Severe respiratory viral infections can lead to viral sepsis (VS), a life-threatening condition characterized by lung and extrapulmonary organ dysfunction. However, the pathology of VS is not clear. Specifically, it is unknown how the cytokine storm and direct virus infection contribute to the damage of extrapulmonary organs.

In this study, we established survival and lethal mouse models of VS by intranasally administering different doses of PR8/H1N1 influenza virus in C57BL/6J male mice, as well as model of bacterial sepsis (BS) caused by Streptococcus pneumoniae as references. Viraemia and extrapulmonary dissemination and infection of the virus were examined. Single-cell sequencing of the lungs and livers was performed at different days post-infection (dpi) in three groups.

While bacteria can spread and colonize extensively in extrapulmonary organs, causing multiple organ injuries, IAVs mainly replicate and cause damage in pulmonary cells. Live virus can be isolated in the blood and extrapulmonary organs. Disseminating via the bloodstream, IAVs transiently infect the liver and spleen, causing liver dysfunction and spleen atrophy, without affecting kidney function, despite systematically elevated cytokine levels. Compared to BS, a more significant decrease in the proportion of alveolar macrophages, epithelial cells, endothelial cells, and fibroblasts in the lungs, as well as endothelial cells and Kupffer cells in the liver, was observed in VS. This was accompanied by a longer activated PANoptosis pathway and downregulated genes responsible for barrier function and antigen presentation in the epithelial and endothelial cells.

Our study suggests that H1N1 influenza virus disseminates through the bloodstream and infects extrapulmonary organs to varying extents, which may lead to differential cell death, organ dysfunction, and trigger VS.

This research was supported by the National Natural Science Foundation of China (82241056, 82170015, 82030002, 82470007, 824B2001), the National Key R&D Program of China (2023YFC2306300), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-048), the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202208), New Cornerstone Science Foundation, National High Level Hospital Clinical Research Funding (2024-NHLHCRF-LX-01-0101, 2024-NHLHCRF-LX-01-0102), Beijing Research Ward Excellence Program (BRWEP2024W114060103), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0506200, 2023ZD0506203) and Special Research Fund for Central Universities, Peking Union Medical College (3332024193).

Sepsis is characterized by severe organ failure due to an impaired response to infection. The underlying pathophysiology of sepsis is characterized by concurrent unbalanced hyperinflammatory and immunoparalysis. This study aimed to identify new key biomarkers that could predict outcomes in sepsis patients and explore theirunderlying molecular mechanisms. Bulk transcriptome data (GSE65682, GSE28750, GSE57065, GSE95233) and scRNA-seq data (GSE167363) of sepsis were obtained from the GEO database. Data for MR analysis were sourced from the eQTLGen Consortium and IEU OpenGWAS project. Prognostic biomarkers and potential drug targets for sepsis were identified through univariate Cox regression and MR analysis. The expression of these biomarkers was further validated using scRNA-seq data to investigate the underlying molecular mechanisms. Significantly higher expression of CHIT1 was found at sepsis non-survivor and associated with 28-day mortality of sepsis. scRNA-seq data of septic samples found that CHIT1 mainly expressed in neutrophils, which was also higher in sepsis non-survivors. The CHIT1 + neutrophils expressed higher inflammation related genes of S100A8, S100A9, S100A11, S100A12, IL1R2, IFNGR2, TLR2 and CXCL8 and reduced expression of HLA related genes of HLA-DMA, HLA-DPA1, HLA-DPB1, HLA-DRA, HLA-DRB1 and HLA-DRB5. Moreover, cell-chat analysis also showed that CHIT1 + neutrophils could interact with other immune cell types, including NK cells, erythroid cells, monocytes/macrophages, and DC by the way of ICAM1-(ITGAM + ITGB2) pathway. We identified CHIT1 as new biomarker and potential drug target for sepsis, which may intensify hyperinflammation and immune suppression of neutrophils. Developing immunotherapeutic strategies aimed at targeting CHIT1 would help to enhance sepsis outcomes.

Background: The delta neutrophil index (DNI) represents the immature granulocyte fraction and is determined by subtracting the fraction of mature polymorphonuclear leucocytes from the sum of myeloperoxidase-reactive cells. The DNI has been proposed as a useful prognostic marker for sepsis. This study evaluated the clinical utility of DNI as a predictive marker in patients with pneumonia-induced sepsis in the intensive care unit (ICU). Methods: We conducted a retrospective study of pneumonia-induced sepsis in patients who were admitted to the Kangdong Sacred Heart Hospital's medical ICUs from July 2022 to March 2024. The DNI was measured on three consecutive days after ICU admission. The primary outcome of this study was a 28-day mortality. Results: A total of 227 patients with pneumonia-induced sepsis were included in this study. A 28-day mortality occurred 20.3% of the time in our study. In a univariate analysis, age (p = 0.05), lymphocyte (p = 0.02), DNI 1 (p = 0.01), DNI 2 (p = 0.00), DNI 3 (p = 0.00), and lactic acid (p = 0.00) were significantly associated with 28-day mortality. In a multivariable analysis, lactate (adj. OR: 0.86, 95% CI: 0.78-0.95, p = 0.002), and DNI 3 (adj. OR: 0.94, 95% CI: 0.89-0.99, p = 0.048) were significantly associated with 28-day mortality. In our study, the most appropriate cut-off values were DNI 1 (7.15), DNI 2 (8.9), and DNI 3 (2.6). Patients with higher DNI 3 (≥2.6) showed higher 28-day mortality than patients with lower DNI 3 values of <2.6 (67.4% vs. 32.6%; p < 0.001). However, those aged ≥70 did not show statistically significantly different DNI 1 values between the survivor and non- survivor groups. Conclusions: The DNI at 72 h after ICU admission is a promising predictive prognostic marker of 28-day mortality in patients with pneumonia-induced sepsis in the ICU. However, the interpretation of the DNI in sepsis patients aged 70 and older on the first day of hospitalization should be approached with caution.

The application of biomimetic and stimuli-responsive nanocarriers displays considerable promise in improving the management of bacterial sepsis and overcoming antimicrobial resistance. Therefore, the study aimed to synthesize a novel hyaluronic acid-lysine conjugate (HA-Lys) and to utilize the attributes of the synthesized HA-Lys with Tocopherol succinate (TS) and Oleylamine (OLA) in the formulation of multifunctional biomimetic pH-responsive HNLCs loaded with vancomycin (VCM-HNLCs), to combat bacterial sepsis.

A novel hyaluronic acid-lysine conjugate (HA-Lys) was synthesized and characterized using FTIR and 1H NMR spectroscopy. Vancomycin-loaded hybrid nanosystems (VCM-HNLCs) were prepared through hot homogenization ultrasonication and evaluated for particle size, polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE%). In vitro biocompatibility was assessed via MTT assay and red blood cell hemolysis test. The binding affinity to TLR2 and TLR4 was measured using microscale thermophoresis (MST). Drug release was evaluated using the dialysis bag method. Antimicrobial activity against MRSA and efflux pump inhibition were also determined. Efficacy was demonstrated in an MRSA-induced sepsis mice model.

