Refractory septic shock can lead to multiorgan failure and death due to myocardial dysfunction-induced inadequate tissue perfusion. Current guidelines advocate inotropic adjuncts to norepinephrine, but the efficacy of milrinone remains understudied in this context. This study aimed to evaluate the hemodynamic changes in septic shock patients treated with adjunctive milrinone compared to those treated with a placebo.

This multicenter, double-blind, randomized controlled trial enrolled adults with septic shock, adequate fluid resuscitation, and a mean arterial pressure ≥ 65 mmHg. Eligible patients exhibited poor tissue perfusion or impaired left ventricular systolic function. Participants were randomized 1:1 to milrinone or placebo. Echocardiographic hemodynamic assessments were performed pre- and postintervention. The primary outcome was the change in cardiac output from baseline to 6 h after drug administration. The study was prospectively registered at www.clinicaltrials.gov (NCT05122884).

Among 271 screened patients, 64 were randomized. The baseline characteristics were comparable between the groups. The milrinone group demonstrated a significantly greater change in cardiac output at 6 h (median [IQR] 0.62 L/min [-0.51 to 1.47]) than did the placebo group (0.13 L/min [-0.59 to 0.46]; p = 0.043). The percentage change in the cardiac index was also significantly greater with milrinone (median [IQR] 22.5% [-10.4% to 45.3%]) than with placebo (4.4% [-10.9% to 11.4%]; p = 0.041). There were no significant differences in complication rates between the groups. The 28-day mortality rates of the groups were also statistically nonsignificant and equivalent (16/32 [50.0%] for both; p = 1.000).

Milrinone administration in septic shock patients improved cardiac output at 6 h, suggesting a potential benefit for patients with persistent tissue hypoperfusion despite norepinephrine.

Sepsis-induced cardiac dysfunction, usually termed sepsis-induced cardiomyopathy or septic cardiomyopathy(SCM), is developed in approximately 70 % of the patients with sepsis, making it is a major concern for sepsis patients. However, the pathogenesis of SCM remain incompletely understood. Ferroptosis, a newly identified mechanism of regulated cell death, characterized by a decline in antioxidant capacity, iron accumulation, and lipid peroxidation(LPO), is involved in sepsis and SCM. Moreover, ferroptosis inhibitors confer a novel therapeutic regimen in SCM. In this Review, we first summarizes the core mechanism of ferroptosis, with an emphasis on how best to interpret ferroptosis leads to the genesis of SCM. We then highlights our focus on the emerging different types of therapeutic ferroptosis inhibitors and summarizes their pharmacological beneficial effect to treat SCM. This review highlights a novel potential therapeutic strategy for SCM by pharmacologically inhibiting ferroptosis.

Septic cardiomyopathy is a considerable complication in sepsis, which has high mortality rates and an incompletely understood pathophysiology, which hinders the development of effective treatments. α‑ketoglutarate (AKG), a component of the tricarboxylic acid cycle, serves a role in cellular metabolic regulation. The present study delved into the therapeutic potential and underlying mechanisms of AKG in ameliorating septic cardiomyopathy. A mouse model of sepsis was generated and treated with AKG via the drinking water. Cardiac function was assessed using echocardiography, while the mitochondrial ultrastructure was examined using transmission electron microscopy. Additionally, in vitro, rat neonatal ventricular myocytes were treated with lipopolysaccharide (LPS) as a model of sepsis and then treated with AKG. Mitochondrial function was evaluated via ATP production and Seahorse assays. Additionally, the levels of reactive oxygen species were determined using dihydroethidium and chloromethyl derivative CM‑H2DCFDA staining, apoptosis was assessed using a TUNEL assay, and the expression levels of mitochondria‑associated proteins were analyzed by western blotting. Mice subjected to LPS treatment exhibited compromised cardiac function, reflected by elevated levels of atrial natriuretic peptide, B‑type natriuretic peptide and β‑myosin heavy chain. These mice also exhibited pronounced mitochondrial morphological disruptions and dysfunction in myocardial tissues; treatment with AKG ameliorated these changes. AKG restored cardiac function, reduced mitochondrial damage and corrected mitochondrial dysfunction. This was achieved primarily through increasing mitophagy and mitochondrial fission. In vitro, AKG reversed LPS‑induced cardiomyocyte apoptosis and dysregulation of mitochondrial energy metabolism by increasing mitophagy and fission. These results revealed that AKG administration mitigated cardiac dysfunction in septic cardiomyopathy by promoting the clearance of damaged mitochondria by increasing mitophagy and fission, underscoring its therapeutic potential in this context.

Existing guidelines emphasize the importance of initial fluid resuscitation therapy in sepsis management. However, in previous meta-analyses, there have been inconsistencies in differentiating between spontaneously breathing and mechanically ventilated septic patients.

To consolidate the literature on the predictive accuracy of changes in the inferior vena cava diameter (∆IVC) for fluid responsiveness in septic patients.

The Embase, Web of Science, Cochrane Library, MEDLINE, PubMed, Wanfang, China National Knowledge Infrastructure (CNKI), Chinese Biomedical (CBM) and VIP (Weipu) databases were comprehensively searched. Statistical analyses were performed with Stata 15.0 software and Meta-DiSc 1.4.

Twenty-one research studies were deemed suitable for inclusion. The sensitivity and specificity of ∆ IVC were 0.84 (95% CI 0.76, 0.90) and 0.87 (95% CI 0.80, 0.91), respectively. With respect to the distensibility of the inferior vena cava (dIVC), the sensitivity was 0.79 (95% CI 0.68, 0.86), and the specificity was 0.82 (95% CI 0.73, 0.89). For collapsibility of the inferior vena cava (cIVC), the sensitivity and specificity values were 0.92 (95% CI 0.83, 0.96) and 0.93 (95% CI 0.86, 0.97), respectively.

The results indicated that ∆IVC is as a dependable marker for fluid responsiveness in sepsis patients. dIVC and cIVC also exhibited high levels of accuracy in predicting fluid responsiveness in septic patients.

The immune system and inflammation are intimately linked to the pathophysiology of sepsis. The neutrophil‒platelet ratio (NPR), associated with inflammation and immunology, may be useful in predicting sepsis outcomes. According to earlier research, the NPR is linked to the prognosis of several diseases. This study aimed to investigate the connection between the NPR and unfavorable outcomes in patients with sepsis.

We retrieved patient clinical data from the Medical Information Mart for Intensive Care IV database (MIMIC-IV 2.2) based on the inclusion and exclusion criteria. The NPR quartile was used to divide the population into four groups. 28-day mortality was the main result, whereas 90-day mortality was the secondary result. The Cox regression model, Kaplan‒Meier survival curve, and limited cubic spline were used to examine the associations between the NPR and the negative outcomes of sepsis. Subgroup analysis was also conducted. At the same time, we used Latent Class Trajectory Model (LCTM) to assess the trajectory of NPR within six days of ICU admission, and to assess the relationship between NPR trajectory and mortality at 28 and 90 days.

This study included 3339 patients. Quartile 4 had the greatest 28-day and 90-day mortality rates, according to the Cox regression model and Kaplan‒Meier survival curve. A J-shaped relationship between the NPR and mortality was found in restricted cubic spline investigations. This means higher and lower NPRs were linked to higher mortality, with NPR = 3.81 as the tipping point. A total of 434 patients were included in the trajectory analysis, and three trajectory patterns were identified. Patients with sepsis had an increased mortality rate in the slow-decline group compared with the stable development group.

