Dysregulated Inflammatory Response Research Articles

Epigenomic Reprogramming in Gout

Gout is a crystal-induced arthropathy in which monosodium urate (MSU) crystals precipitate within joints as a result of persistent hyperuricemia and elicit an inflammatory response. An intriguing aspect is the occurrence of gout in only 10–15% of hyperuricemic individuals, suggesting the presence of additional risk factors. Although MSU crystal deposition is widely recognized as the cause of gout flares, the variability in initiating the inflammatory response to hyperuricemia and MSU deposition is not well understood. Several studies bring up-to-date information about the environmental and genetic influences on the progression towards clinical gout. Elevated urate concentrations and exposure to different external factors precipitate gout flares, highlighting the potential involvement of epigenetic mechanisms in gouty inflammation. A better understanding of the alteration of the epigenetic landscape in gout may provide new perspectives on the dysregulated inflammatory response. In this review, we focus on understanding the current view of the role of epigenomic reprogramming in gout and the mechanistic pathways of action.

Cordycepin Alleviates Lipopolysaccharides-Induced Preeclampsia-Like Impairments in Rats

ABSTRACT Introduction Preeclampsia is a serious pregnancy complication that can lead to life-threatening conditions such as seizures, strokes, and even death. A dysregulated inflammatory response in the placenta plays a crucial role in the development of preeclampsia. Cordycepin, known for its anti-inflammatory and antioxidant properties, was the focus of this study, which aimed to investigate its effects on preeclampsia. Methods A preeclampsia-like rat model was established via tail vein injection of lipopolysaccharides (LPS) at a dose of 1 μg/kg in pregnant rats. These rats were then treated with cordycepin at doses of 5, 25, or 50 mg/kg from embryonic day 6 (E6) today 18 (E18). Systolic blood pressures and urinary protein levels were monitored, and pregnancy outcomes, such as fetal body length and weight, were measured. The expression of target genes or proteins was assessed by qPCR, ELISA, and Western blot. Results Our findings revealed that cordycepin significantly reduced systolic blood pressure and proteinuria in preeclampsia-like rats. Additionally, cordycepin improved pregnancy outcomes, as shown by increased fetal body length and weight. The treatment also lowered serum sFlt-1 levels, elevated PIGF levels, decreased placental pro-inflammatory cytokine levels (IL-1β, TNF-α, IL-6, MCP-1, and MIP-2), and raised levels of anti-inflammatory cytokine IL-10 level in preeclampsia-like rats. Furthermore, cordycepin helped restore macrophage population imbalances, increasing M1-type macrophage markers (iNOS, TNF-α, and IL-1β) and reducing M2-type macrophage markers (Arg 1, IL-10, and TGF-β). Conclusion This study suggests that cordycepin alleviates LPS-induced preeclampsia by reducing placental inflammation and correcting the M1/M2 macrophage imbalance, offering potential therapeutic benefits for managing preeclampsia.

Integrating transcriptomics, eQTL, and Mendelian randomization to dissect monocyte roles in severe COVID-19 and gout flare.

There are considerable similarities between the pathophysiology of gout flare and the dysregulated inflammatory response in severe COVID-19 infection. Monocytes are the key immune cells involved in the pathogenesis of both diseases. Therefore, it is critical to elucidate the molecular basis of the function of monocytes in gout and COVID-19 in order to develop more effective therapeutic approaches. The single-cell RNA sequencing (scRNA-seq), large-scale genome-wide association studies (GWAS), and expression quantitative trait loci (eQTL) data of gout and severe COVID-19 were comprehensively analyzed. Cellular heterogeneity and intercellular communication were identified using the scRNA-seq datasets, and the monocyte-specific differentially expressed genes (DEGs) between COVID-19, gout and normal subjects were screened. In addition, the correlation of the DEGs with severe COVID-19 and gout flare was analyzed through GWAS statistics and eQTL data. The scRNA-seq analysis exhibited that the proportion of classical monocytes was increased in both severe COVID-19 and gout patient groups compared to healthy controls. Differential expression analysis and MR analysis showed that NLRP3 was positively associated with the risk of severe COVID-19 and involved 11 SNPs, of which rs4925547 was not significantly co-localized. In contrast, IER3 was positively associated with the risk of gout and involved 9 SNPs, of which rs1264372 was significantly co-localized. Monocytes have a complex role in gout flare and severe COVID-19, which underscores the potential mechanisms and clinical significance of the interaction between the two diseases.