The VCM-HNLCs, produced via hot homogenization ultrasonication, exhibited particle size (PS), polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE%) of 110.77 ± 1.692 nm, 0.113 ± 0.022, - 2.92 ± 0.210 mV, and 76.27 ± 1.200%, respectively. In vitro, biocompatibility was proven by hemolysis and cytotoxicity studies. The VCM-HNLCs demonstrated targetability to human Toll-like receptors (TLR 2 and 4) as validated by microscale thermophoresis (MST). VCM-HNLCs showed a twofold reduction in MIC values at physiological pH compared to the bare VCM against S. aureus and MRSA for 48 h. While at pH 6.0, MIC values were reduced by fourfold in the first 24 h and by eightfold in the subsequent 48 and 72 h against tested strains. Furthermore, VCM-HNLCs showed inhibitory effects against MRSA efflux pumps, reactive oxygen species (ROS), and lipopolysaccharide (LPS)-induced hyperinflammation. In an MRSA-induced sepsis mice model, VCM-HNLCs demonstrated superior efficacy compared to free VCM, significantly eliminated bacteria and improved survival rates.

Overall, these results highlight the potential of VCM-HNLCs as novel multifunctional nanocarriers to combat antimicrobial resistance (AMR) and enhance sepsis outcomes.

Sepsis is a life-threatening disease with a high mortality rate, for which the pathogenetic mechanism still unclear. DNA damage repair (DDR) is essential for maintaining genome integrity. This study aimed to explore the role of DDR-related genes in the development of sepsis and further investigated their molecular subtypes to enrich potential diagnostic biomarkers. Two Gene Expression Omnibus datasets (GSE65682 and GSE95233) were implemented to investigate the underlying role of DDR-related genes in sepsis. Three machine learning algorithms were utilized to identify the optimal feature genes. The diagnostic value of the selected genes was evaluated using the receiver operating characteristic curves. A nomogram was built to assess the diagnostic ability of the selected genes via "rms" package. Consensus clustering was subsequently performed to identify the molecular subtypes for sepsis. Furthermore, CIBERSORT was used to evaluate the immune cell infiltration of samples. Three different expressed DDR-related genes (GADD45A, HMGB2, and RPS27L) were identified as sepsis biomarkers. Receiver operating characteristic curves revealed that all 3 genes showed good diagnostic value. The nomogram including these 3 genes also exhibited good diagnostic efficiency. A notable difference in the immune microenvironment landscape was discovered between sepsis patients and healthy controls. Furthermore, all 3 genes were significantly associated with various immune cells. Our findings identify potential new diagnostic markers for sepsis that shed light on novel pathogenetic mechanism of sepsis and, therefore, may offer opportunities for potential intervention and treatment strategies.

Codonopsis Pilosula (CP), as a well-known traditional Chinese medicine (TCM) with medicinal and edible herb, is one of the most representative tonic Chinese herbal medicine. It has been widely used for regulating immune function with hardly any adverse effects in clinical practice.

This study aimed to elucidate the immunomodulatory effect and to explore probable mechanism of Codonopsis Pilosula Extract (CPE) in septic rats.

The model of septic rat was established by cecal ligation and perforation (CLP). The thymus index, spleen index and cerebral index were calculated. Histological changes were observed by Hematoxylin-eosin (HE). The positive expression of CD4+ T cells was determined in the thymus and spleen by immunohistochemical (IHC). The expression level of 24 h CD4 was corroborated by real-time quantitative polymerase chain reaction (RT-QPCR). Infectious factors, immune factors and inflammatory factors were determined by enzyme-linked immunosorbent assay (ELISA). Blood cells were detected by automatic biochemical analyzer. The metabolite changes and gene expression levels, the potential targets and pathways of CPE in regulating immune function of thymus were analyzed by integrative analysis of transcriptomic and metabolomic methods.

High dose of CPE increased the thymus index and spleen index of septic rats at different stages, and the brain index at different stages could be increased at medium dose and high dose. Medium and high doses of CPE reduced the pathological changes of thymus, spleen and brain tissue. CPE promoted the expression levels of CD4 in the thymus and spleen. CPE improved the levels of red blood cells (RBC), lymphocytes (LYM) and hemoglobin (HGB), and decreased the levels of neutrophils (NEUT), NLR (NEUT/LYM) and PLR (PLT/LYM). CPE dynamically regulated the levels of white blood cells (WBC) and PLT (platelet). CPE dynamically regulated the expression levels of infectious factors, immune factors, and inflammatory factors related to disease severity.

CPE has the ability to dynamically modulate the expression levels of infectious factors, immune factors, and inflammatory factors related to disease severity, and alleviate the damages of immune organs. The research has provided a global view of the integration of metabolomics and transcriptomics to elucidate the immunomodulatory effects and mechanisms of CPE. CPE could affect a series of biological processes in glycerophospholipid metabolism by interfering with the B cell receptor (BCR) signaling pathway in the thymus, to maintain immune homeostasis of septic rats on the whole, especially humoral immunity.

Interleukin-6 (IL-6) plays a central role in sepsis-induced cytokine storm involving immune hyperactivation and early neutrophil activation. Programmed death protein-1 (PD-1) is associated with sepsis-induced immunosuppression and lymphocyte apoptosis. However, the effects of simultaneous blockade of IL-6 and PD-1 in a murine sepsis model are not well understood.

In this study, sepsis was induced in male C57BL/6 mice through cecal ligation and puncture (CLP). IL-6 blockade, PD-1 blockade, or combination of both was administered 24 h after CLP. Peripheral blood count, cytokine level, lymphocyte apoptosis in the spleen, neutrophil infiltration in the lungs and liver, and survival rate were measured. The mortality rate of the IL-6/PD-1 group was lower, though not statistically significant (p = 0.164), than that of CLP mice (75.0% vs. 91.7%). The IL-6/PD-1 group had lower neutrophil percentage and platelet count compared with the CLP group; no significant difference was observed in other cytokine levels. The IL-6/PD-1 group also showed reduced T lymphocyte apoptosis in the spleen and decreased neutrophil infiltration in the liver and lungs.

IL-6/PD-1 dual blockade reduces neutrophil infiltration, lymphocyte apoptosis, and bacterial burden while preserving tissue integrity in sepsis. Although the improvement in survival was not statistically significant, these findings highlight its potential as a therapeutic approach in sepsis.

Lipopolysaccharide (LPS)-neutralizing peptides are emerging as new potential therapeutic modalities to treat sepsis and skin infections. Purinergic ligand-gated ion channels (P2X receptors) play a critical role in various biological processes, including inflammation. Recent drug development efforts have significantly focused on the modulation of P2X receptors. Here, we investigated the effects of the synthetic LPS-neutralizing peptide Pep19-2.5 on human P2X receptors in cells of the innate immune system. Pep19-2.5 concentration-dependently triggered Ca2+ influx, interleukin (IL)-1β, and lactate dehydrogenase (LDH) release in Toll-like receptor-stimulated human macrophages and monocytes. Ca2+ influx was mediated at least partially by P2X7 receptors, and IL-1β and LDH release by P2X7 receptors, respectively. Confocal microscopy confirmed the colocalization of Pep19-2.5 with P2X7 receptors. Pep19-2.5-induced IL-1β release in primed cells was dependent on K+ efflux, caspase-1, and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 inflammasome. In the presence of the P2X7 receptor agonist 2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate, Pep19-2.5 reduced IL-1β and LDH release. In 1321N1, astrocytoma cells stably transfected with human P2X receptors, Pep19-2.5 potently modulated P2X7 and P2X4 receptors (IC50 values of 0.346 and 0.146 μM, respectively) but showed less (P2X1, P2X3) or no activity (P2X2) at other P2X receptor subtypes. Our findings underline the potential of LPS-neutralizing peptides as modulators of P2X receptors, thus expanding their applicability beyond the treatment of sepsis to the treatment of inflammatory diseases.