The NPR has prognostic value for patients with sepsis, and there is a J-shaped relationship between the two variables. Patients with sepsis who have a slowly declining NPR have an increased mortality rate.

Not applicable.

To explore the role and underlying mechanisms of Piezo1 in sepsis-induced myocardial dysfunction (SIMD). A SIMD model was established in mice via intraperitoneal lipopolysaccharide (LPS) injection. Cardiac function, histology, Piezo1 protein expression, and cardiac troponin T (cTnT) were assessed. Piezo1's role in SIMD was investigated using the agonist Yoda1, inhibitor GsMTx-4, and cardiomyocyte-specific Piezo1 knockout (Piezo1ΔCM) mice. Dual Specificity Phosphatase 3 (DUSP3) protein levels were also assessed to explore potential mechanisms. SIMD mice exhibited significantly impaired cardiac function, along with increased Piezo1 protein and cTnT levels. Piezo1 activation improved cardiac function and reduced tissue damage, while inhibition worsened SIMD. Piezo1ΔCM mice exhibited more severe cardiac dysfunction and injury, especially with LPS treatment. DUSP3 protein levels were significantly elevated in Piezo1ΔCM and LPS-treated hearts. Piezo1 exerted a protective role in SIMD, potentially through the modulation of DUSP3.

Sepsis is a life-threatening condition that often leads to severe complications, including acute lung injury (ALI), which carries high morbidity and mortality in critically ill patients. Melatonin (Mel) has shown significant protective effects against sepsis-induced ALI, but its precise mechanism remains unclear.

A cecal ligation and puncture (CLP) model was used to induce sepsis in male C57BL/6 mice, which were divided into four groups: Control, Sham, CLP, and CLP + Mel. ALI severity was evaluated via hematoxylin and eosin (H&E) staining, lung wet/dry ratio, and serum biomarkers (SP-D, sRAGE). Inflammatory cytokines (IL-1β, IL-6, TNF-α) were measured in serum and bronchoalveolar lavage fluid using ELISA. Circulating mitochondrial DNA (mtDNA) subtypes (D-loop, mt-CO1, mMito) were quantified by real-time PCR. TUNEL staining was performed to assess lung cell apoptosis. Necroptosis and STING pathway activation were analyzed via Western blot and immunofluorescence.

Sepsis led to increased circulating mtDNA levels and activation of necroptosis signaling pathways. Melatonin treatment alleviated sepsis-induced ALI, improving survival, reducing inflammatory cytokines and mtDNA release, and suppressing necroptosis. Intraperitoneal injection of mtDNA in mice activated necroptosis, while RIP1 inhibitor Nec-1 counteracted mtDNA-induced lung damage and necroptosis in sepsis-induced ALI. Additionally, melatonin significantly inhibited STING pathway activation. Further experiments revealed that STING modulation influenced necroptosis protein expression and mediated melatonin's protective effects in sepsis-induced ALI.

Melatonin mitigates sepsis-induced ALI by suppressing necroptosis through inhibition of STING activation and reduction of mtDNA release. These findings suggest melatonin as a potential therapeutic strategy for sepsis-induced ALI.

Sepsis is a life-threatening complication caused by the overwhelming immune response to bacterial infection leading to the fatal organ damage and even death. Helminth infections modulate host's immune system through secreting functional proteins to reduce host immune attack as a survival strategy, therefore have been used for the therapy of some inflammatory or autoimmune diseases. Sj-Cys is a cysteine protease inhibitor secreted by Schistosoma japonicum exerting strong immunomodulatory function which has been used to treat sepsis, however, the mechanism underlying the therapeutic efficacy has not been fully elucidated. In this study, we expressed Sj-Cys as recombinant protein (rSj-Cys) in prokaryotic system and rSj-Cys was used to incubate with mouse bone marrow derived dendritic cells (BMDCs) in vitro. Our study revealed that rSj-Cys was able to induce differentiation of BMDCs to tolerant property (TolDCs). Adoptive transfer of rSj-Cys induced-TolDCs into mice with cecal ligation and puncture (CLP)-induced sepsis conferred a significant therapeutic effect on CLP-induced sepsis in mice with reduced mortality and vital organ damage. The therapeutic effect of Sj-Cys-induced TolDCs was associated with upregulation of CD3+CD4+CD25+Foxp3+ regulatory T cells (Tregs) and reduced inflammatory cytokines IL-6 and TNF-α and boosted level of regulatory cytokines IL-10 and TGF-β. The results identified in this study further suggest rSj-Cys has the potential to be developed into a drug substance for the treatment of inflammatory or autoimmune diseases due to its immunomodulatory effect on tolerant dendritic cells and regulatory T cells.

Acute circulatory failure plays a major role in the development of sepsis-related organ dysfunction. Current 'bundles' of the Surviving Sepsis Campaign (SSC) include the administration of a fluid loading of 30 mL/kg in the presence of hypotension within the first hour of sepsis identification. The impact of haemodynamic assessment using echocardiography at the early phase of management of septic patients in the Emergency Department (ED) on patient-centred outcomes is unknown.

This is a two-parallel arm randomised trial with blinded assessment comparing early haemodynamic assessment using transthoracic echocardiography aimed at guiding therapeutic management to standard of care according to current SSC recommendations in septic patients during initial management in 13 French EDs. Patients with suspected or documented infection and a qualifying quick Sequential Organ Failure Assessment (qSOFA) score (haemodynamic criterion required: systolic blood pressure≤100 mm Hg) will be 1:1 randomised after 500 mL of fluid loading initiation. In the intervention group, echocardiography will allow identifying the haemodynamic profile at the origin of sepsis-induced circulatory failure and monitoring the efficacy and tolerance of fluid resuscitation, or of any other therapeutic intervention according to a predefined therapeutic algorithm. The control group will receive conventional 30 mL/kg fluid resuscitation (unless pulmonary venous congestion) according to SSC recommendations. Primary outcome will be the course of organ dysfunction assessed by the crude change in the modified SOFA score between baseline and 24 hours after randomisation. Secondary outcomes will be the nature of therapeutic interventions resulting from echocardiography (fluid loading, early initiation of vasopressor support or inotrope), the prevalence of the different haemodynamic profiles, the evolution of lactatemia, the safety of the initial therapeutic, the proportion of patients who develop secondarily septic shock, the orientation of patients after ED discharge and both day 7 and in-hospital mortality. We plan to randomise 312 patients.

Approved by the Ethics Committee CPP Ouest V on 18 January 2021 (ref: 20/075-2-20.10.16.57638). The dissemination plan includes presentations at scientific conferences and publication of results in a peer-reviewed journal.

NCT04580888.