KC-like chemokine as a biomarker of sepsis in dogs with pyometra

BackgroundSepsis, defined as a dysregulated inflammatory response to infection inducing organ dysfunction, is a common cause of mortality in both humans and animals. Early detection and treatment is essential for survival, but accurate diagnosis is challenging due to the lack of specific biomarkers for sepsis. This study explored the potential of the keratinocyte-derived chemokine (KC)-like protein in dogs as a biomarker of sepsis in dogs with bacterial uterine infection (pyometra). The aim was to compare KC-like concentrations in dogs with pyometra with or without sepsis and to assess associations between KC-like and clinical variables, including days of hospitalization as an outcome.ResultsA mouse KC ELISA was validated and used to determine the concentrations of KC-like in serum from 34 dogs with pyometra and 18 healthy controls. Dogs with pyometra were classified as having sepsis based on two different criteria for systemic inflammatory response syndrome (SIRS), resulting in 74% and 30% sepsis-positive, respectively. The concentration of KC-like protein was higher in pyometra dogs with sepsis than in pyometra dogs without sepsis (p < 0.05) and in healthy controls (p < 0.0001) when using either of the two SIRS criteria. Moreover, KC-like was slightly increased in dogs with pyometra without sepsis compared with healthy controls when using the more stringent SIRS criteria (p < 0.05). Analyses of all dogs showed that KC-like concentrations correlated positively with hospitalization days, C-reactive protein (CRP) concentrations, white blood cells, and percentage of band neutrophils; however, KC-like correlated negatively with hemoglobin and did not correlate with circulating creatinine.ConclusionsOur results suggest that circulating KC-like protein increases in dogs with sepsis in pyometra and that KC-like is associated with more severe clinical illness. These findings support a potential role of KC-like as a biomarker of sepsis; however, the true identity of KC-like in dogs has yet to be uncovered.

Intercambio de plasma y enfermedades autoinmunes críticas

Introduction: Renal replacement therapy (RRT) has evolved significantly since its introduction; initially used to treat acute renal failure, it is applied in various clinical scenarios due to improved membranes and equipment. Other techniques have emerged, such as therapeutic apheresis and hemoadsorption, which allow specific components to be removed from the blood. These therapies have shown promise in the treatment of various diseases. Important points: Sepsis and septic shock are the most common causes of admission to intensive care units (ICU), and extracorporeal therapies (ECT) have shown promise in their management. Sepsis is characterized by a dysregulated inflammatory response, which can lead to multiorgan damage. ECT can help modulate this response, eliminating inflammatory mediators and restoring immune balance. Although clinical evidence is inconclusive for all indications, studies have shown improvements in clinical parameters, such as decreased need for vasopressors and improved oxygenation. The response to ECT may be variable between patients due to genetic, epigenetic, and sociodemographic factors. Conclusion: extracorporeal therapies are presented as a promising tool in the management of critically ill patients, and their use is expanding beyond sepsis. As more scientific evidence accumulates, it is expected that these techniques will become consolidated as part of the standard treatment in various pathologies.

Released bacterial ATP shapes local and systemic inflammation during abdominal sepsis

Sepsis causes millions of deaths per year worldwide and is a current global health priority declared by the WHO. Sepsis-related deaths are a result of dysregulated inflammatory immune responses indicating the need to develop strategies to target inflammation. An important mediator of inflammation is extracellular adenosine triphosphate (ATP) that is released by inflamed host cells and tissues, and also by bacteria in a strain-specific and growth-dependent manner. Here, we investigated the mechanisms by which bacteria release ATP. Using genetic mutant strains of Escherichia coli (E. coli), we demonstrate that ATP release is dependent on ATP synthase within the inner bacterial membrane. In addition, impaired integrity of the outer bacterial membrane notably contributes to ATP release and is associated with bacterial death. In a mouse model of abdominal sepsis, local effects of bacterial ATP were analyzed using a transformed E. coli bearing an arabinose-inducible periplasmic apyrase hydrolyzing ATP to be released. Abrogating bacterial ATP release shows that bacterial ATP suppresses local immune responses, resulting in reduced neutrophil counts and impaired survival. In addition, bacterial ATP has systemic effects via its transport in outer membrane vesicles (OMV). ATP-loaded OMV are quickly distributed throughout the body and upregulated expression of genes activating degranulation in neutrophils, potentially contributing to the exacerbation of sepsis severity. This study reveals mechanisms of bacterial ATP release and its local and systemic roles in sepsis pathogenesis.

Released bacterial ATP shapes local and systemic inflammation during abdominal sepsis.

