Intestine‐Decipher Engineered Capsules Protect Against Sepsis‐induced Intestinal Injury via Broad‐spectrum Anti‐inflammation and Parthanatos Inhibition

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

Abstract Sepsis is a severe systemic inflammatory syndrome characterized by dysregulated immune response to infection, often leading high mortality rates. The intestine, owing its distinct structure and physiological environment, plays pivotal role in the pathophysiology of sepsis. It functions as “central organ” or “engine” progression sepsis, with intestinal injury exacerbating condition. Despite availability current therapies that offer partial symptom relief, they fall short adequately protecting barrier. In this study, an advanced nanodrug formulation (OLA@MΦ NPs) developed coating macrophage membranes onto polymeric organic nanoparticles encapsulating olaparib. When loaded into pH‐responsive capsules, intestine‐decipher engineered capsule (cp‐OLA@MΦ successfully formulated. Upon oral administration septic mice, these capsules withstand gastric acid release their contents specifically targeting injured tissues. released OLA@MΦ NPs effectively neutralize pro‐inflammatory cytokines via membrane receptors, while olaparib inhibits epithelial parthanatos (a form programmed cell death) suppressing poly(ADP‐ribose) polymerase 1 (PARP1) activation. This strategy significantly reduces bacterial translocation, slows enhances survival thus presenting promising therapeutic approach for sepsis clinical applications.

Language: Английский

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Plasma EphA2 level is a superior biomarker to Del-1 for sepsis diagnosis and prognosis

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 24, 2025

Background Sepsis, characterized by a dysregulated host response to infection, often leads organ dysfunction, and vascular endothelial dysfunction plays central role. The erythropoietin-producing hepatocellular carcinoma (Eph)A2 receptor is associated with increased permeability; however, the developmental locus-1 (Del-1), has contrasting effects on function. Hence, we examined their potential as biomarkers of sepsis. Methods In total, 117 participants, including 20 healthy controls, 21 patients systemic inflammatory syndrome (SIRS), 76 sepsis, were enrolled in this study. Sepsis severity was assessed using Acute Physiology Chronic Health Evaluation (APACHE) II Sequential Organ Failure Assessment (SOFA) scores. Results Median plasma EphA2 levels progressively from controls SIRS sepsis cases (154.29, 293.52, 554.24 pg/mL; all p < 0.05). median Del-1 highest lowest SIRS, intermediate level (101.27, 16.88, 36.9 0.001). both higher 28-day non-survivors than survivors, (EphA2:898.09 vs. 475.88 pg/mL, 0.001; Del-1:46.09 32.68 = 0.193); only statistically significant. area under curve for 0.74 receiver operating characteristic analysis predicting mortality, whereas APACHE II, SOFA, showed values 0.762, 0.614, 0.595, respectively. Kaplan–Meier these cutoffs revealed that survival significantly group low compared high markers ( Conclusion Plasma consistently severity, suggesting its biomarker value diagnosis prognosis. contrast, variable, indicating limited prognostic utility.

Language: Английский

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Protective role of olfactomedin-4 gene polymorphisms in preterm neonates with sepsis

Early Human Development, Journal Year: 2025, Volume and Issue: 202, P. 106223 - 106223

Published: Feb. 20, 2025

Language: Английский

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Sepsis: the evolution of molecular pathogenesis concepts and clinical management

MedComm, Journal Year: 2025, Volume and Issue: 6(3)

Published: Feb. 23, 2025

Abstract The mortality rate of sepsis is approximately 22.5%, accounting for 19.7% the total global mortality. Since Lewis Thomas proposed in 1972 that “it our response makes disease (sepsis)” rather than invading microorganisms, numerous drugs have been developed to suppress “overwhelming” inflammatory response, but none them has achieved desired effect. Continued failure led investigators question whether deaths septic patients are indeed caused by uncontrolled inflammation. Here, we review history clinical trials based on evolving concepts pathogenesis over past half century, summarize factors these historical and prerequisites success future drugs, propose basic principles preclinical research ensure successful translation. strategy targeting like attempting eliminate invaders suppressing host's armed forces, which logically untenable. Sepsis may not be complex; rather, result a fight microbes when force an pathogen overwhelms defenses. Thus, strengthening body's defense forces instead correct overcome sepsis.