Sepsis is a systemic inflammatory response syndrome due to infection with a high incidence and high mortality. The Tanshinone IIA (TSN) is an active ingredient extracted from the traditional Chinese medicine Danshen. This work attempted to investigate the functional role of TSN is sepsis. It was found that the ratio of Th17/Treg was increased in sepsis patients and mouse model. TSN reduced the ratio of Th17/Treg and the levels of IL-17, IL-23, TGF-β1, and IL-10 in CD4+ T cells. Proliferation of CD4+CD25-Teff cells was inhibited by TSN. The expression of co-stimulatory molecules ICOS and CTLA-4 was decreased in CD4+ cells following TSN treatment. Additionally, TSN elevated LC3-II/I expression and down-regulated p62, p-mTOR and p-p70S6K to activate autophagy. Autophagy activator rapamycin (Rapa) activated autophagy to reduce the ratio of Th17/Treg in CD4+ T cells. Autophagy inhibitor (3-MA) in activated autophagy to elevate the ratio of Th17/Treg in CD4+ T cells, which was abolished by TSN treatment. TSN alleviated the damage of kidney, lung and liver tissues and inhibited the ratio of Th17/Treg in sepsis mice by activating autophagy. In summary, this work demonstrated that TSN ameliorates sepsis-associated immunosuppression by activating autophagy and balancing the Th17/Treg cell ratio.

The endotoxin, which is a highly pathogenic toxin released from the cell wall of gram-negative bacteria after death, can lead to critical diseases such as sepsis and intestinal inflammation. Poly 2-hydroxyethyl methacrylate (HEMA)-glycidyl methacrylate (GMA)/polyethyleneimine (PEI) cryogel membranes employed for endotoxin removal were synthesized via the immobilization of PEI solution with poly(HEMA-GMA) membranes. The concentration of the treated PEI% solution, the concentration of the endotoxin solution, and the ambient temperature influenced the endotoxin binding percentage of poly(HEMA-GMA) cryogel membranes. Maximum endotoxin removal was observed with poly(HEMA-GMA) cryogel membranes treated with a 25 % PEI solution at 25 °C. Additionally, it was noted that poly(HEMA-GMA)/PEI cryogel membranes exhibited increased endotoxin binding with rising endotoxin concentrations. The percentage of endotoxin bound by cryogel membranes in both aqueous solutions and artificial plasma media increases with the endotoxin concentration in the solutions. The Limulus Amebocyte Lysate (LAL) assay results show that the percentages of bound endotoxin in artificial plasma and aqueous solutions are approximately equivalent. The prepared poly(HEMA-GMA)/PEI adsorbent exhibited good reusability and offered high removal ability for endotoxin. The adsorption process can be accurately described by Langmuir adsorption isotherm model.

The plasma histidine-rich glycoprotein concentration is a marker of sepsis severity. In this study, we generated selective and specific monoclonal antibodies against histidine-rich glycoprotein for use in a prototype enzyme-linked immunosorbent assay-based in vitro diagnostic system. First, we investigated the properties of monoclonal antibodies produced by 21 hybridomas that we developed using immunized mice, and we identified monoclonal antibodies 69-1A and 75-2D to be the most suitable combination for use in the sandwich enzyme-linked immunosorbent assay. Wild-type histidine-rich glycoprotein (Form-1, 75 kDa) with a proline residue at amino acid position 204 is the most common isoform of the protein in humans, followed by its variant (Form-2, 77 kDa), which has a serine residue at position 204. The epitope mapping was examined for the HRG amino acid sequence with 69-1A and 75-2D mAbs to achieve the identification of respective specific binding domains, though the other kinds of mAbs showed considerably complex domains. The identified epitopes recognized by 69-1A and 75-2D monoclonal antibodies did not span position 204. Furthermore, immunoprecipitation-immunoblotting analysis showed that the 69-1A and 75-2D monoclonal antibodies could bind to both Form-1 and Form-2 in human plasma samples. Thus, these two new antibodies can be used to clearly detect both forms of histidine-rich glycoproteins in human plasma samples. In our analysis of clinical samples by enzyme-linked immunosorbent assays using various combinations of our newly synthesized antibodies, we found that the histidine-rich glycoprotein concentration was significantly lower in plasma samples from septic patients than in those from healthy volunteers (p < 0.01). Thus, our novel analysis system using the new antibodies is expected to be a useful tool for sepsis research, and it may be adapted as an in vitro diagnostic tool for many other kinds of diseases in the future.

Myocardial dysfunction is one of the most severe sepsis syndromes. EZH2 participates in regulating the inflammatory response in tissues; however, its role in septic myocarditis remains unclear. In this study, various concentrations of lipopolysaccharide (LPS) were used to treat H9C2 cells in order to mimic sepsis. Cell pyroptosis was detected by flow cytometry, and further confirmed by the expression of biomarkers and levels of cytokines. Caspase-1 activity was evaluated by flow cytometry and immunofluorescence assays. Gene expression was detected by reverse transcription-PCR (RT-PCR) and western blotting. Chromatin Immunoprecipitation - Quantitative PCR was used to detect the levels of histone methylation in the Nrf2 promoter region. Our results showed that LPS activated cell pyroptosis, promoted EZH2 expression, and inhibited Nrf2 expression in H9C2 cells. Overexpression of EZH2 enhanced LPS-induced cell pyroptosis, as shown by increased Caspase-1 activity, increased expression of N-GSDMD and NLRP3 proteins, and higher levels of IL-1β, IL-18, and LDH. Moreover, overexpression of EZH2 inhibited Nrf2 transcription. In contrast, knockdown of EZH2 suppressed pyroptosis and promoted Nrf2 expression in LPS-treated H9C2 cells. Results of chromatin immunoprecipitation - quantitative PCR verified that EZH2 regulated Nrf2 transcription via H3K27me3 modification. Furthermore, overexpression of Nrf2 inhibited cell pyroptosis and knockdown of Nrf2 promoted cell pyroptosis. Knockdown of Nrf2 reversed the cardioprotective effect of EZH2 knockdown. Collectively, our results suggest that EZH2 promotes cell pyroptosis by enhancing H3K27me3 expression and inhibiting Nrf2 transcription in cardiomyocytes under inflammatory conditions.

Swertianolin is one of the main components of Gentianaceae Swertia plants, a traditional Chinese medicine used for the treatment of infection, fever, viral hepatitis, and pneumonia. An expansion of myeloid-derived suppressor cells (MDSCs) contributes to sepsis induced immunosuppression. We investigated the mechanism by which Swertianolin regulates MDSCs in a mouse model of sepsis.

Severe sepsis was induced in mice using caecal ligation and puncture. These mice received an intraperitoneal injection of Swertianolin. MDSCs were isolated and analyzed by flow cytometry; serum concentrations of immunosuppressive factors were detected by ELISA; and mitogen-activated protein kinase and nuclear factor-κB (NFκB) were detected by Western blots.

We found that Swertianolin reduced the number of MDSCs in the marrow and the spleen while increased the number of CD4+ T cells in the spleen of mice with sepsis in comparison to controls (p < 0.05). Swertianolin reduced lung damage and improved the survival rate in mice with secondary infection of Legionella pneumophila (p < 0.05). Swertianolin inhibited the phosphorylation of p38 and nuclear translocation of p65 in MDSCs (p < 0.05), leading to decreased production of IL-10 and nitric oxide (both p < 0.05).

Swertianolin may improve immunosuppressive function of MDSCs and increased T cell activity by inhibiting p38 phosphorylation and NF-κB activation.