Coronavirus disease 2019 (COVID-19) is associated with a high incidence of thromboembolic events, both venous and arterial. There are currently no specific clinical or laboratory markers to guide antithrombotic therapy for COVID-19 patients. Immature platelets represent a population of hyper-reactive platelets associated with arterial thrombotic events. This prospective study compared consecutive severe COVID-19 patients (n = 53, median age = 73 years) versus patients with sepsis from another origin (n = 41, median age = 69 years). Total platelet counts, immature platelet fraction (IPF) and immature platelet count (IPC) were determined by the Sysmex XN-3000 auto-analyzer on admission and at subsequent time-points. IPC levels three days after admission were significantly higher in the COVID-19 group compared to the sepsis group (13.4 × 109/ L [IQR 9.1-18.5] in the COVID-19 group vs 9 × 109/ L [5.5-14.7] in the sepsis group, P = 0.007). COVID-19 patients with respiratory disease show increased platelet turnover and reactivity, as seen in higher levels of immature platelet indices, especially IPC, compared to the sepsis control group. While these platelet indices remained high, CRP levels decreased, particularly in patients treated with tocilizumab. This reduction in CRP was not accompanied by any apparent clinical improvement. These findings suggest that immature platelets may serve as a biomarker for disease severity in COVID-19 patients and their CRP may not be a reliable marker for disease severity.

Cordyceps spp. (CS), a well-known medicinal mushroom that belongs to Tibetan medicine and is predominantly found in the high altitudes in the Himalayas. CS is a rich reservoir of various bioactive substances including nucleosides, sterols flavonoids, peptides, and phenolic compounds. The bioactive compounds and CS extract have antibacterial, antioxidant, immunomodulatory, and inflammatory properties in addition to organ protection properties across a range of disease states. The study aimed to review the potential of CS, a medicinal mushroom, as a treatment for sepsis. While current sepsis drugs have side effects, CS shows promise due to its anti-inflammatory, antioxidant, and antibacterial properties. We have performed an extensive literature search based on published original and review articles in Scopus and PubMed. The keywords used were Cordyceps, sepsis, and inflammation. Studies indicate that CS extract and bioactive compounds target free radicals including oxidative as well as nitrosative stress, lower inflammation, and modulate the immune system, all of which are critical components in sepsis. The brain, liver, kidneys, lungs, and heart are among the organs that CS extracts may be able to shield against harm during sepsis. Traditional remedies with anti-inflammatory and protective qualities, such as Cordyceps mushrooms, are promising in sepsis. However, more research including clinical trials is required to validate the usefulness of CS metabolites in terms of organ protection and fight infections in sepsis.

The United Nations Inter-Agency Group for Child Mortality Estimation (UNIGME) estimates that every year 2.5 million neonates die in their first month of life, accounting for nearly one-half of deaths in children under 5 years of age. Neonatal sepsis is the third leading cause of neonatal mortality. The worldwide burden of bacterial sepsis is expected to increase in the next decades due to the lack of effective molecular therapies to replace the administration of antibiotics whose efficacy is compromised by the emergence of resistant strains. In addition, prolonged exposure to antibiotics can have negative effects by increasing the risk of infection by other organisms. With the global burden of sepsis increasing and no vaccine nor other therapeutic approaches proved efficient, the World Health Organization (WHO) stresses the need for new therapeutic targets for sepsis treatment and infection prevention (WHO, A73/32). In response to this unresolved clinical issue, the P2X7 receptor (P2X7R), a key component of the inflammatory cascade, has emerged as a potential target for treating inflammatory/infection diseases. Indeed numerous studies have demonstrated the relevance of the purinergic system as a pharmacological target in addressing immune-mediated inflammatory diseases by regulating immunity, inflammation, and organ function. In this review, we analyze key features of sepsis immunopathophysiology focusing in neonatal sepsis and on how the immunomodulatory role of P2X7R could be a potential pharmacological target for reducing the burden of neonatal sepsis.

Root resorption consists of complex, multistep processes that involve cell signalling caused by inflammation and stromal cells, which promotes the secretion of receptor activator of nuclear factor κB ligand/ macrophage-colony stimulating factor (RANKL/M-CSF) resulting in a resorptive process.

The aim of this narrative review was to analyse the literature related to root resorption resulting from microbial infection and to comparing it with non-microbial infection.

An electronic literature search was performed using the PubMed database and applying keywords of articles published in English. Eligible papers were reviewed to reveal the descriptions of bone and root resorption processes. The abstracts were searched manually to identify articles about infection-stimulating bone and root resorption.

Three main types of root resorption were identified, two associated with primary bacterial infection and one secondary to bacterial infection. These include external inflammatory resorption, internal inflammatory resorption and external cervical (invasive) resorption.

The magnitude of cytokine involvement that promotes resorption and M-CSF/RANKL production depends on multiple factors, including pathogen virulence, site of infection and host genetic factors that activate the inflammation at the infection site. Two mechanisms activate the resorption mechanisms-the canonical and non-canonical pathways that can activate clastic cells independently of the RANKL/RANK canonical pathways.

Two pathways of root resorption co-exist in the body. When resorption is caused by infection, chronic inflammation due to bacterial infection prolongs the secretions of pro-inflammatory cytokines that intensify root and bone resorption. The second pathway is bacterial independent of the non-infection root resorption that is part of the wound healing process, which is limited in time due to its innate ability.

Although the discovery of antibiotics has made significant positive contributions to public health and medicine, it now poses a serious threat due to the increasing antibiotic resistance in various bacteria. Carbapenem-resistant and multidrug-resistant (MDR) Acinetobacter baumannii is spreading globally, exacerbating respiratory diseases such as chronic obstructive pulmonary disease and cystic fibrosis. Antimicrobial peptides (AMPs), with broad antibacterial activity, have emerged as promising alternatives for treating MDR A. baumannii infections. The AMP P5 exhibits strong antibacterial and anti-biofilm activities against MDR A. baumannii strains isolated from patients. Compared to colistin, a commonly used antibiotic for MDR A. baumannii infections, P5 has a lower potential for inducing drug resistance. Additionally, P5 displays stability in human serum and minimal cytotoxicity in human cell lines. P5 not only suppressed the overexpression of pro-inflammatory cytokines and inflammatory transcription factors in lung epithelial cells (A549) and in a mouse model of respiratory infection but also alleviated lung tissue damage caused by infection. Moreover, P5 effectively alleviated excessive mucin secretion in vitro and in vivo by inhibiting inflammatory transcription factors, epidermal growth factor receptor, and signal transducer and activator of transcription 3-key regulators of mucin expression, a hallmark of inflammatory respiratory diseases. These findings highlight the therapeutic potential of P5 in treating MDR A. baumannii infections and associated inflammatory respiratory conditions.