Sepsis causes millions of deaths per year worldwide and is a current global health priority declared by the WHO. Sepsis-related deaths are a result of dysregulated inflammatory immune responses indicating the need to develop strategies to target inflammation. An important mediator of inflammation is extracellular adenosine triphosphate (ATP) that is released by inflamed host cells and tissues, and also by bacteria in a strain-specific and growth-dependent manner. Here, we investigated the mechanisms by which bacteria release ATP. Using genetic mutant strains of Escherichia coli (E. coli), we demonstrate that ATP release is dependent on ATP synthase within the inner bacterial membrane. In addition, impaired integrity of the outer bacterial membrane notably contributes to ATP release and is associated with bacterial death. In a mouse model of abdominal sepsis, local effects of bacterial ATP were analyzed using a transformed E. coli bearing an arabinose-inducible periplasmic apyrase hydrolyzing ATP to be released. Abrogating bacterial ATP release shows that bacterial ATP suppresses local immune responses, resulting in reduced neutrophil counts and impaired survival. In addition, bacterial ATP has systemic effects via its transport in outer membrane vesicles (OMV). ATP-loaded OMV are quickly distributed throughout the body and upregulated expression of genes activating degranulation in neutrophils, potentially contributing to the exacerbation of sepsis severity. This study reveals mechanisms of bacterial ATP release and its local and systemic roles in sepsis pathogenesis.

LC-MS metabolomics and lipidomics in cerebrospinal fluid from viral and bacterial CNS infections: a review.

There is compelling evidence that a dysregulated immune inflammatory response in neuroinfectious diseases results in modifications in metabolic processes and altered metabolites, directly or indirectly influencing lipid metabolism within the central nervous system (CNS). The challenges in differential diagnosis and the provision of effective treatment in many neuroinfectious diseases are, in part, due to limited understanding of the pathophysiology underlying the disease. Although there are numerous metabolomics studies, there remains a deficit in neurolipidomics research to provide a comprehensive understanding of the connection between altered metabolites and changes in lipid metabolism. The brain is an inherently high-lipid organ; hence, understanding neurolipidomics is the key to future breakthroughs. This review aims to provide an integrative summary of altered cerebrospinal fluid (CSF) metabolites associated with neurolipid metabolism in bacterial and viral CNS infections, with a particular focus on studies that used liquid chromatography-mass spectrometry (LC-MS). Lipid components (phospholipids) and metabolites (carnitine and tryptophan) appear to be the most significant indicators in both bacterial and viral infections. On the basis of our analysis of the literature, we recommend employing neurolipidomics in conjunction with existing neurometabolomics data as a prospective method to enhance our understanding of the cross link between dysregulated metabolites and lipid metabolism in neuroinfectious diseases.

Unlocking the Bioactive Potential and Exploring Novel Applications for Portuguese Endemic Santolina impressa.

The infusion of Santolina impressa, an endemic Portuguese plant, is traditionally used to treat various infections and disorders. This study aimed to assess its chemical profile by HPLC-DAD-ESI-MSn and validate its anti-inflammatory potential. In addition, the antioxidant capacity and effects on wound healing, lipogenesis, melanogenesis, and cellular senescence, all processes in which a dysregulated inflammatory response plays a pivotal role, were unveiled. The anti-inflammatory potential was assessed in lipopolysaccharide (LPS)-stimulated macrophages, cell migration was determined using a scratch wound assay, lipogenesis was assessed on T0901317-stimulated keratinocytes and melanogenesis on 3-isobutyl-1-methylxanthine (IBMX)-activated melanocytes. Etoposide was used to induce senescence in fibroblasts. Our results point out a chemical composition predominantly characterized by dicaffeoylquinic acids and low amounts of flavonols. Regarding the infusion's bioactive potential, an anti-inflammatory effect was evident through a decrease in nitric oxide production and inducible nitric oxide synthase and pro-interleukin-1β protein levels. Moreover, a decrease in fibroblast migration was observed, as well as an inhibition in both intracellular lipid accumulation and melanogenesis. Furthermore, the infusion decreased senescence-associated β-galactosidase activity, γH2AX nuclear accumulation and both p53 and p21 protein levels. Overall, this study confirms the traditional uses of S. impressa and ascribes additional properties of interest in the pharmaceutical and dermocosmetics industries.