Bacterial infections in the blood (sepsis) have been recognized as a leading cause of mortality in the clinical field due to limitations in the detection of bacteria at low concentration and their resistance to antibiotics by excessive misuse. Some of the common symptoms are fever, chills, rapid heartbeat, difficulty breathing, confusion, and changes in mental status with occasionally pale, clammy, and mottled skin. Early diagnosis and identification are the keys to a successful treatment for sepsis patients. Researchers have developed nanoparticles to enrich bacterial populations followed by detection and applied them to conventional methods such as phenotypic and molecular diagnostics to enhance different detectors' responses toward pathogens. This short review systematically overviews steps that are followed in clinical labs for bacterial detection, identification, and their drawbacks. In this context, we discuss the role that nanoparticles can play in overcoming the limits of traditional microbiology methods in terms of turnaround times (TATs) and accuracy. We believe that this short review will provide up-to-date information about the applications of nanoparticles in the enrichment, separation, and identification of bacterial infection in the clinical field and, therefore, a way of rapid treatment.

Sepsis, a multifaceted disorder, emerges from dysregulated host response to infection, culminating in organ dysfunction and heightened risk of mortality. Present umbrella systematic review was conducted to impart accurate data regarding the effect of urinary trypsin inhibitor (UTI) alone, UTI in combination with thymosin α1, and UTI in combination with Xuebijing on sepsis and inflammation, 28-day mortality rate survival day, time of mechanical ventilation, length of intensive care unit stay, and acute physiology and chronic health evaluation (APACHE II) score.

Relevant studies were searched in international databases, including PubMed, Scopus, EMBASE, Web of Science, and Cochrane Central Library up to March 2024. Our study included meta-analyses that evaluated the effects of ulinastatin (UTI) alone, or in combination with thymosin α1 or Xuebijing, on sepsis and inflammatory biomarkers.

Nine studies were deemed relevant and subsequently included in the study. The age of the study's participants was between 42.3 and 55.7 years. In total, the dose varied between 166 and 570 KIU/12 h. Moreover, the duration varied between 3 and 8.5 days.

A comprehensive assessment of ulinastatin's overall efficacy necessitates a careful consideration of the combined effects of ulinastatin with other interventions. Future research is warranted to disentangle the specific contributions of ulinastatin in combination therapies and to enhance our understanding of its independent effects in clinical settings.

Systemic inflammatory conditions are classically characterized by an acute hyperinflammatory phase, followed by a late immunosuppressive phase that elevates the susceptibility to secondary infections. Comprehensive mechanistic understanding of these phases is largely lacking. To address this gap, we leveraged a controlled, human in vivo model of lipopolysaccharide (LPS)-induced systemic inflammation encompassing both phases. Single-cell RNA sequencing during the acute hyperinflammatory phase identified an inflammatory CD163+SLC39A8+CALR+ monocyte-like subset (infMono) at 4 h post-LPS administration. The late immunosuppressive phase was characterized by diminished expression of type I interferon (IFN)-responsive genes in monocytes, impaired myelopoiesis and a pronounced attenuation of the immune response on a secondary LPS challenge 1 week after the first. The infMono gene program and impaired myelopoiesis were also detected in patient cohorts with bacterial sepsis and coronavirus disease. IFNβ treatment restored type-I IFN responses and proinflammatory cytokine production and induced monocyte maturation, suggesting a potential treatment option for immunosuppression.

Sepsis-related acute liver injury involves complex immune dysfunctions. Epoxyeicosatrienoic acids (EETs), bioactive molecules derived from arachidonic acid (AA) via cytochrome P450 (CYP450) and rapidly hydrolyzed by soluble epoxide hydrolase (sEH), possess anti-inflammatory properties. Nevertheless, the impact of the sEH inhibitor TPPU on sepsis-related acute liver injury remains uncertain.

This study utilized comprehensive single-cell analysis to investigate the immunoregulatory mechanism of TPPU in alleviating sepsis-related acute liver injury.

Hepatic bulk RNA sequencing and proteomics analyses were employed to investigate the mechanisms underlying sepsis-related acute liver injury induced by cecal ligation and puncture in mice. Cytometry by time-of-flight and single-cell RNA sequencing were conducted to thoroughly examine the immunoregulatory role of TPPU at single-cell resolution.

Downregulation of AA metabolism and the CYP450 pathway was observed during sepsis-related acute liver injury, and TPPU treatment reduced inflammatory cytokine production and mitigated sepsis-related hepatic inflammatory injury. Comprehensive single-cell analysis revealed that TPPU promotes the expansion of anti-inflammatory CD206+CD73+ M2-like macrophages and PDL1-CD39-CCR2+ neutrophils, reprogramming liver neutrophils to an anti-inflammatory CAMP+NGP+CD177+ phenotype. Additionally, TPPU inhibits the CCL6-CCR1 signaling mediated by M2-like macrophages and CAMP+NGP+CD177+ neutrophils, altering intercellular communication within the septic liver immune microenvironment.

This study demonstrated TPPU's protective efficacy against sepsis-related acute liver injury, underscoring its vital role in modulating liver macrophages and neutrophils and enhancing prospects for personalized immunomodulatory therapy.

Sepsis is a life-threatening condition characterized by widespread inflammatory response syndrome in the body resulting from infection. Previous studies have demonstrated that some inflammatory factors or nutritional elements contributed to deaths in patients diagnosed with sepsis. Nevertheless, the correlation between the (neutrophil + monocyte)/albumin (NMa) ratio and all-cause mortality of patients diagnosed with sepsis remains unclear. This study aims to investigate the association between the NMa ratio and all-cause mortality in sepsis patients and to develop a predictive model using machine learning techniques.

The clinical data were harvested from 13,851 patients with sepsis from the MIMIC-IV (3.1) database. We divided the subjects into four groups based on quartiles of the NMa ratio. The main endpoint was 30-day all-cause mortality, and the secondary endpoint was 90-day all-cause mortality. The relationship between the NMa ratio and adverse prognosis was investigated employing Cox proportional hazard regression, restricted cubic splines, and Kaplan‒Meier curves. Moreover, we employed Boruta algorithm to evaluate the predictive potential of the NMa ratio and established the prediction models utilizing machine learning algorithms.

After adjusting for confounders, each unit increase in the NMa ratio was associated with a 1.8% and 1.6% higher risk of 30-day and 90-day all-cause mortality, respectively (P < 0.001), indicating a linear relationship, and when treated as a categorical variable, the Quartile 4 group demonstrated a significantly higher mortality risk. Boruta feature selection also displayed that the NMa ratio possessed a higher Z score, and the models established utilizing the Cox and Random Forest algorithm identified excellent predictive performance (area under the curve (AUC) = 0.72, AUC = 0.74, respectively).

The NMa ratio is strongly and linearly associated with 30-day and 90-day all-cause mortality, with higher levels significantly increasing mortality risk, even after adjusting for potential confounders. Predictive models using Cox regression and Random Forest algorithms showed strong performance, indicating that the NMa ratio could function as a predictor of negative prognosis in patients with sepsis.