Sepsis is a severe systemic inflammatory syndrome triggered by infection and is a leading cause of morbidity and mortality in intensive care units (ICUs). Immune dysfunction is a hallmark of sepsis. In this study, the authors investigated cell-cell communication among lymphoid-derived leucocytes using single-cell RNA sequencing (scRNA-seq) to gain a deeper understanding of the underlying mechanisms in late-stage sepsis. The authors' findings revealed that both the number and strength of cellular interactions were elevated in septic patients compared to healthy individuals, with several pathways showing significant alterations, particularly in conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs). Notably, pathways such as CD6-ALCAM were more activated in sepsis, potentially due to T cell suppression. This study offers new insights into the mechanisms of immunosuppression and provides potential avenues for clinical intervention in sepsis.

Sepsis, a severe condition instigated by infections, continues to be a primary global cause of death, typified by systemic inflammation and advancing immune dysfunction. Comprehending the complex pathological processes that underlie sepsis is integral to the creation of efficacious treatments. Despite the inability of animal models to entirely reproduce the clinical intricacies related to sepsis, they are invaluable instruments for the exploration and development of therapeutic approaches. Within this context, the zebrafish model is particularly noteworthy due to its genetic tractability, transparency, and appropriateness for high-throughput screening of genetic mutants and therapeutic compounds. This scholarly review emphasizes the crucial role that the zebrafish disease model plays in enhancing our comprehension of sepsis, by exploring its applications in deciphering immune and inflammatory responses, evaluating the consequences of genetic alterations, and examining novel therapeutic agents. The Insights derived from zebrafish research not only augment our understanding of the underlying mechanisms of sepsis, but also possess considerable potential for the transference of these discoveries into clinical therapies, thus potentially transforming the approach to sepsis management. The objective of this scholarly article is to underscore the importance of zebrafish in the realm of biomedical research pertaining to sepsis, and to delineate forthcoming opportunities for utilizing this model in clinical applications.

Although there have been remarkable advances in the treatment of hepatocellular carcinoma (HCC), the prognosis remains poor in those with advanced stage and more effective therapeutic options are urgently needed. Lenvatinib (Len), a multiple receptor tyrosine kinase inhibitor, is an emerging molecular targeted agent for HCC, whose immunomodulatory activities have been investigated. However, Len utilization is limited because of its low metabolic stability, poor bioavailability and dose-dependent toxicity, rendering its direct use insufficient for immune modulation. Stimuli-responsive nanoparticles, which are drug-targeted delivery platforms for on-demand drug release, facilitate deeper and uniform tumour penetration, providing alternative solutions to overcome current limitations. Ultrasound (US) exhibits superior tissue penetration abilities and can produce reactive oxygen species (ROS) at the tumour site to treat deeper tumours. In addition, US serves as an excellent and selective drug delivery mediator for tumour treatment. Herein, we designed US-triggered lenvatinib nanoparticles (Len-RNPs) for selective drug delivery that utilize US-triggered ROS to induce in situ oxidation reactions, resulting in nanoparticle disintegration. Len-RNPs mitigate the toxicity of Len and effectively trigger robust systemic anti-tumour immune responses in a H22 tumour model, resulting in a tumour suppression rate of 95.7%, with 60% of mice being cured. Our study elucidates a novel and precise strategy of combining Len and US therapy for enhanced HCC immunotherapy.

Reversing the hepatic inflammatory and immunosuppressive microenvironment caused by gut microbiota-derived lipopolysaccharides (LPS), accumulating to the liver through the gut-liver axis, is crucial for suppressing hepatocellular carcinoma (HCC) and metastasis. However, synergistically manipulating LPS-induced inflammation and gut microbiota remains a daunting task. Herein, a Trojan-horse strategy is proposed using an oral dextran-carbenoxolone (DEX-CBX) conjugate, which combines prebiotic and glycyrrhetinic acid (GA) homologs, to targeted delivery GA to HCC through the gut-liver axis for simultaneous modulation of hepatic inflammation and gut microbiota. In the orthotopic HCC model, a 95-45% reduction in the relative abundances of LPS-associated microbiota is observed, especially Helicobacter, caused by DEX-CBX treatment over phosphate-buffered saline (PBS) treatment. Notably, a dramatic increase (37-fold over PBS) in the abundance of Akkermansia, which is known to strengthen systemic immune response, is detected. Furthermore, DEX-CBX significantly increased natural killer T cells (5.7-fold) and CD8+ T cells (3.9-fold) as well as decreased M2 macrophages (59% reduction) over PBS treatment, resulting in a tumor suppression rate of 85.4%. DEX-CBX is anticipated to offer a novel strategy to precisely modulate hepatic inflammation and the gut microbiota to address both the symptoms and root causes of LPS-induced immunosuppression in HCC.

Sepsis-induced acute kidney injury (AKI) remains a major challenge in intensive care, contributing significantly to morbidity and mortality. Tibolone, known for its neuroprotective and hormonal properties, has not been explored for its potential in AKI management. This study investigates the protective effects of Tibolone and its underlying mechanisms involving Sirtuin-1 (SIRT1) and Yes-Associated Protein (YAP) in a rat sepsis model.

Thirty-six female Wistar albino rats underwent cecal ligation and puncture (CLP) to induce sepsis. They were randomly assigned to control, CLP+Saline, and CLP+Tibolone groups. Tibolone was administered intraperitoneally. Biomarkers, including Sirtuin (SIRT1), Yes-associated protein (YAP), Tumor necrosis factor (TNF-α), High mobility group box 1 (HMGB1), malondialdehyde (MDA), creatinine, and urea, were assessed. Histopathological examination evaluated renal damage.

Tibolone administration significantly reduced plasma TNF-α, HMGB1, MDA, creatinine, and urea levels compared to the CLP+Saline group. Moreover, Tibolone elevated SIRT1 and YAP levels in kidney tissues. Histopathological examination demonstrated a significant decrease in tubular epithelial necrosis, luminal debris, dilatation, hemorrhage, and interstitial inflammation in Tibolone-treated rats.

This study unveils the protective role of Tibolone against sepsis-induced AKI in rats. The improvements in inflammatory and oxidative biomarkers and histological evidence suggest Tibolone's potential as a therapeutic intervention in sepsis-associated kidney injury. The upregulation of SIRT1 and YAP indicates their involvement in Tibolone's renoprotective mechanisms. Further investigations are warranted to explore Tibolone's translational potential in human sepsis-induced AKI.

Sepsis is a life-threatening organ malfunction induced by an imbalanced immunological reaction to infection in the host. Many studies have utilized traditional RNA sequencing (RNA-seq) data to identify important biological targets to predict sepsis prognosis. However, alterations in core cells and functional status cannot be effectively detected in sepsis patients. The goal of this study was to identify key cells through single-cell RNA-seq (scRNA-seq), and combine bulk RNA-seq data and multiple algorithm analysis to construct a stable prognostic model for sepsis. The scRNA-seq and bulk RNA-seq data from sepsis patients were collected from the Gene Expression Omnibus (GEO) database. The R package "Seurat" was used to process the scRNA-seq data. Cell communication was investigated using the R package "CellChat". The pseudo-time of the cells was calculated using the R package "monocle". The R package "limma" was used to identify differentially expressed genes (DEGs) between the sepsis group and the control group. Weighted gene correlation network analysis (WGCNA) was used to identify critical modules. Eight kinds of machine learning and 90 algorithm combinations were used to construct the prognostic model for sepsis. Quantitative real-time PCR (qRT‒PCR) was performed to determine the expression of key genes in the cecal ligation and puncture (CLP)-induced sepsis mouse model. The immunological status and related properties of DEGs were then investigated in the high- and low-risk groups delineated by the model. By combining the scRNA-seq data from nine samples, 13 clusters and 9 cell types were identified. CellChat analysis revealed that the number and strength of interactions between platelets and a variety of cells increased. We identified key platelet genes from the scRNA-seq data and combined these genes and the results of differential analysis and WGCNA of the bulk RNA-seq data. After univariate Cox regression analysis, we calculated the Cindex of the model constructed by the combination of 90 algorithms, and we finally determined the "CoxBoost + Lasso" combination. Multivariate Cox regression was used to construct the final prognostic model. The qRT-PCR results revealed significant differences in five key prognostic genes between the CLP and sham groups. The data was classified into high- and low-risk groups based on the model score. The high-risk group had a poorer survival rate and less immune infiltration. We identified the importance of platelets in sepsis patients through scRNA-seq, and established prognostic models with key genes that were identified via scRNA-seq combined with bulk RNA-seq analysis. The results of this model were closely associated with patient survival rates and immunological status and this model is useful for the prognostic management of sepsis.

