Sepsis-Induced Endothelial Dysfunction: Permeability and Regulated Cell Death DOI Creative Commons

Wei Zhang,

Luofeng Jiang, Xirui Tong

et al.

Journal of Inflammation Research, Journal Year: 2024, Volume and Issue: Volume 17, P. 9953 - 9973

Published: Nov. 1, 2024

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. Endothelial cells (ECs) are an important cell type typically affected in sepsis, resulting compromised barrier function and various forms of regulated death (RCD). However, the precise mechanisms underlying sepsis-induced EC damage remain unclear. This review summarizes recent research progress on factors that may affect permeability RCD ECs under septic conditions, including glycocalyx, damage-associated molecular patterns, ECs, such as apoptosis, pyroptosis, ferroptosis, autophagy. offers insights into endothelial aiming contribute developing small-molecule targeted clinical therapies.

Language: Английский

From gut to liver: Exploring the crosstalk between gut-liver axis and oxidative stress in metabolic dysfunction-associated steatotic liver disease DOI Creative Commons

Mi Zhou,

Jianyu Lv, Han Y. H. Chen

et al.

Annals of Hepatology, Journal Year: 2025, Volume and Issue: unknown, P. 101777 - 101777

Published: Jan. 1, 2025

Non-alcoholic fatty liver disease (NAFLD), now recognized as metabolic dysfunction-associated steatotic (MASLD), represents a significant and escalating global health challenge. Its prevalence is intricately linked to obesity, insulin resistance, other components of the syndrome. As our comprehension MASLD deepens, it has become evident that this condition extends beyond liver, embodying complex, multi-systemic with hepatic manifestations mirror broader landscape. This comprehensive review delves into critical interplay between gut-liver axis oxidative stress, elucidating their pivotal roles in etiology progression MASLD. Our analysis reveals several key findings: (1) Bile acid dysregulation can trigger stress through enhanced ROS production hepatocytes Kupffer cells, leading mitochondrial dysfunction lipid peroxidation; (2) Gut microbiota dysbiosis disrupts intestinal barrier function, allowing increased translocation endotoxins like LPS, which activate inflammatory pathways TLR4 signaling promote via NADPH oxidase activation; (3) The redox-sensitive transcription factors NF-κB Nrf2 serve crucial mediators axis, regulating responses orchestrating antioxidant defenses; (4) Oxidative stress-induced damage function creates destructive feedback loop, further exacerbating inflammation progression. These findings highlight complex interrelationship pathogenesis, suggesting potential therapeutic targets for management.

Language: Английский

Citations

1
Targeting NINJ1-mediated cell rupture to treat inflammatory diseases DOI Creative Commons

Claire Ju-Eun Hur,

Benjamin E. Steinberg

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: Feb. 14, 2025

Abstract Cell death can terminate in plasma membrane rupture to release potent pro-inflammatory intracellular contents thereby contributing inflammatory diseases. is an active process, mediated by the protein ninjurin-1 (NINJ1) pyroptosis, post-apoptosis lysis, ferroptosis, and forms of necrosis. Once activated, NINJ1 clusters into large oligomers within initiate cellular lysis. Recent preclinical studies have demonstrated that inhibiting a new strategy for treating immune-mediated Indeed, both small molecule inhibitors neutralizing antibodies target clustering preserve integrity mitigate disease pathogenesis. In this Perspective , we provide summary current state knowledge recent developments targeting during cell through inhibition treat disease, with focus on liver injury. As these NINJ1-mediated pathways are pivotal maintaining health contribute pathogenesis when dysregulated, discussed broad implications across immunologic basis molecular medicine.

Language: Английский

Citations

1
Current status and perspective on molecular targets and therapeutic intervention strategy in hepatic ischemia-reperfusion injury DOI Creative Commons
Jia Liu,

Ranyi Luo,

Yinhao Zhang

et al.

Clinical and Molecular Hepatology, Journal Year: 2024, Volume and Issue: 30(4), P. 585 - 619

Published: July 1, 2024

Hepatic ischemia‒reperfusion injury (HIRI) is a common and inevitable complication of hepatic trauma, liver resection, or transplantation. It contributes to postoperative organ failure tissue rejection, eventually affecting patient prognosis overall survival. The pathological mechanism HIRI highly complex has not yet been fully elucidated. proposed underlying mechanisms include mitochondrial damage, oxidative stress imbalance, abnormal cell death, immune hyperactivation, intracellular inflammatory disorders other events. In addition serious clinical limitations, available antagonistic drugs specific treatment regimens are still lacking. Therefore, there an urgent need only clarify the exact etiology but also reveal possible reactions bottlenecks existing drugs, helping reduce morbidity shorten hospitalizations. We analyzed HIRI, discussed various outcomes among different animal models explored neglected potential therapeutic strategies for treatment. By thoroughly reviewing analyzing literature on we gained comprehensive understanding current research status in related fields identified valuable references future scientific investigations.

Language: Английский

Citations

7
Recipient Toll-like Receptor 4 Determines the Outcome of Ischemia-Reperfusion Injury in Steatotic Liver Transplantation in Mice DOI
Kosuke Tanaka, Yoichiro Uchida,

Kentaro Kadono

et al.