Background: The rapid and accurate identification of the pathogens responsible for sepsis is essential for prompt and effective antimicrobial therapy. The T2Bacteria® Panel (T2B) and T2Candida® Panel (T2C) are rapid molecular tests performed on whole blood that exploit T2 Magnetic Resonance (T2MRsup®) technology. Objectives: This study evaluates the impact of the T2MR system as a point-of-care device for managing sepsis and septic shock patients. Methods: This single-center retrospective study was conducted at the Sant' Elia Hospital of Caltanissetta from 1 January 2023 to 31 July 2023. The study population was composed of patients with suspected sepsis and septic shock according to the Sepsis-3 criteria and for whom concurrent T2MR and BC samples were requested for diagnosis. Results: A total of 81 consecutive patients were enrolled in this study. Concordant T2/BC results were obtained in 69/81 (85.2%) patients; 58/81 (71.6%) were concordant-negative and 11/81 (13.6%) were concordant-positive. Discordant T2MR+/BC- results were observed in 9/81 patients (11.1%), while T2MR-/BC+ results were detected in 3/81 patients (3.7%). Furthermore, the median time for reporting positive T2MR test results (5.2 h) was significantly shorter than that for BC (122 h). Conclusions: Due to its high reliability, faster detection time, and simple workflow, T2MR in combination with BC improved the etiological diagnosis of sepsis in the enrolled patients.

As an important self-protection response mechanism of the body, inflammation can not only remove the necrotic or even malignant cells in the body, but also take a series of targeted measures to eliminate the pathogen of foreign invasion and block the foreign substances that may affect the life and health of the body. Flavonoids have known anti-inflammatory, anti-oxidation, anti-cancer and other effects, including glycyrrhizin molecules is one of the representatives. Licochalcone D has known anti-inflammatory and antioxidant properties and is effective in the treatment of a variety of inflammatory diseases. However, the underlying mechanism for the treatment of sepsis remains unclear. In this study, the therapeutic potential of Licochalcone D for sepsis was studied by analyzing network pharmacology and molecular dynamics simulation methods. Sepsis-related genes were collected from the database to construct PPI network maps and drug-targeting network profiles. The potential mechanism of Licochalcone D in sepsis was predicted by gene ontology, KEGG and molecular dynamics simulation. Sixty drug-disease genes were subsequently validated. Go analysis showed that monomeric small molecule Licochalcone D could regulate the process of intracellular enzyme system. The KEGG pathway analysis showed that the signal pathway of the main effect was related to the calcium pathway. The results of intersections with iron death-related target genes showed that ALOX5, ALOX15B and other nine targets all had the effect of possibly improving sepsis, while GSE 54,514, GSE 95,233 and GSE 69,528 were used to analyze the survival rate and ROC curve. Five genes were screened, including ALOX5, ALOX15B, NFE2L2 and NR4A1, HIF1A. The results of molecular docking showed that ALOX5 and Licochalcone D had strong binding activity. Finally, the results of molecular dynamics simulation showed that there was good binding power between drug and target. In the present study, we utilized molecular dynamics simulation techniques to assess the binding affinity between the small-molecule ligand and the protein receptor. The simulation outcomes demonstrate that the binding interface between the ligand and receptor remains stable, with a calculated binding free energy (ΔG) of -32.47 kJ/mol. This signifies a high-affinity interaction between the ligand and receptor, suggesting the long-term stability of the small molecule under physiological conditions. These findings provide critical insights for drug development efforts. This study elucidates the therapeutic potential of Licochalcone D, a traditional Chinese medicine monomer, in improving sepsis through the regulation of ferroptosis, thereby providing a new direction and option for subsequent clinical drug development in the treatment of sepsis.

Infections, cancer, and trauma can cause life-threatening hyperinflammation. In the present study, using single-cell RNA sequencing of circulating immune cells, we found that the mammalian target of rapamycin (mTOR) pathway plays a critical role in myeloid cell regulation in COVID-19 patients. Previously, we developed an mTOR-inhibiting nanobiologic (mTORi-nanobiologic) that efficiently targets myeloid cells and their progenitors in the bone marrow. In vitro, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the in vivo effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using 18F-FDG uptake and flow cytometry readouts, we found mTORi-nanobiologic therapy to efficiently reduce hematopoietic organ metabolic activity and inflammation to levels comparable to those of healthy control animals. Together, we show that regulating myelopoiesis with mTORi-nanobiologics is a compelling therapeutic strategy to prevent deleterious organ inflammation in infection-related complications.

Sepsis is a highly dangerous and complex condition that can result in death. It is characterized by a strong reaction to an infection, causing dysfunction in multiple bodily systems and a high risk of mortality. The transformation of macrophages is a vital stage in the procedure as they possess the capability to interchange between two separate types: M1, which promotes inflammation, and M2, which inhibits inflammation. The choice greatly affects the immune response of the host. This analysis underscores the rapidly expanding roles of exosomes and microRNAs (miRNAs) in regulating the trajectory of macrophage polarization during episodes of sepsis. Exosomes, extremely small extracellular vesicles, facilitate cellular communication by transferring biologically active compounds, including miRNAs, proteins, and lipids. We investigate the impact of changes in exosome production and composition caused by sepsis on macrophage polarization and function. Unique microRNAs present in exosomes play a significant role in controlling crucial signaling pathways that govern the phenotype of macrophages. Through thorough examination of recent progress in this area, we clarify the ways in which miRNAs derived from exosomes can either aggravate or alleviate the inflammatory reactions that occur during sepsis. This revelation not only deepens our comprehension of the underlying mechanisms of sepsis, but it also reveals potential new biomarkers and targets for treatment. This assessment aims to amalgamate diverse research investigations and propose potential avenues for future investigations on the influence that exosomes and miRNAs have on macrophage polarization and the body's response to sepsis. These entities are essential for controlling the host's reaction to sepsis and hold important functions in this mechanism.

Sepsis is a medical emergency requiring timely management and available global evidence suggests that healthcare workers and students are poorly prepared to effectively diagnose and treat such patients. This study evaluates the inter-relationship of healthcare students' attitudes towards, knowledge of and practice of sepsis management as they progress through training in Jamaica.

A prospective cross-sectional survey using an anonymous self-administered questionnaire with convenience sampling was performed among healthcare students at all levels of training. All available medical and nursing students from the major public medical and nursing schools in the Kingston Metropolitan Area were included in the study. The questionnaire was composed of 25 items covering aspects of the knowledge, attitudes, and practice of sepsis management.

The study population consisted of 292 respondents; 210 medical and 82 nursing students. The need for fluid resuscitation before ICU admission (72.6%) was the practice question that was correctly identified by the majority of students. Most of the remaining items were correctly identified by approximately half of the students including signs of sepsis such as altered mental state (56.1%), low systolic blood pressure (53.7%) and tachypnea (50.6%). In contrast, very few students could identify the signs that indicated the presence of septic shock such as high serum lactate and the need for vasopressors and only 7% of students knew the correct annual sepsis mortality rate. Nursing students had higher overall mean correct knowledge and correct practice scores compared to medical students and lower incorrect practice scores, although there was no difference in incorrect knowledge scores between the 2 respondent groups. A subgroup analysis of students in their final stage of training revealed a more comparable performance of the 2 student groups, highlighting the improved performance by both nursing and medical students who received either formal sepsis training or were in the late stage of training. Jamaican healthcare students agree that more training on sepsis is needed (98.3%) and that sepsis care bundles should be implemented during their training courses (94.2%).

This study revealed differences in the healthcare students' attitudes, knowledge of and practice of sepsis in Jamaica. There is the need for training on sepsis and implementation of sepsis care bundles.