Recent advancements highlight the intricate interplay between the extracellular matrix (ECM) and immune responses, notably in respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). The ECM, a dynamic structural framework within tissues, orches-trates a plethora of cellular processes, including immune cell behavior and tissue repair mecha-nisms. WNT1-inducible-signaling pathway protein 1 (WISP1), a key ECM regulator, controls immune cell behavior, cytokine production, and tissue repair by modulating integrins, PI3K, Akt, β-catenin, and mTOR signaling pathways. WISP1 also induces macrophage migration inhibitory factor (MIF) expression via Src kinases and epidermal growth factor receptor (EGFR) activation. MIF, through its wide range of activities, enhances inflammation and tissue restructuring. Rec-ognized for its versatile roles in regulating the immune system, MIF interacts with multiple immune components, such as the NLRP3 inflammasome, thereby sustaining inflammatory pro-cesses. The WISP1-MIF axis potentially unveils complex molecular mechanisms governing im-mune responses and inflammation. Understanding the intricate roles of WISP1 and MIF in the pathogenesis of chronic respiratory diseases such as asthma and COPD could lead to the identi-fication of novel targets for therapeutic intervention to alleviate disease severity and enhance patient outcomes.

Septic shock is associated with high mortality and there is significant heterogeneity in the host response. The aim of this study was to understand the genome-wide expression transcriptomic signatures in children with septic shock and correlate them with outcomes.

This was a prospective study conducted on children (aged 1 month to 18 years) admitted to the PICU (June-December 2021) with septic shock. Demographic details, clinical details, and administered treatment were collected. Differential gene expression analysis was performed to understand the genes and pathways affecting in different subjects.

Fifteen patients were recruited (Septic shock survivors (n = 5), nonsurvivors (n = 5), and non-sepsis controls (n = 5). The median age of the patients in survivors and nonsurvivors was 15 (13, 24) months and 180 (180, 184) months, respectively. The sepsis-survivors vs nonsepsis possessed 983 upregulated and 624 downregulated genes while comparing sepsis nonsurvivors (SNS) with nonsepsis yielded 1,854 upregulated and 1,761 downregulated genes. Further, the lowest number of deregulated genes (383 upregulated and 486 downregulated) were present in SNS compared to sepsis survivors. The major Reactome pathways, found upregulated in SNSs relative to survivors included CD22 mediated B cell receptor (BCR) regulation, scavenging of heme from plasma, and creation of C4 and C2 activators while T cell receptor (TCR) signaling, the common pathway of fibrin clot formation and generation of second messenger molecules were found to be downregulated.

Mortality-related gene signatures are promising diagnostic biomarkers for pediatric sepsis.

Lalitha AV, Vasudevan A, Moorthy M, Ramaswamy G. Profiling Molecular Changes of Host Response to Predict Outcome in Children with Septic Shock. Indian J Crit Care Med 2024;28(9):879-886.

Sepsis is a life-threatening organ dysfunction caused by an excessive host response to infection, manifested by elevated levels of inflammatory cytokines. At present, the use of hemoperfusion to remove inflammatory cytokines from the bloodstream has been expanding. Meanwhile, the pharmacokinetics and pharmacodynamics characteristics of antibiotics in critically ill patients may be impacted by hemoperfusion.

The patient was a 69-year-old male with poorly controlled type 2 diabetes. When admitted to the ICU, Multiple Organ Dysfunction Syndrome (MODS) appeared within 48 h, and he was suspected of septic shock due to acute granulocytopenia and significantly increased procalcitonin. Broad-spectrum antibiotics imipenem was administered according to Sepsis 3.0 bundle and hemoperfusion lasting 4 h with a neutron-macroporous resin device (HA-380, Jafron, China) five times was conducted to lower the extremely high value of serum inflammatory factors. Blood samples were collected to measure imipenem plasma concentration to investigate the effect of hemoperfusion quantitatively. This study showed that 4 h of hemoperfusion had a good adsorption ability on inflammatory factors and could remove about 75.2% of imipenem.

This case demonstrated the high adsorption capacity of hemoperfusion on imipenem in critically ill patients. It implies a timely imipenem supplement is required, especially before hemoperfusion.

Sepsis stands as a prominent contributor to sickness and death on a global scale. The most current consensus definition characterizes sepsis as a life-threatening organ dysfunction stemming from an imbalanced host response to infection. This definition does not capture the intricate array of immune processes at play in sepsis, marked by simultaneous states of heightened inflammation and immune suppression. This overview delves into the immune-related processes of sepsis, elaborating about mechanisms involved in hyperinflammation and immune suppression. Moreover, we discuss stratification of patients with sepsis based on their immune profiles and how this could impact future sepsis management.

This study evaluates the role of D-dimer in identifying neonatal sepsis and their potential value in clinical decision-making due to challenges in early detection.

A case-control study was conducted on 102 neonates at the Children's Clinical Hospital "Louis Turcanu" in Timisoara, Romania, from October 2018 to July 2023. The participants were divided into two groups: those with neonatal sepsis and those without sepsis.

The study found that neonates with sepsis were more likely to be delivered by cesarean section and had higher rates of premature ruptured membranes compared to those without sepsis. The D-dimer biomarker's predictive value for sepsis was assessed using a receiver operating characteristic (ROC) curve, with an area under the curve (AUC) exceeding 0.982 and an optimum cutoff value of 342 ng/mL. An increase in neonatal D-dimer significantly increases the likelihood of sepsis by 2.7% per unit increase. A value above 250 ng/mL indicates a 127-fold increased likelihood of sepsis. The D-dimer's ability to predict mortality in newborns with sepsis is unsatisfactory, with an AUC of 0.528.

D-dimer, a potential biomarker of neonatal sepsis, warrants further clinical investigation to enhance diagnostic sensitivity and specificity, demonstrating its potential in conjunction with other sepsis markers.

The objective of this study was to determine the role of cerebrospinal fluid (CSF) bacterial load in adults with pneumococcal meningitis.

We quantified bacterial load in CSF samples from the diagnostic lumbar puncture of adults with community-acquired pneumococcal meningitis. We also measured CSF concentrations of complement component 5a (C5a), and determined associations between bacterial load, clinical characteristics, C5a and unfavourable outcome (Glasgow Outcome Scale score <5).

