Daily Sepsis Research Analysis
Analyzed 37 papers and selected 3 impactful papers.
Summary
Three high-impact sepsis studies span translational mechanisms and pragmatic care. Preclinical work identifies Akt-driven microglial glycolysis and a HO-1–TFE3–Golgi stress axis as actionable pathways in sepsis-related brain and lung injury, respectively. Clinically, early beta-blocker therapy for sepsis-induced new-onset atrial fibrillation is associated with lower 28-day and 1-year mortality, warranting prospective trials.
Research Themes
- Immunometabolic mechanisms in sepsis-related organ dysfunction
- Translational targets: HO-1/TFE3/Golgi stress and microglial Akt signaling
- Cardiovascular management in sepsis: beta-blockers for new-onset atrial fibrillation
Selected Articles
1. Tangeretin ameliorates sepsis-induced neurocognitive impairment in adult male mice by suppressing Akt-driven glycolytic reprogramming and neuroinflammation.
In a CLP-induced sepsis model, tangeretin improved cognitive performance, reduced hippocampal microglial activation and cytokines, and directly bound Akt to inhibit its signaling. It curtailed microglial glycolysis, linking immunometabolic reprogramming to sepsis-associated neurocognitive protection.
Impact: This study identifies Akt-driven glycolysis in microglia as a druggable pathway for sepsis-related cognitive impairment and provides target engagement evidence for tangeretin. It advances mechanistic understanding and nominates a candidate adjunct therapy.
Clinical Implications: While preclinical, the data support exploring brain-penetrant Akt-modulating strategies or tangeretin derivatives to prevent or treat sepsis-associated cognitive deficits within post-ICU care pathways.
Key Findings
- Tangeretin improved cognitive performance and reduced hippocampal microglial activation and proinflammatory cytokines after CLP-induced sepsis.
- Target engagement was demonstrated: tangeretin bound Akt (SPR and cellular thermal shift assays) and inhibited Akt signaling; Akt activation abrogated its anti-inflammatory effects.
- Tangeretin suppressed LPS-induced glycolysis in microglia (lower ECAR and glycolytic capacity), linking metabolic reprogramming to reduced neuroinflammation.
Methodological Strengths
- Multi-level mechanistic validation (behavior, cellular assays, target engagement via SPR and CETSA)
- In vivo CLP sepsis model with complementary in vitro microglial metabolism assays
Limitations
- Preclinical mouse study; translational dosing, pharmacokinetics, and safety in humans are unknown
- Male-only mice and specific behavioral paradigms may limit generalizability
Future Directions: Conduct dose-ranging and PK/PD studies, test brain-penetrant derivatives, compare across sepsis models (e.g., polymicrobial), and design early-phase trials targeting post-sepsis cognitive dysfunction.
BACKGROUND AND PURPOSE: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, frequently leads to long-term cognitive impairment. Tangeretin, a polymethoxylated citrus flavonoid, has neuroactive and anti-inflammatory properties. We investigated whether tangeretin protects against sepsis-associated neurocognitive deficits and delineated the underlying mechanisms, focusing on Akt signalling and microglial metabolism.
EXPERIMENTAL APPROACH: Sepsis was induced by caecal ligation and puncture in mice. Tangeretin (15 or 30 mg·kg KEY RESULTS: Tangeretin improved sepsis-induced cognitive deficits, decreased hippocampal microglial activation, and lowered proinflammatory cytokine levels and microglial migration. It exerted anti-inflammatory effects via inhibition of the Akt pathway, and pharmacological Akt activation blocked these effects. Surface plasmon resonance and cellular thermal shift assay showed hat tangeretin binds Akt. Metabolically, tangeretin reduced LPS-induced glycolysis (decreased extracellular acidification rate and glycolytic capacity), consistent with diminished Akt phosphorylation and microglial activation.