Background/Objectives: Sepsis remains a leading cause of mortality worldwide, necessitating the development of effective prognostic markers for early risk stratification. The C-reactive protein-albumin-lymphocyte (CALLY) index is a novel biomarker that integrates inflammatory, nutritional, and immunological parameters. This study aimed to evaluate the association between the CALLY index and 30-day all-cause mortality in sepsis patients. Methods: This retrospective cohort study included adult patients diagnosed with sepsis in the emergency department between 1 January 2022, and 1 January 2025. The CALLY index was calculated as (CRP × absolute lymphocyte count)/albumin. The primary outcome was 30-day all-cause mortality. Five machine learning models-extreme gradient boosting (XGBoost), multilayer perceptron, random forest, support vector machine, and generalized linear model-were developed for mortality prediction. Four feature selection strategies (gain score, SHAP values, Boruta, and LASSO regression) were used to evaluate predictor consistency. The clinical utility of the CALLY index was assessed using decision curve analysis (DCA). Results: A total of 1644 patients were included, of whom 345 (21.0%) died within 30 days. Among the five machine learning models, the XGBoost model achieved the highest performance (AUC: 0.995, R2: 0.867, MAE: 0.063, RMSE: 0.145). In gain-based feature selection, the CALLY index emerged as the top predictor (gain: 0.187), followed by serum lactate (0.185) and white blood cell count (0.117). The CALLY index also ranked second in SHAP analysis (mean value: 0.317) and first in Boruta importance (mean importance: 37.54). DCA showed the highest net clinical benefit of the CALLY index within the 0.10-0.15 risk threshold range. Conclusions: This study demonstrates that the CALLY index is a significant predictor of 30-day mortality in sepsis patients. Machine learning analysis further reinforced the prognostic value of the CALLY index.

TLR7 (Toll-like receptor 7) has been indicated as an important sensor for single -stranded RNA contributes to systemic inflammation and mortality in acute lung injury (ALI), which is an acute diffuse inflammatory lung injury. Cumulative results show that macrophages contribute to the development and progression of ALI through the secretion of inflammatory cytokines/chemokines. Here we show that macrophage polarizes towards M1 phenotype and TLR7 signaling is activated in septic mice. Moreover, TLR7 deficiency promotes macrophage polarized towards M2 phenotype and attenuates ALI. Strikingly, the natural product of flavone apigenin (Xu et al., 2017 [1]) significantly improves sepsis-induced lung inflammation and lung injury via inhibiting inflammatory macrophages in a TLR7-dependent manner. Mechanically, Api blocked the binding of TLR7 with its agonist miR-146a. This finding reveals TLR7 is an important therapeutic target and Api as a modulator of TLR7 is a potential lead compound for treatment of septic diseases and inflammation related diseases.

Sepsis is a life-threatening condition caused by a dysregulated host response to infection, remaining a major global health challenge despite clinical advances. Therapeutic challenges arise from antibiotic misuse, incomplete understanding of its complex pathophysiology, and the unresolved interplay of immune dysregulation and microbiota disruption. Investigating microbial homeostasis in the shift from cytokine storm to immunosuppression may elucidate the interplay between microbial metabolites, immune dysfunction, and organ injury, providing a foundation for targeted therapies and drug development. Traditional Chinese Medicine (TCM) has demonstrated significant advantages in mitigating sepsis-associated cytokine storms and modulating gut microbiota homeostasis, offering a promising strategy for developing highly effective and less toxic targeted monomeric compounds. Elucidating the interactions within the immune-inflammation-microbiota network in sepsis paves the way for biomarker-driven personalized therapeutic approaches.

Sepsis, a life-threatening condition characterized by a dysregulated immune response to infection, remains a significant cause of mortality in both humans and veterinary patients. This study explores oxylipins as potential indicators of sepsis in dogs through in vivo plasma analysis and an ex vivo lipopolysaccharide (LPS)-treated skin organ culture model. By employing a robust analytical platform, 52 oxylipins and 4 polyunsaturated fatty acids were profiled in plasma and skin cultures. Results revealed distinct biochemical and morphological changes, with LPS triggering capillary vasodilation and time-dependent increases in pro-inflammatory mediators such as PGE2 and isoprostanes. Importantly, PGE2 exhibited consistent trends across both models, highlighting its potential as a diagnostic biomarker. This study underscores the utility of the skin organ culture model in mimicking early inflammatory events, offering novel insights into oxylipin dynamics during sepsis and their implications for disease resolution.

Bacterial detection is pivotal for the timely diagnosis and effective treatment of infectious diseases. Microfluidic platforms offer advantages over traditional methods, including heightened sensitivity, rapid analysis, and minimal sample volume requirements. Traditional clinical methods for bacterial identification often involve extended processing times and necessitate high pathogen concentrations, resulting in delayed diagnoses and missed treatment opportunities. Microfluidic technology overcomes these limitations by facilitating rapid bacterial identification at lower biomass levels, thus ensuring prompt and precise treatment interventions. Additionally, bacteria-driven inflammation has been associated with the development and progression of various diseases, including cancer. Elucidating the complex interplay between bacteria, inflammation, and disease is essential for devising effective disease models and therapeutic strategies. Microfluidic platforms have been used to construct in vitro disease models that accurately replicate the intricate microenvironment that bacteria-driven inflammation affects. These models offer valuable insights into bacteria-driven inflammation and its impact on disease progression, such as cancer metastasis and therapeutic responses. This review examines recent advancements in bacterial detection using microfluidics and assesses the potential of this technology as a robust tool for exploring bacteria-driven inflammation in the context of cancer.

The triglyceride-glucose (TyG) index is a marker for insulin resistance (IR) linked to diabetes complications and poor outcomes. Its connection to all-cause mortality in non-diabetic critically ill patients is unknown. This study aims to investigate the TyG index's impact on mortality in this population, evaluating how IR affects their prognosis.

This study is retrospective observational research utilizing data from the eICU Collaborative Research Database. A total of 14,089 non-diabetic critically ill patients were included and categorized into three groups based on the TyG index measured on the first day of admission (T1, T2, and T3). Kaplan-Meier survival analysis was performed to compare the 28-day mortality rates among the different groups. Cox proportional hazards models were used to assess the relationship between the TyG index and 28-day mortality. Additionally, we conducted sensitivity analyses, subgroup analyses, and interaction analyses to assess the robustness of the results.

During the observation period, 730 patients (5.18%) died in the ICU, while 1,178 patients (8.36%) died in the hospital. The 28-day ICU mortality rate and hospital mortality rate significantly increased with higher TyG index values (P < 0.001). Cox proportional hazards models were used to assess the relationship between the TyG index and 28-day mortality. Specifically, Cox proportional hazards models were used to assess the relationship between the TyG index and 28-day mortality. Furthermore, the analysis showed a nonlinear effect of the TyG index on mortality in non-diabetic critically ill patients, with a critical point at 9.94. While Below 9.94, ICU and hospital mortality rates rose with higher TyG index values. But above 9.94, mortality didn't significantly increase despite further rises in the TyG index. Sensitivity and subgroup analyses confirmed the robustness of these results, and E-value analysis indicated strong resistance to unmeasured confounding factors.