Bacterial load was quantified in 152 CSF samples. Median age of these patients was 61 years (interquartile range [IQR] 51-68), and 69 of 152 (45%) were female. Median CSF bacterial load was 1.6 × 104 DNA copies/mL (IQR 3.4 × 103-1.2 × 105), and did not correlate with CSF white cell count nor with CSF protein concentrations. Median CSF C5a concentration was 35.8 mg/L (IQR 15.9-105.6), and was moderately correlated with CSF bacterial loads (Spearman's rho = 0.42; p < 0001). High bacterial loads were associated with development of complications, such as circulatory shock (OR per logarithmic increase: 2.4, 95% CI: 2.0-2.9; p < 0.001) and cerebrovascular complications [OR: 1.9, 95% CI: 1.6-2.3; p < 0.001]). High bacterial loads were also associated with unfavourable outcome (OR: 2.8, 95% CI: 2.4-3.3; p < 0.001) and death (OR: 3.1, 95% CI: 2.6-3.8; p < 0.001). In a multivariable regression model including age, immunocompromised state, extrameningeal infection focus, admission Glasgow Coma Scale score and CSF C5a concentration, CSF bacterial load remained an independent predictor of unfavourable outcome (adjusted OR: 2.5, 95% CI: 1.6-3.9; p < 0.001).

High CSF bacterial load predicts the development of complications and unfavourable outcome in adults with pneumococcal meningitis.

Stony corals (Order: Scleractinia) are central to vital marine habitats known as coral reefs. Numerous stressors in the Anthropocene are contributing to the ongoing decline in coral reef health and coverage. While viruses are established modulators of marine microbial dynamics, their interactions within the coral holobiont and impact on coral health and physiology remain unclear. To address this key knowledge gap, we investigated diverse stony coral genomes for 'endogenous' viruses. Our study uncovered a remarkable number of integrated viral elements recognized as 'Polintoviruses' (Class Polintoviricetes) in thirty Scleractinia genomes; with several species harboring hundreds to thousands of polintoviruses. We reveal massive paralogous expansion of polintoviruses in stony coral genomes, alongside the presence of integrated elements closely related to Polinton-like viruses (PLVs), a group of viruses that exist as free virions. These results suggest multiple integrations of polintoviruses and PLV-relatives, along with paralogous expansions, shaped stony coral genomes. Re-analysis of existing gene expression data reveals all polintovirus structural and non-structural hallmark genes are expressed, providing support for free virion production from polintoviruses. Our results, revealing a significant diversity of polintovirus across the Scleractinia order, open a new research avenue into polintovirus and their possible roles in disease, genomic plasticity, and environmental adaptation in this key group of organisms.

Effective responses against severe systemic infection require coordination between two complementary defense strategies that minimize the negative impact of infection on the host: resistance, aimed at pathogen elimination, and disease tolerance, which limits tissue damage and preserves organ function. Resistance and disease tolerance mostly rely on divergent metabolic programs that may not operate simultaneously in time and space. Due to evolutionary reasons, the host initially prioritizes the elimination of the pathogen, leading to dominant resistance mechanisms at the potential expense of disease tolerance, which can contribute to organ failure. Here, we summarize our current understanding of the role of physiological perturbations resulting from infection in immune response dynamics and the metabolic program requirements associated with resistance and disease tolerance mechanisms. We then discuss how insight into the interplay of these mechanisms could inform future research aimed at improving sepsis outcomes and the potential for therapeutic interventions.

Sepsis is characterized as life-threatening organ dysfunction caused by a dysregulated host response to an infection. Despite numerous clinical trials that addressed this syndrome, there is still no causative treatment available to dampen its severity. Curtailing the infection at an early stage with anti-infectives is the only effective treatment regime besides intensive care. In search for additional treatment options, we recently discovered the inhibition of the sphingosine 1-phosphate (S1P) lyase and subsequent activation of the S1P receptor type 3 (S1PR3) in pre-conditioning experiments as promising targets for sepsis prevention. Here, we demonstrate that treatment of septic mice with the direct S1P lyase inhibitor C31 or the S1PR3 agonist CYM5541 in the advanced phase of sepsis resulted in a significantly increased survival rate. A single dose of each compound led to a rapid decline of sepsis severity in treated mice and coincided with decreased cytokine release and increased lung barrier function with unaltered bacterial load. The survival benefit of both compounds was completely lost in S1PR3 deficient mice. Treatment of the murine macrophage cell line J774.1 with either C31 or CYM5541 resulted in decreased protein kinase B (Akt) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) phosphorylation without alteration of the mitogen-activated protein kinase (MAPK) p38 and p44/42 phosphorylation. Thus, activation of S1PR3 in the acute phase of sepsis by direct agonism or S1P lyase inhibition dampened Akt and JNK phosphorylation, resulting in decreased cytokine release, improved lung barrier stability, rapid decline of sepsis severity and better survival in mice.

GPX4 (Glutathione peroxidase 4) serves as a crucial intracellular regulatory factor, participating in various physiological processes and playing a significant role in maintaining the redox homeostasis within the body. Ferroptosis, a form of iron-dependent non-apoptotic cell death, has gained considerable attention in recent years due to its involvement in multiple pathological processes. GPX4 is closely associated with ferroptosis and functions as the primary inhibitor of this process. Together, GPX4 and ferroptosis contribute to the pathophysiology of several diseases, including sepsis, nervous system diseases, ischemia reperfusion injury, cardiovascular diseases, and cancer. This review comprehensively explores the regulatory roles and impacts of GPX4 and ferroptosis in the development and progression of these diseases, with the aim of providing insights for identifying potential therapeutic strategies in the future.

Several observational studies have proposed a potential link between gut microbiota and the onset and progression of sepsis. Nevertheless, the causality of gut microbiota and sepsis remains debatable and warrants more comprehensive exploration.

We conducted a two-sample Mendelian randomization (MR) analysis to test the causality between gut microbiota and the onset and progression of sepsis. The genome-wide association study (GWAS) summary statistics for 196 bacterial traits were extracted from the MiBioGen consortium, whereas the GWAS summary statistics for sepsis and sepsis-related outcomes came from the UK Biobank. The inverse-variance weighted (IVW) approach was the primary method used to examine the causal association. To complement the IVW method, we utilized four additional MR methods. We performed a series of sensitivity analyses to examine the robustness of the causal estimates.

We assessed the causality of 196 bacterial traits on sepsis and sepsis-related outcomes. Genus Coprococcus2 [odds ratio (OR) 0.81, 95% confidence interval (CI) (0.69-0.94), p = 0.007] and genus Dialister (OR 0.85, 95% CI 0.74-0.97, p = 0.016) had a protective effect on sepsis, whereas genus Ruminococcaceae UCG011 (OR 1.10, 95% CI 1.01-1.20, p = 0.024) increased the risk of sepsis. When it came to sepsis requiring critical care, genus Anaerostipes (OR 0.49, 95% CI 0.31-0.76, p = 0.002), genus Coprococcus1 (OR 0.65, 95% CI 0.43-1.00, p = 0.049), and genus Lachnospiraceae UCG004 (OR 0.51, 95% CI 0.34-0.77, p = 0.001) emerged as protective factors. Concerning 28-day mortality of sepsis, genus Coprococcus1 (OR 0.67, 95% CI 0.48-0.94, p = 0.020), genus Coprococcus2 (OR 0.48, 95% CI 0.27-0.86, p = 0.013), genus Lachnospiraceae FCS020 (OR 0.70, 95% CI 0.52-0.95, p = 0.023), and genus Victivallis (OR 0.82, 95% CI 0.68-0.99, p = 0.042) presented a protective effect, whereas genus Ruminococcus torques group (OR 1.53, 95% CI 1.00-2.35, p = 0.049), genus Sellimonas (OR 1.25, 95% CI 1.04-1.50, p = 0.019), and genus Terrisporobacter (OR 1.43, 95% CI 1.02-2.02, p = 0.040) presented a harmful effect. Furthermore, genus Coprococcus1 (OR 0.42, 95% CI 0.19-0.92, p = 0.031), genus Coprococcus2 (OR 0.34, 95% CI 0.14-0.83, p = 0.018), and genus Ruminiclostridium6 (OR 0.43, 95% CI 0.22-0.83, p = 0.012) were associated with a lower 28-day mortality of sepsis requiring critical care.