American Journal of Transplantation, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
HMGB1-Mediated Cell Death—A Crucial Element in Post-Hepatectomy Liver Failure DOI Open Access

Laura Brunnthaler,

Thomas Hammond, David Pereyra

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7150 - 7150

Published: June 28, 2024

Liver resection (LR) is the primary treatment for hepatic tumors, yet posthepatectomy liver failure (PHLF) remains a significant concern. While precise etiology of PHLF elusive, dysregulated inflammatory processes are pivotal. Therefore, we explored theragnostic potential extracellular high-mobility-group-box protein 1 (HMGB1), key damage-associated molecular pattern (DAMP) released by hepatocytes, in recovery post LR patients and animal models. Plasma from 96 tissues subset 24 were analyzed HMGB1 levels, associations with injury markers assessed. In murine model, inhibitor glycyrrhizin, was administered to assess its impact on regeneration. Furthermore, plasma levels keratin-18 (K18) cleaved cytokeratin-18 (ccK18) quantified suitability as predictive biomarkers PHLF. Patients experiencing exhibited elevated intrahepatic circulating HMGB1, correlating injury. inhibition improved function, reduced steatosis, enhanced regeneration decreased cell death. Elevated death K18 ccK18 detected correlations observed. Our study underscores therapeutic mitigation. K18, correlate patient outcomes, highlighting their significance. Targeting enhances models, emphasizing role intervention prediction strategies surgery.

Language: Английский

Citations

2
Spinal cord microglia drive sex differences in ethanol-mediated PGE2-induced allodynia DOI Creative Commons
Shevon N. Alexander,

Olivia A. Reed,

Michael D. Burton

et al.

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 122, P. 399 - 421

Published: Aug. 14, 2024

The mechanisms of how long-term alcohol use can lead to persistent pain pathology are unclear. Understanding earlier events short-term lower the threshold non-painful stimuli, described as allodynia could prove prudent understand important initiating mechanisms. Previously, we observed that low-dose intake induced female-specific and increased microglial activation in spinal cord dorsal horn. Other literature describes chronic ethanol exposure activates Toll-like receptor 4 (TLR4) initiate inflammatory responses. TLR4 is expressed on many cell types, aimed investigate whether microglia sufficient potentiate during a short-term/low-dose paradigm. Our study used novel genetic model where expression removed from entire body by introducing floxed transcriptional blocker (TLR4-null background (TLR4LoxTB)), then restricted breeding TLR4LoxTB animals with Cx3CR1:CreERT2 animals. As previously reported, after 14 days administration alone, no behavior. However, significant priming effects 3 hrs post intraplantar injection subthreshold dose prostaglandin E2 (PGE2) wild-type microglia-TLR4 female mice. We also shift pro-inflammatory phenotype morphological changes lumbar Investigations priming-associated neuronal subtypes showed an increase c-Fos FosB activity PKCγ interneurons horn mice directly corresponding activity. This uncovers cell- roles sexual dimorphisms induction among non-pathological drinkers.

Language: Английский

Citations

1
Chemoproteogenomic stratification of the missense variant cysteinome DOI Creative Commons
Heta S. Desai, Katrina H. Andrews,

Kristina V. Bergersen

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 28, 2024

Abstract Cancer genomes are rife with genetic variants; one key outcome of this variation is widespread gain-of-cysteine mutations. These acquired cysteines can be both driver mutations and sites targeted by precision therapies. However, despite their ubiquity, nearly all remain unidentified via chemoproteomics; identification a critical step to enable functional analysis, including assessment potential druggability susceptibility oxidation. Here, we pair cysteine chemoproteomics—a technique that enables proteome-wide pinpointing functional, redox sensitive, potentially druggable residues—with genomics reveal the hidden landscape variation. Our chemoproteogenomics platform integrates chemoproteomic, whole exome, RNA-seq data, customized two-stage false discovery rate (FDR) error controlled proteomic search, which further enhanced user-friendly FragPipe interface. Chemoproteogenomics analysis reveals acquisition ubiquitous feature healthy cancer elevated in context decreased DNA repair. Reference proximal missense variants also found pervasive, supporting heretofore untapped opportunities for variant-specific chemical probe development campaigns. As distinguished sample-matched combinatorial variant databases compatible proteomics small molecule screening, expect utility guiding proteoform-specific biology therapeutic discovery.

Language: Английский

Citations

1
IFNγ initiates TLR9-dependent autoimmune hepatitis in DNase II deficient mice DOI
Kaiyuan Hao, Kevin Gao,

M. J. Strauss

et al.

Published: July 16, 2024

Patients with biallelic hypomorphic mutation in

Language: Английский

Citations

0
Sepsis-Induced Endothelial Dysfunction: Permeability and Regulated Cell Death DOI Creative Commons

Wei Zhang,

Luofeng Jiang, Xirui Tong

et al.

Journal of Inflammation Research, Journal Year: 2024, Volume and Issue: Volume 17, P. 9953 - 9973

Published: Nov. 1, 2024

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. Endothelial cells (ECs) are an important cell type typically affected in sepsis, resulting compromised barrier function and various forms of regulated death (RCD). However, the precise mechanisms underlying sepsis-induced EC damage remain unclear. This review summarizes recent research progress on factors that may affect permeability RCD ECs under septic conditions, including glycocalyx, damage-associated molecular patterns, ECs, such as apoptosis, pyroptosis, ferroptosis, autophagy. offers insights into endothelial aiming contribute developing small-molecule targeted clinical therapies.

Language: Английский

Citations

0