CONCLUSION AND IMPLICATIONS: Tangeretin mitigates sepsis-associated neuroinflammation and cognitive impairment by targeting microglial Akt signalling and restraining glycolytic reprogramming. These data support tangeretin as a mechanistically informed candidate for adjunctive therapy in sepsis-related neurocognitive dysfunction.
2. HO-1 alleviates lipopolysaccharide-induced acute lung injury in mice by downregulating TFE3 expression and nuclear translocation and suppressing Golgi stress response.
This mechanistic study defines a HO-1–TFE3–Golgi stress axis in LPS-induced lung injury. TFE3 promotes inflammation and Golgi stress; its genetic suppression mitigates ALI, whereas Hmox1 loss worsens injury via increased TFE3 nuclear translocation. HO-1 counteracts ALI by downregulating TFE3 and Golgi stress.
Impact: It uncovers a novel, targetable signaling axis linking HO-1 to TFE3-driven Golgi stress in septic lung injury, expanding therapeutic concepts beyond conventional anti-inflammatory strategies.
Clinical Implications: Findings motivate exploration of pharmacologic HO-1 induction or TFE3/Golgi stress modulation as adjunctive strategies for sepsis-induced acute lung injury, pending translational validation.
Key Findings
- LPS induced TFE3 expression and nuclear translocation, amplifying Golgi stress response and inflammatory cytokines, thereby worsening ALI in vivo and in vitro.
- Tfe3 knockdown/knockout reduced Golgi stress markers, inflammatory cytokines, reactive oxygen species, and mitigated lung injury.
- Hmox1 loss increased TFE3 nuclear translocation and dysregulated Golgi stress proteins, exacerbating ALI; conversely, HO-1 downregulated TFE3 and Golgi stress, conferring protection.
Methodological Strengths
- Complementary in vivo and in vitro models with genetic knockdown/knockout approaches
- Mechanistic linkage of transcriptional regulation (TFE3) to organelle stress (Golgi) and inflammatory phenotypes
Limitations
- LPS-induced ALI may not fully recapitulate polymicrobial sepsis pathophysiology
- Translational relevance requires validation in human tissues and clinically relevant models
Future Directions: Test HO-1 inducers and TFE3 modulators in polymicrobial sepsis models; evaluate biomarkers of Golgi stress in human ARDS/ALI; assess synergy with lung-protective ventilation and anti-inflammatory agents.
Sepsis-induced acute lung injury (ALI) is associated with increased morbidity and mortality rates in the intensive care unit. Transcription factor E3(TFE3) is reported to drive inflammation and Golgi stress response in some pathological conditions. However, the functions and regulatory mechanisms of TFE3 in ALI have not been elucidated. This study demonstrated that lipopolysaccharide (LPS)-induced TFE3 expression and nuclear translocation promoted Golgi stress response and inflammatory cytokine upregulation and exacerbated septic lung injury in vivo and in vitro. The knockdown or knockout of Tfe3 alleviated ALI by downregulating Golgi stress response, inflammatory cytokines, and reactive oxygen species. Meanwhile, the knockout or knockdown of Hmox1 promoted TFE3 nuclear translocation, dysregulating the expression of Golgi stress response-related proteins and exacerbating sepsis induced ALI in vivo and in vitro. Thus, TFE3 exacerbates inflammation, apoptosis, and oxidative stress and induces Golgi stress response in sepsis-induced ALI. Additionally, HO-1 exerted protective effects against ALI by downregulating TFE3 expression and nuclear translocation and suppressing Golgi stress response. The regulatory mechanism of HO-1 in the TFE3/Golgi stress response signaling pathway can be a potential therapeutic target for ALI.
3. Association of anti-catecholaminergic antiarrhythmic drugs with survival in sepsis-associated new-onset atrial fibrillation.
In matched sepsis patients with new-onset AF, early beta-blocker therapy was associated with significantly lower 28-day and 1-year mortality and more vasopressor- and ventilator-free days, with less bradycardia but more hypotension. Benefits appeared greater in high-risk subgroups and were partly mediated by reduced vasopressor exposure.