This MR analysis unveiled a causality between the 21 bacterial traits and sepsis and sepsis-related outcomes. Our findings may help the development of novel microbiota-based therapeutics to decrease the morbidity and mortality of sepsis.

Thioredoxin domain containing protein-5 (TXNDC5), also known as endothelial protein-disulfide isomerase (Endo-PDI), is confined to the endoplasmic reticulum through the structural endoplasmic reticulum retention signal (KDEL), is a member of the PDI protein family and is highly expressed in the hypoxic state. TXNDC5 can regulate the rate of disulfide bond formation, isomerization and degradation of target proteins through its function as a protein disulfide isomerase (PDI), thereby altering protein conformation, activity and improving protein stability. Several studies have shown that there is a significant correlation between TXNDC5 gene polymorphisms and genetic susceptibility to inflammatory diseases such as rheumatoid, fibrosis and tumors. In this paper, we detail the expression characteristics of TXNDC5 in a variety of diseases, summarize the mechanisms by which TXNDC5 promotes malignant disease progression, and summarize potential therapeutic strategies to target TXNDC5 for disease treatment.

Microparticles (MPs) packaged with numerous bioactive molecules are essential vehicles in cellular communication in various pathological conditions, including systemic inflammation, Whereas MPs are studied mostly upon isolation, their detection in vivo is limited. Impact of MPs might depend on target cell type and cargo they carry; thus herein, we aimed at verifying MPs' impact on macrophages. Unlike neutrophils, monocytes/macrophages are rather inactive during sepsis, and we hypothesized this might be at least partially controlled by MPs. For the above reasons, we focused on the detection of MPs with intravital microscopy (IVM) and report the presence of putative neutrophil-derived MPs in the vasculature of cremaster muscle of endotoxemic mice. Subsequently, we characterized MPs isolated not only from their blood but also from the peritoneal cavity and observed differences in their size, concentration, and cargo. Such MPs were then used to study their impact on RAW 264.7 macrophage cell line performance (cell viability/activity, cytokines, oxygen, and nitrogen reactive species). Addition of MPs to macrophages with or without co-stimulation with lipopolysaccharide did not affect respiratory burst, somewhat decreased mitochondrial activity but increased inducible nitric oxide synthase (iNOS) expression, and NO production especially in case of plasma-derived MPs. The latter MPs carried more iNOS-controlling ceruloplasmin than those discharged into the peritoneal cavity. We conclude that MPs can be detected in vivo with IVM and their cellular origin identified. They are heterogeneous in nature depending on the site of their release. Consequently, microparticles released during systemic inflammation to various body compartments differentially affect macrophages.

Significant variations in the variables collected in clinical studies focusing on bacteraemia lead to inconsistency in the evaluation of risk factors for mortality.

We aimed to define a minimum set of risk factors that should be assessed and reported in all studies assessing survival in bacteraemia.

We conducted a systematic review including observational prospective and retrospective cohort studies that assessed all-cause mortality among patients with bacteraemia. We included only studies computing an adjusted analysis for mortality, with >500 participants.

Independently significant risk factors for all-cause, preferably 30-day, mortality.

PubMed was used to identify eligible studies published between 2000 and 2020. A Delphi survey among experts was used to evaluate and prioritize the factors identified by the systematic review.

SIGN checklist complemented by risk of bias assessment of the adjusted analysis.

Definite universal risk factors were defined as those assessed in >50% of all included studies and significant in >50% of those. Potential universal risk factors were defined as those significant in >50% of studies evaluating the factor and a subgroup analysis was performed for studies of Staphylococcus aureus bacteraemia.

We included in the systematic review 62 studies, comprising more than 300,000 patients, from which a list of 17 risk factors was derived, whose association with all-cause mortality was statistically significant in most studies. The factors address baseline patient variables, the setting of infection acquisition, factors associated with the specific infection, the inflammatory response at onset of sepsis and management parameters where relevant. There were 14 risk factors for S. aureus bacteraemia.

We identified a minimum set of universal factors to be collected, reported, and assessed, in all future studies evaluating factors associated with mortality in bacteraemia to improve study quality and harmonization.

Innate immune cells play essential roles in modulating both immune defense and inflammation by expressing a diverse array of cytokines and inflammatory mediators, phagocytizing pathogens to promote immune clearance, and assisting with the adaptive immune processes through antigen presentation. Rudimentary innate immune "memory" states such as training, tolerance, and exhaustion develop based on the nature, strength, and duration of immune challenge, thereby enabling dynamic transcriptional reprogramming to alter present and future cell behavior. Underlying transcriptional reprogramming are broad changes to the epigenome, or chromatin alterations above the level of DNA sequence. These changes include direct modification of DNA through cytosine methylation as well as indirect modifications through alterations to histones that comprise the protein core of nucleosomes. In this review, we will discuss recent advances in our understanding of how these epigenetic changes influence the dynamic behavior of the innate immune system during both acute and chronic inflammation, as well as how stable changes to the epigenome result in long-term alterations of innate cell behavior related to pathophysiology.

SMI (severe mental illness) has been identified as a risk factor for sepsis in observational studies; however, the causal association between them has yet to be firmly established. We conducted MR (mendelian randomization) to unveil the causal relationship between SMI and sepsis as well as sepsis mortality.

GWAS (Genome-wide association) data for major depression and schizophrenia were selected as exposure. GWAS data for sepsis and sepsis mortality were selected as outcome. Genetic variants significantly associated with the exposure (P value<1x10-6) were selected as instruments. We primarily employed the IVW (inverse-variance weighted) method for analysis. Furthermore, we employed Cochrane's Q test to assess heterogeneity and the MR-Egger intercept test to identify horizontal pleiotropy.

We selected 108 SNPs (single nucleotide polymorphism) used to predict major depression and 260 SNPs that predicted schizophrenia. Genetically predicted major depression was suggestively linked to a higher sepsis risk (OR=1.13, 95%CI 1.02-1.26, P=0.023). In contrast, MR analysis did not find an association between schizophrenia and sepsis risk (OR=1.00, 95%CI 0.97-1.04, P=0.811). Furthermore, no significant causal evidence was found for genetically predicted SMI in sepsis mortality. Moreover, no heterogeneity and horizontal pleiotropy were detected.

Our research revealed a suggestive association between genetically predicted major depression and an elevated risk of sepsis in individuals of European ancestry. This finding can serve as a reminder for clinicians to consider the possibility of subsequent infection and sepsis in depressive patients, which may help reduce the incidence of sepsis in individuals with depression.