Language: Английский

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Mitochondria at the Heart of Sepsis: Mechanisms, Metabolism, and Sex Differences

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4211 - 4211

Published: April 29, 2025

Sepsis is a life-threatening condition that occurs when the body unable to effectively combat infection, leading systemic inflammation and multi-organ failure. Interestingly, females exhibit lower sepsis incidence improved clinical outcomes compared males. However, mechanisms underlying these sex-specific differences remain poorly understood. While sex hormones have been primary focus, emerging evidence suggests non-hormonal factors also play contributory roles. Despite in sepsis, management same for both males females, with treatment focused on combating infection using antibiotics hemodynamic support through fluid therapy. even interventions, mortality remains high, highlighting need more effective targeted therapeutic strategies. Sepsis-induced cardiomyopathy (SIC) key contributor failure characterized by left ventricular dilation impaired cardiac contractility. In this review, we explore SIC, particular focus mitochondrial metabolism. Mitochondria generate ATP required function fatty acid glucose oxidation, recent studies revealed distinct metabolic profiles between which can further differ context of SIC. Targeting pathways could provide new avenues treatment.

Language: Английский

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Sepsis-induced immunosuppression: mechanisms, biomarkers and immunotherapy

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

Published: April 29, 2025

Sepsis, a life-threatening organ dysfunction resulting from dysregulated host response to infection, initiates complex immune that varies over time, characterized by sustained excessive inflammation and immunosuppression. Sepsis-induced immunosuppression is now recognized as major cause of septic death, identifying effective strategies counteract it poses significant challenge. This results the disruption homeostasis, abnormal death effector cells, hyperproliferation suppressor release anti-inflammatory cytokines, expression checkpoints. Preclinical studies targeting immunosuppression, particularly with checkpoint inhibitors, have shown promise in reversing immunocyte dysfunctions establishing resistance pathogens. Here, our review highlights mechanisms sepsis-induced current diagnostic biomarkers, well immune-enhancing evaluated patients therapeutics under investigation.

Language: Английский

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Endothelial soluble guanylyl cyclase enzyme inhibitors as novel target for treatment of sepsis related hypotension

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

Background Sepsis-related hypotension is a life-threatening condition due to systemic infection leading widespread inflammation and blood vessel dilation. This can cause dramatic drop in pressure, impairing flow vital organs potentially organ failure death. NO was recognized as significant factor sepsis 1990 became an important therapeutic target. plays dual role sepsis, exhibiting both beneficial harmful effects. Inhibiting sGC may help reduce the excessive vasodilation associated with sepsis-induced vasoplegia. Methods study utilized CADD screen over 320 naturally occurring compounds from PubChem database for potential inhibitors. A comprehensive virtual screening process, which included protein-ligand docking, binding free energy calculations, pharmacokinetic profiling, led identification of promising candidates such Hypericin Hypocrellin A2. Results These demonstrated superior affinities properties compared existing achieved docking score -14.232, indicating strong interactions receptor. It also exhibited favourable characteristics, including tissue-binding stability within pocket, well low predicted toxicity substantial safety margin. Conclusions research lays groundwork future vitro vivo studies, could improve Hypericin-based effective therapies vasoplegia hypotension.

Language: Английский

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The Need for Standardized Guidelines for the Use of Monocyte Distribution Width (MDW) in the Early Diagnosis of Sepsis

Journal of Personalized Medicine, Journal Year: 2024, Volume and Issue: 15(1), P. 5 - 5

Published: Dec. 27, 2024

Sepsis is a complex and potentially life-threatening syndrome characterized by an abnormal immune response to infection, which can lead organ dysfunction, septic shock, death. Early diagnosis crucial improving prognosis reducing hospital management costs. This narrative review aims summarize evaluate the current literature on role of monocyte distribution width (MDW) as diagnostic biomarker for sepsis, highlighting its advantages, limitations, potential clinical applications. MDW measures volumetric monocytes, reflecting monocytic anisocytosis, detected using advanced hematological analyzers. In 2019, it was approved FDA sepsis due ability identify systemic inflammatory at early stage. Thirty-one studies analyzed us have shown that increased value associated with higher risk combination parameters (such qSOFA) other biomarkers (CRP, PCT) enhance sensitivity stratification capacity. Despite high sensitivity, has lower specificity compared more established such procalcitonin, thus requiring multimodal integration accurate diagnosis. The use in emergency intensive care settings represents opportunity improve critical patient management, particularly when combined markers tools. However, further are needed define universal cut-off confirm validity different contexts pathological scenarios.

Language: Английский

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