The TyG index demonstrates a significant positive correlation with all-cause mortality in non-diabetic critically ill patients, exhibiting a nonlinear relationship. Consequently, the TyG index serves as a crucial tool for identifying high-risk patients, thereby assisting clinicians in formulating more effective monitoring and intervention strategies.

Group A Streptococcus (GAS) is a pathogen that is capable of colonizing various infection sites and can potentially elicit an inadequate immune response that will lead to sepsis. The processes underlying this misdirected immune reaction remain poorly understood, and reliable biomarkers for indicating impending organ failure during sepsis are still missing. The present study aims to identify parameters that can predict the onset of end-organ damage in the course of sepsis. To that extent, we investigated key aspects of the immune response in early-phase sepsis following infection of different tissues in a mouse model, using Brefeldin A to link cytokine production to specific cell types through multi-parameter flow cytometry. Subcutaneous and intravenous GAS infections resulted in clinical sepsis, which was paralleled by peripheral blood lymphopenia. Intravenous infection in particular was associated with a higher bacterial burden in the liver that strongly correlated with an increased granulocyte-to-lymphocyte ratio of the peripheral blood. Strikingly, IL-6 overexpression was more pronounced in intravenous infection and strongly correlated with hepatic stress, indicated by elevated bacterial loads in the liver. Collectively, our data highlight the potential utility of IL-6 in conjunction with an elevated granulocyte-to-lymphocyte ratio as promising early indicators of concomitant liver stress in sepsis.

The accurate and prompt diagnosis of infections is essential for improving patient outcomes and preventing bacterial drug resistance. Host gene expression profiling as an approach to infection diagnosis holds great potential in assisting early and accurate diagnosis of infection.

To improve the precision of infection diagnosis, we developed InfectDiagno, a rank-based ensemble machine learning algorithm for infection diagnosis via host gene expression patterns. Eleven data sets were used as training data sets for the method development, and the InfectDiagno algorithm was optimized by multi-cohort training samples. Nine data sets were used as independent validation data sets for the method. We further validated the diagnostic capacity of InfectDiagno in a prospective clinical cohort.

After selecting 100 feature genes based on their gene expression ranks for infection prediction, we trained a classifier using both a noninfected-vs-infected area under the receiver-operating characteristic curve (area under the curve [AUC] 0.95 [95% CI, 0.93-0.97]) and a bacterial-vs-viral AUC 0.95 (95% CI, 0.93-0.97). We then used the noninfected/infected classifier together with the bacterial/viral classifier to build a discriminating infection diagnosis model. The sensitivity was 0.931 and 0.872, and specificity 0.963 and 0.929, for bacterial and viral infections, respectively. We then applied InfectDiagno to a prospective clinical cohort (n = 517), and found it classified 95% of the samples correctly.

Our study shows that the InfectDiagno algorithm is a powerful and robust tool to accurately identify infection in a real-world patient population, which has the potential to profoundly improve clinical care in the field of infection diagnosis.

Sepsis, characterized by immune dysregulation, inflammatory cascades, and coagulation dysfunction, remains a global health challenge with high mortality, particularly in patients with multiple organ dysfunction syndrome (MODS). Existing prognostic tools, such as SOFA and APACHE II scores, are limited by complexity and lack of real-time monitoring, necessitating simple and reliable biomarkers for risk stratification and individualized management.

This study aimed to evaluate the prognostic value of the neutrophil-to-lymphocyte-to-platelet ratio (NLPR) for mortality in sepsis patients and explore its potential utility in dynamic risk stratification and treatment optimization.

We conducted a retrospective cohort study using the MIMIC-IV database (v3.1), including adult sepsis patients meeting Sepsis-3.0 criteria. NLPR was calculated based on neutrophil, lymphocyte, and platelet counts within 24 h of admission. Patients were stratified into quartiles (Q1-Q4) based on NLPR values. Kaplan-Meier survival analysis, Cox regression models, and restricted cubic spline (RCS) analysis were performed to assess NLPR's association with 28-day, 90-day, and 365-day mortality. Subgroup analyses examined NLPR's performance in diverse clinical populations.

NLPR was a strong and independent predictor of mortality at all time points. Patients in the highest NLPR quartile (Q4) had significantly higher 28-day (28.22% vs. 12.64%), 90-day (36.82% vs. 18.06%), and 365-day (44.94% vs. 25.58%) mortality compared to the lowest quartile (Q1, all P < 0.001). Cox regression confirmed the independent association of high NLPR with mortality after adjusting for confounders such as age, gender, BMI, and SOFA scores. RCS analysis identified nonlinear relationships between NLPR and mortality, with critical thresholds (e.g.,NLPR = 6.5 for 365-day mortality) providing actionable targets for early risk identification. Subgroup analysis revealed consistent predictive performance across clinical populations, with amplified risks in younger patients, malnourished individuals, and those with acute kidney injury.

NLPR is a simple, accessible, and robust biomarker for sepsis risk stratification, integrating inflammation and coagulation data. It complements traditional scoring systems, provides actionable thresholds for early intervention, and facilitates dynamic monitoring. These findings underscore NLPR's potential to improve clinical decision-making and outcomes in sepsis management, warranting validation in prospective multicenter studies.

In this study, we aimed to explore the association between the choice of empirical antibiotic therapy and outcomes in ED patients with sepsis.

Patients admitted to ED with sepsis were identified from a single center in the United States, and the data is stored in the MIMIC-IV-ED database. Propensity score matched model was used to match patients receiving empirical mono or combination antibiotic therapy. Logistic regression model was used to assess the associations between empirical antibiotic therapy and in-hospital mortality.

A total of 11,380 ED patients with sepsis were included in the data analysis. After PSM, 3920 pairs of patients were matched between the empirical mono-antibiotic therapy group and combination antibiotic therapy group. No significant benefit was observed among the empirical combination antibiotic therapy patients compared with the mono-antibiotic therapy in in-hospital mortality (OR, 0.96; 95 % CI, 0.81-1.15; P: 0.684). Empirical quinolones mono-therapy was associated with significantly lower mortality compared to cephalosporins (OR, 2.12; 95 % CI, 1.35-3.50; P:0.002), penicillins (OR, 1.87; 95 % CI, 1.08-3.34; P:0.029) and vancomycin mono-therapy (OR, 2.15; 95 % CI, 1.19-3.97; P:0.012).

Empirical combination antibiotic therapy was not associated with reduced mortality in ED patients with sepsis. Compared with cephalosporins, penicillins and vancomycin, quinolone mono-antibiotic therapy was significantly associated with a decreased risk of in-hospital mortality, especially in patients with respiratory tract infections.

Sepsis and septic shock are major healthcare problems worldwide, associated with substantial mortality. Early administration of norepinephrine in septic shock patients has been associated with an increased survival rate, but the timing from septic shock to norepinephrine initiation is controversial. This study examined the associations between the timing of initial norepinephrine administration and clinical outcomes in adult patients with septic shock.

This prospective cohort study was conducted from September 2021 to June 2022 in an intensive care unit (ICU) of a tertiary general hospital. All enrolled patients were divided into early and late norepinephrine groups according to whether the time from the onset of septic shock to the first application of norepinephrine was >1 h. The primary outcome was 28-day mortality. Secondary outcomes included ICU length of stay (LOS), hospital LOS, time to achieve a mean arterial pressure (MAP) ≥65 mmHg, 24-hour infusion volume, 6-hour Lac clearance, mechanical ventilation days, and continuous renal replacement therapy (CRRT )ratio. Multivariable logistic regression analysis was used to evaluate the independent risk factors for 28-day mortality.