Impact: Provides clinically actionable evidence suggesting survival benefit with early beta-blockade in sepsis-induced AF, an area with practice uncertainty. Signals justify prospective trials and may inform current rhythm/rate control strategies.
Clinical Implications: Consider early beta-blocker therapy for sepsis-associated new-onset AF when hemodynamically feasible, with vigilant monitoring for hypotension; randomized trials are needed before guideline changes.
Key Findings
- Early beta-blockers vs. alternative antiarrhythmics: lower 28-day mortality (36.1% vs 51.1%; adjusted HR 0.53, 95% CI 0.41–0.67) and 1-year mortality (50.7% vs 63.6%; adjusted HR 0.68, 95% CI 0.55–0.85).
- More vasopressor-free and ventilator-free days in the beta-blocker group; ICU mortality also reduced.
- Safety profile: less bradycardia but more hypotension; mediation analysis indicated ~16% of benefit mediated via reduced vasopressor use.
Methodological Strengths
- Use of a large, granular ICU database with propensity score matching and adjusted survival analyses
- Subgroup and mediation analyses to explore effect modification and mechanisms
Limitations
- Retrospective, non-randomized design with potential residual confounding and confounding by indication
- Heterogeneity in beta-blocker agents, dosing, and timing; single-center MIMIC-IV cohort limits generalizability
Future Directions: Prospective, multicenter randomized trials comparing early beta-blockade vs. alternatives in sepsis-induced AF; hemodynamic phenotyping and dose–response studies to optimize safety.
Sepsis-induced new-onset atrial fibrillation (NOAF) is a potentially life-threatening arrhythmogenic complication, partially driven by catecholamine-mediated atrial remodeling. While β-adrenergic receptor blockers may mitigate this pathophysiology through sympatholytic and rate-controlling mechanisms, their association with patient survival remains incompletely characterized due to heterogeneous evidence. To elucidate the association between the administration of anti-catecholaminergic antiarrhythmic drugs and all-cause mortality in critically ill patients with sepsis-induced NOAF.This retrospective cohort study utilized data from the Medical Information Mart for Intensive Care-IV database. We included adult patients admitted to a tertiary academic medical center between 2008 and 2019 who fulfilled the Sepsis-3 criteria and developed NOAF during their ICU stays.Based on the initial antiarrhythmic drug administration within 24 h following time-zero, patients were categorized into either β-blocker group or alternative antiarrhythmic drug group. The matched cohort comprised 560 patients (mean age 74.1 [SD 11.5] years; 64.6% male), among whom 280 were assigned to the β-blocker group and 280 to the alternative antiarrhythmic drug group. The β-blocker group demonstrated significantly lower 28-day mortality (36.1 vs. 51.1%; adjusted HR, 0.53; 95% CI, 0.41-0.67; P < .001) and 1-year mortality (50.7 vs. 63.6%; adjusted HR, 0.68; 95% CI, 0.55-0.85; P = .001). ICU mortality was also reduced in the β-blocker group (22.1 vs. 42.5%; P < .001). Furthermore, this group had more vasopressor-free days (median [IQR], 24.0 [18.0-26.0] vs. 16.0 [0.0-23.0]) and ventilator-free days (24.0 [18.0-26.0] vs. 17.0 [0.0-24.0]) (both P < .001). Safety outcomes included less bradycardia (12.5 vs. 20.0%; P = .016) but more hypotension (26.4 vs. 18.6%; P = .039). Subgroup and mediation analyses suggested greater benefit in high-risk patients, partially mediated (15.92%) by reduced vasopressor requirements. In critically ill patients with sepsis-induced NOAF, early β-blocker therapy was associated with markedly lower 28-day and 1-year mortality, along with decreased organ-support burden, warranting prospective trials are warranted to confirm these survival benefits.