Monocyte exhaustion with sustained pathogenic inflammation and immune-suppression, a hallmark of sepsis resulting from systemic infections, presents a challenge with limited therapeutic solutions. This study identified Methoxy-Mycolic Acid (M-MA), a branched mycolic acid derived from Mycobacterium bovis Bacillus Calmette-Guérin (BCG), as a potent agent in alleviating monocyte exhaustion and restoring immune homeostasis. Co-treatment of monocytes with M-MA effectively blocked the expansion of Ly6Chi/CD38hi/PD-L1hi monocytes induced by LPS challenges and restored the expression of immune-enhancing CD86. M-MA treatment restored mitochondrial functions of exhausted monocytes and alleviated their suppressive activities on co-cultured T cells. Independent of TREM2, M-MA blocks Src-STAT1-mediated inflammatory polarization and reduces the production of immune suppressors TAX1BP1 and PLAC8. Whole genome methylation analyses revealed M-MA's ability to erase the methylation memory of exhausted monocytes, particularly restoring Plac8 methylation. Together, our data suggest M-MA as an effective agent in restoring monocyte homeostasis with a therapeutic potential for treating sepsis.

This comprehensive review thoroughly explores the intricate relationship between chemokines, cytokines, and the cytokine storm in sepsis, offering a nuanced understanding of the molecular mechanisms underpinning this life-threatening syndrome. Beginning with examining sepsis stages and immune response dynamics, the review emphasizes the dysregulation leading to the cytokine storm, where pro- and anti-inflammatory cytokines disrupt the delicate immune equilibrium. Delving into chemokines, the discussion encompasses subfamilies, receptors, and functions, highlighting their critical roles in immune cell migration and activation during sepsis. The implications for clinical practice are substantial, suggesting avenues for targeted diagnostics and therapeutic interventions. The review identifies areas for future research, including the search for novel biomarkers, deeper insights into cytokine regulation, and the pursuit of personalized medicine approaches. This comprehensive exploration aims to guide clinicians, researchers, and policymakers in navigating the complexities of sepsis, fostering a foundation for transformative advancements in understanding and managing this formidable clinical challenge.

Sepsis is a life-threatening state that arises due to a hyperactive inflammatory response stimulated by infection and rarely other insults (e.g., non-infections tissue injury). Although changes in several proinflammatory cytokines and signals are documented in humans and small animal models, far less is known about responses within affected tissues of large animal models. We sought to understand the changes that occur during the initial stages of inflammation by administering intravenous lipopolysaccharide (LPS) to Yorkshire pigs and assessing transcriptomic alterations in the brain, kidney, and whole blood. Robust transcriptional alterations were found in the brain, with upregulated responses enriched in inflammatory pathways and downregulated responses enriched in tight junction and blood vessel functions. Comparison of the inflammatory response in the pig brain to a similar mouse model demonstrated some overlapping changes but also numerous differences, including oppositely dysregulated genes between species. Substantial changes also occurred in the kidneys following LPS with several enriched upregulated pathways (cytokines, lipids, unfolded protein response, etc.) and downregulated gene sets (tube morphogenesis, glomerulus development, GTPase signal transduction, etc.). We also found significant dysregulation of genes in whole blood that fell into several gene ontology categories (cytokines, cell cycle, neutrophil degranulation, etc.). We observed a strong correlation between the brain and kidney responses, with significantly shared upregulated pathways (cytokine signaling, cell death, VEGFA pathways) and downregulated pathways (vasculature and RAC1 GTPases). In summary, we have identified a core set of shared genes and pathways in a pig model of systemic inflammation.

Sepsis is a life-threatening condition caused by an excessive inflammatory response to an infection, associated with high mortality. However, the regulatory mechanism of sepsis remains unclear.

In this study, bioinformatics analysis revealed the novel key biomarkers associated with sepsis and potential regulators. Three public datasets (GSE28750, GSE57065 and GSE95233) were employed to recognize the differentially expressed genes (DEGs). Taking the intersection of DEGs from these three datasets, GO and KEGG pathway enrichment analysis revealed 537 shared DEGs and their biological functions and pathways. These genes were mainly enriched in T cell activation, differentiation, lymphocyte differentiation, mononuclear cell differentiation, and regulation of T cell activation based on GO analysis. Further, pathway enrichment analysis revealed that these DEGs were significantly enriched in Th1, Th2 and Th17 cell differentiation. Additionally, five hub immune-related genes (CD3E, HLA-DRA, IL2RB, ITK and LAT) were identified from the protein-protein interaction network, and sepsis patients with higher expression of hub genes had a better prognosis. Besides, 14 drugs targeting these five hub related genes were revealed on the basis of the DrugBank database, which proved advantageous for treating immune-related diseases.

These results strengthen the new understanding of sepsis development and provide a fresh perspective into discriminating the candidate biomarkers for predicting sepsis as well as identifying new drugs for treating sepsis.

Inflammation is crucial in diseases, and proteins play a key role in the interplay between innate immunity and pathology. This review explores how proteomics helps understanding this relationship, focusing on diagnosis and treatment. We explore the dynamic innate response and the significance of proteomic techniques in deciphering the complex network of proteins involved in prevalent diseases, including infections, cancer, autoimmune and neurodegenerative disorders. Proteomics identifies key proteins in host-pathogen interactions, shedding light on infection mechanisms and inflammation. These discoveries hold promise for diagnostic tools, therapies, and vaccines. In cancer research, proteomics reveals innate signatures associated with tumor development, immune evasion, and therapeutic response. Additionally, proteomic analysis has unveiled autoantigens and dysregulation of the innate immune system in autoimmunity, offering opportunities for early diagnosis, disease monitoring, and new therapeutic targets. Moreover, proteomic analysis has identified altered protein expression patterns in neurodegenerative diseases like Alzheimer's and Parkinson's, providing insights into potential therapeutic strategies. Proteomics of the innate immune system provides a comprehensive understanding of disease mechanisms, identifies biomarkers, and enables effective interventions in various diseases. Despite still in its early stages, this approach holds great promise to revolutionize innate immunity research and significantly improve patient outcomes across a wide range of diseases.

Introduction: Gut microbiota dysbiosis is associated with susceptibility to sepsis and poor outcomes. However, changes to the intestinal microbiota during sepsis and their value as biomarkers are unclear. In this study, we compared the intestinal microbiota of patients with sepsis and healthy controls. Methods: Stool was collected from patients with sepsis (subdivided according to mortality) and controls. Microbiome diversity and composition were analyzed by 16S rRNA gene pyrosequencing. The α-diversity of the intestinal microbiome was determined using operational taxonomic unit counts and the Chao1, Shannon, and ACE indices. Adjusted Cox regression analyses assessed 6-month mortality risk factors. Results: Fifty-nine patients (14 in-hospital deaths) and 29 healthy controls were enrolled. Operational taxonomic unit counts and Chao1 and ACE indices were lower in the nonsurvivor than in the other groups. The controls showed a higher Shannon and lower Simpson index than did the sepsis group. The genus Blautia was more abundant in controls than in the sepsis group, and Faecalibacterium less abundant in the nonsurvivor than in the other groups. Regression analysis associated low Shannon index with 6-month mortality. Conclusions: Survivors of sepsis, nonsurvivors, and healthy controls have different gut microbiomes, and a low Shannon index is a risk factor for 6-month mortality.