assay (light-dark test) further evaluate from determine possible off-target side effects. identified 29 with > 60% mortality. Three (Ketanserin, Tegaserod, Brexpiprazole) produced 100% did not differ controls light-dark test, suggesting lack Further testing these three nearly lethal concentration Klebsiella pneumoniae (45 µg/mL) showed 88–100% mitigation against edema. success warrants evaluation mammalian models.

Language: Английский

Citations

0