Daily Sepsis Research Analysis
Analyzed 5 papers and selected 3 impactful papers.
Summary
Analyzed 5 papers and selected 3 impactful articles.
Selected Articles
1. EP300 confers protection against acute pancreatitis via acetylating HSF1 and promoting PRKN-mediated mitophagy in pancreatic acinar cells.
The authors show that HSF1 deficiency worsens two experimental acute pancreatitis models with increased mortality, necrosis, and systemic inflammation. Mechanistically, EP300-mediated acetylation stabilizes HSF1, which transcriptionally upregulates PRKN (parkin), promoting mitophagy, reducing ROS, and suppressing NLRP3 inflammasome activation; pharmacologic EP300 activation restores HSF1 and mitigates inflammation.
Impact: Identifies a novel EP300-HSF1-PRKN axis that links epigenetic regulation to mitophagy and inflammatory control in acute pancreatitis, suggesting a druggable node with translational potential.
Clinical Implications: Although preclinical, the work points to EP300 activation or HSF1 stabilization as potential therapeutic strategies to limit pancreatic necrosis and systemic inflammation in acute pancreatitis; clinical translation would require safety and pharmacokinetic evaluation of EP300 modulators.
Key Findings
- HSF1 deficiency aggravates disease severity in two mouse models (L-arginine and cerulein) with higher mortality and pancreatic necrosis.
- HSF1 directly upregulates PRKN transcription, promoting PRKN-mediated mitophagy and reducing ROS and NLRP3 inflammasome activation in pancreatic acinar cells.
- EP300 acetylates and stabilizes HSF1; pharmacologic EP300 activation (e.g., CTB) restores HSF1 levels, enhances mitophagy, and attenuates inflammation in vivo and in vitro.
Methodological Strengths
- Two complementary in vivo AP models (L-arginine and cerulein) increase generalizability of findings.
- Multilevel approaches combining genetic manipulation, pharmacologic modulation, cell culture mechanistic assays, and histology.
Limitations
- Preclinical models only; relevance to human acute pancreatitis and safety of EP300 modulation remain to be established.
- Quantitative dose–response and long-term outcome data for EP300 activators were not fully explored.
Future Directions: Translate findings to human tissue studies and early-phase trials: assess HSF1/PRKN expression in human acute pancreatitis, test safety/PK of EP300 activators, and evaluate therapeutic windows for mitophagy modulation.
2. Inhibition of the RIPK1-driven necroptotic pathway protects against hypotensive and tachycardic responses to LPS in a rat model of septic shock.
In a rat LPS model, the RIPK1 inhibitor Nec-1s prevented LPS-induced hypotension and tachycardia, attenuated renal histopathology scores, and modulated arterial expression of proteins in TLR4/TRIF, RIPK1/RIPK3/MLKL, and caspase-8-related pathways. Nec-1s reduced systemic markers associated with inflammation/injury (iNOS, HMGB1, MPO, LDH) and suggests that suppressing RIPK1-driven necroptosis can protect against hemodynamic collapse in septic shock.
Impact: Provides mechanistic preclinical evidence that targeting RIPK1-driven necroptosis can prevent key hemodynamic derangements of septic shock, linking cell-death pathways to circulatory failure.
Clinical Implications: Supports further evaluation of RIPK1 inhibitors as adjunctive therapy in septic shock; next steps include dose-finding, safety profiling, and testing in larger animal models or translational human tissue studies before clinical trials.
Key Findings
- Nec-1s prevented LPS-induced hypotension and tachycardia in conscious rats.
- Nec-1s attenuated LPS-induced increases in serum iNOS, HMGB1, MPO, and LDH.
- Nec-1s modulated arterial expression of proteins in TLR4/TRIF/RIPK1/RIPK3/MLKL and caspase-8-related pathways and reduced renal histopathological damage scores.
Methodological Strengths
- Multimodal assessment: conscious hemodynamic recording, biochemical markers, immunoblotting, immunohistochemistry, and histopathology across multiple organs.
- Use of a selective RIPK1 inhibitor (Nec-1s) to interrogate pathway-specific effects in vivo.
Limitations
- Animal (rat) model limits direct translation to humans; dose translation and off-target effects of Nec-1s require evaluation.
- Sample sizes and long-term outcomes (survival beyond acute phase) are not specified in the abstract.
Future Directions: Perform dose-response and safety studies in larger animals, validate findings in human septic tissue or ex vivo systems, and explore combination therapies with standard sepsis care in translational models.
3. [Cerebral and extrancerebral complications combined with otogenic meningitis with various outcomes].
Retrospective series of 51 patients with otogenic purulent meningitis found that two-thirds had combined central nervous system complications (encephalitis, epidural empyema, sinus thrombophlebitis, intracerebral abscess). Frequency of cerebral complications was markedly higher in fatal cases, especially when associated with acute purulent otitis media, indicating combined CC/ECC substantially raise risk of death.
Impact: Provides clinical evidence that coexisting brain and extracerebral complications strongly predict fatal outcomes in otogenic purulent meningitis, informing risk stratification and the need for aggressive management.
Clinical Implications: Suggests clinicians should actively screen for and promptly treat combined CC and ECC in otogenic meningitis (e.g., early imaging, multidisciplinary ENT/neurosurgery/ID involvement), as their presence substantially increases mortality risk.
Key Findings
- 66.7±6.6% of OPM cases had combined central nervous system complications (encephalitis, epidural empyema, cerebral sinus thrombophlebitis, intracerebral abscess).
- Fatal OPM cases had a significantly higher frequency of cerebral complications, particularly when associated with acute purulent otitis media (increase from 50.0±10.7% to 92.9±8.5%).
- Combined CC and ECC are associated with increased risk of death in otogenic purulent meningitis.
Methodological Strengths
- Systematic collection and analysis of a defined clinical series (51 patients) with reporting of specific complication types and immediate causes of death.
- Provides specific frequency estimates with confidence intervals (presented as ± values) enabling clinical interpretation.
Limitations
- Retrospective design with potential for selection and information bias; details on interventions and timing are limited in the abstract.
- Relatively small sample size and single-center (likely regional) experience may limit generalizability.
Future Directions: Prospective multicenter studies with standardized imaging/treatment protocols to quantify the impact of early intervention on outcomes and to develop risk scores for OPM patients.