This study enrolled 120 patients, including 42 patients (35.0%) and 78 patients (65.0%) in the early and late norepinephrine groups, respectively. The 28-day mortality was lower in the early group than in the late group (28.6% vs. 47.4%, P=0.045). The median time to achieve MAP ≥65 mmHg was shorter in the early group than in the late group (1.0 h vs. 1.5 h, P=0.010). The median 24-hour intravenous fluids volume in the early group was lower than that in the late group (40.7% vs. 14.9%, P=0.030). The median 6-hour lactate (Lac) clearance rate in the early group was higher than that in the late group (40.7% vs. 14.9%, P=0.009). There were no significant differences between early and late groups by ICU LOS (P=0.748), hospital LOS (P=0.369), mechanical ventilation time (P=0.128), and CRRT ratio (P=0.637). The independent risk factors for 28-day mortality included being male (odds ratio [OR]=3.288, 95% confidence interval [CI]: 1.236 to 8.745, P = 0.017), time to norepinephrine initiation >1 h (OR=4.564, 95% CI: 1.382 to 15.079, P = 0.013), and time to achieve MAP ≥65 mmHg (OR=1.800, 95% CI: 1.171 to 2.767, P = 0.007).

Norepinephrine initiation ≤1 h is associated with lower 28-day mortality in patients with septic shock. Early norepinephrine administration is also associated with a shorter time to achieve MAP ≥65 mmHg, lower 24-hour intravenous fluids volume, and higher 6-hour Lac clearance rate. Being male, time to achieve MAP ≥65 mmHg, and norepinephrine initiation >1 h are independent risk factors for 28-day mortality.Trial registration Chinese Clinical Trial Registry Identifier: ChiCTR2100044071.

Silver sulfadiazine (SSD) is a widely used antibacterial agent for burn wound treatment owing to its capability in re-epithelialization and wound healing. However, due to its low solubility, the need for an effective drug delivery system is mandatory. This study aimed to optimize SSD nanostructured lipid-based carriers (NLCs), incorporated in a collagen sponge form as an innovative topical dosage form for effective burn wound treatment. SSD-NLCs were prepared by applying Box-Behnken design and characterized in terms of particle size, zeta potential, and entrapment efficiency (EE). The optimized SSD-NLCs formula was selected and incorporated into a cross-linked collagen sponge and lyophilized for 24 h. The SSD-NLCs sponge morphological structure, porosity, swelling ratio, in vitro drug release profile and antibacterial activity were assessed. Furthermore, investigating the competitive inhibitory efficiency of SSD against para-aminobenzoic acid (PABA), the native ligand for the dihydropteroate synthetase enzyme based on the calculated binding free energy using the CB-Dock docking server was evaluated. Additionally, the wound healing activity and histopathological studies were evaluated on a second-degree burn wounds in a rat model. The optimized SSD-NLCs were spherical, possessing size of 115.69 ± 3.25 nm, EE% of 89.69 ± 1.36 % and a porosity of 71.22 %. Furthermore, the SSD-NLCs sponge showed an enhanced swelling ratio and improved antimicrobial activity compared to SSD. Finally, in vivo studies in rats showed that SSD-NLCs sponge are effective wound healing formulation owing to their ability to improve the quality of tissue regeneration without scars formation. Results showed that SSD-NLCs sponge can enhance the SSD efficacy in treatment of burn wounds. Further toxicological studies are still needed before clinical application.

Our aim was to explore the IL-27 effect in sepsis (SP)-related acute hepatic injury (AHI) as well as its possible mechanism.

Herein, we utilized both wild-type (WT) and IL-27 receptor (WSX-1)-deficient (IL-27R-/-) mice alongside RAW264.7 cells. Our study established an SP-associated AHI model through the intraperitoneal injections of lipopolysaccharide (LPS) + D-galactosamine (D-G). For examining the IL-27 impact on AHI, mice serum and liver tissue samples were gathered. Inflammatory factor levels in the liver and serum were detected using ELISA and immunohistochemistry. Immunofluorescence and Western blot techniques were employed for the detection of protein expression associated with polarization and pyroptosis in the liver, including iNOS, ARG-1, caspase-11, RAGE, and GSDMD. To further verify the IL-27 effects on macrophage polarization and pyroptosis and explore possible mechanisms involved, we used LPS-triggered RAW264.7 macrophages to assess AMPK/SIRT1 expression after IL-27 intervention. This study utilized Compound C (CC) to block the AMPK/SIRT1 pathway. The inflammatory response level and protein expression related to macrophage polarization and pyroptosis were measured again to reveal IL-27 implication in AHI and determine whether its role is associated with the AMPK/SIRT1 pathway.

The results revealed that IL-27 exacerbated systemic inflammation and liver damage in AHI mice by promoting M1 macrophage polarization, thereby increasing pro-inflammatory phenotype macrophages (M1). This further exacerbated the inflammatory response and pyroptosis in vivo and in vitro. Additionally, IL-27 down-regulated p-AMPK and SIRT1 protein expression while overexpressing macrophage inflammatory mediators including IL-1β/6 and TNFα. Furthermore, IL-27 promoted increased RAGE and caspase-11 protein expression, aggravating macrophage pyroptosis. Employing CC to block the AMPK pathway further aggravated M1 macrophage polarization and pyroptosis in vitro and in vivo, ultimately worsening liver injury.

Here, IL-27 aggravates AHI by promoting macrophage M1 polarization to induce caspase-11-mediated pyroptosis in vitro and in vivo, which may be linked to the AMPK/SIRT1 signaling pathway.

Sepsis is an underappreciated yet severe threat to human life, marked by organ dysfunction and high mortality resulting from disordered inflammatory responses to blood infection. Unfortunately, no specific drugs are available for effective sepsis treatment. As a pivotal biomarker for sepsis, lactate levels are closely related to vascular permeability and sepsis-associated mortality. Herein, a dual-pipeline lactate removal strategy is reported from circulating blood to ameliorate vascular permeability and lipopolysaccharide (LPS)-induced sepsis. This is achieved by formulating lactate oxidase (LOX)-encapsulated hollow manganese dioxide (HMnO2) nanohybrids (LOX@HMnO2-P[5]A) bearing pillar[5]arene (P[5]A) macrocycle with excellent host-guest properties. The highly biocompatible nanohybrids enable direct lactate consumption through LOX catalytic degradation and block lactate production by P[5]A-mediated LPS trapping, allowing for dual-pipeline lactate removal to maximize the reversal of lactate-mediated vascular hyperpermeability. Besides, HMnO2 cores decompose hydrogen peroxide produced from lactate oxidation into oxygen, further contributing to lactate consumption and mitigating the hypoxic inflammatory environment. In vivo investigations demonstrate that intravenous administration of LOX@HMnO2-P[5]A nanohybrids with extended blood circulation can effectively ameliorate endothelial barrier dysfunction, inflammatory responses, and multiple organ injury, ultimately improving survival outcomes in LPS-induced sepsis. Taken together, this dual-pipeline lactate removal strategy offers a promising approach for efficient sepsis treatment.