Molecular Crossfires between Inflammasome Signalling and Dietary Small Molecule Inhibitors in Neurodegenerative Diseases: Implications for Medical Nutrition Therapy

Neurodegenerative disorders are a range of debilitating conditions that manifest due to the progressive loss of neuronal cells in specific brain regions. Current therapeutic options are less than adequate in many respects. Protein misfolding and aggregation are hallmarks of the most common neurodegenerative disorders. Consequently, they elicit cellular homeostasis disruption, synaptic connection loss, and subsequent cellular apoptosis. In recent years, research has increasingly linked dysregulated inflammatory responses mediated by the inflammasome complex to several neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, Epilepsy, Huntington’s disease, Autism, stroke etc. The inflammasome is a cytosolic multiprotein complex that is essential for innate immunity. Microglia are the primary cells expressing inflammasomes in the central nervous system, although astrocytes, neurons, and infiltrating myeloid cells can also express and activate inflammasomes. Regrettably, dysregulated inflammasome signaling upregulates the release of pro-inflammatory cytokines, as well as activating caspase-1. This process contributes to the continuation of neuroinflammation and subsequent damage to neurons. In this review of existing literatures, we collated empirical evidences about various inflammasome signaling pathways in selected neurological disorders. Majorly, we emphasised their influence on the advancement of diseases and neuronal cell death. Available empirical data showed that dietary small molecule inhibitors offer multi-targeted interactions to inhibit inflammasome signalling and upstream neuroinflammation. Notably, the baseline mechanisms involve suppression of free radicals, downregulating NF-κB and NLRP3 oligomerization, activating anti-inflammatory pathways, reducing ER stress, and modulating the Nrf2-ARE pathway. This shows promise for developing innovative medical nutrition therapies for various neurological conditions.

Recruitment of neutrophils in glomeruli in early mouse sepsis is associated with E-selectin expression and activation of endothelial NF-κB and MAPK pathways.

Sepsis is a dysregulated systemic inflammatory response to an infection, which can lead to multiple organ dysfunction syndrome that includes the kidney. Leukocyte recruitment is an important process of the host immune defense in response to sepsis. Endothelial cells (EC) actively regulate leukocyte recruitment by expressing adhesion molecules following the activation of dedicated intracellular signal transduction pathways. Previous studies reported that the expression of adhesion molecules was associated with the activation of endothelial NF-κB p65 and MAPK c-Jun pathways in vitro in response to conditions that mimic processes that occur in inflammation. This study aimed to investigate the spatiotemporal patterns of leukocyte recruitment, expression of adhesion molecules, and endothelial nuclear p65 and c-Jun localization in renal microvascular beds of septic mice. Here, we used a cecal ligation and puncture (CLP) sepsis mouse model and RT-qPCR and immunohistochemical staining. We showed that neutrophils, macrophages, and T lymphocytes were all present in the kidney, yet only neutrophils accumulated in a spatiotemporally discernible pattern, mainly in glomeruli at 4 hours after CLP-sepsis initiation. E-selectin, not VCAM-1, was expressed in glomeruli at the same time point. In a subset of mice at 72 hours after CLP-sepsis started, VCAM-1 expression was prominent in glomerular EC, which was not related to changes in mmu-microRNA(miR)-126a-3p levels, a short noncoding microRNA previously shown to inhibit the translation of VCAM-1 mRNA into protein. Nuclear localization of p65 and c-Jun occurred in EC of all microvascular segments at 4 and 7 hours after CLP-sepsis initiation. In summary, sepsis-induced recruitment of neutrophils, E-selectin expression, and NF-κB p65 and MAPK c-Jun pathway activation coincided in glomeruli at the early stage of the disease. In the other microvascular beds, sepsis led to NF-κB p65 and MAPK c-Jun pathway activation with limited expression of E-selectin and no association with VCAM-1 expression or leukocyte recruitment.

BPOZ-2-deficient mice exhibit aggravated inflammation-associated tissue damage after acute dextran sodium sulfate or diethylnitrosamine exposure

An excessive inflammatory response plays an important role in pathological tissue damage associated with pathogen infection and tumorigenesis. Blood POZ-containing gene type 2 (BPOZ-2), an adaptor protein for the E3 ubiquitin ligase scaffold protein CUL3, is a negative regulator of the inflammatory response. In this study, we investigated the pathophysiological functions of BPOZ-2 in dextran sodium sulfate (DSS)-induced colon injury and diethylnitrosamine (DEN)-induced liver damage. Our results indicated that BPOZ-2 deficiency increased IL-1β induction after DSS and DEN treatment. In addition, BPOZ-2-deficient mice were more susceptible to DSS-induced colitis. Notably, BPOZ-2 deficiency aggravated DEN-induced acute liver injury. These results revealed that BPOZ-2 protected against pathological tissue damage with a dysregulated inflammatory response.

Neutralizing gut-derived lipopolysaccharide as a novel therapeutic strategy for severe leptospirosis.

Leptospirosis is an emerging infectious disease caused by pathogenic Leptospira spp. Humans and some mammals can develop severe forms of leptospirosis accompanied by a dysregulated inflammatory response, which often results in death. The gut microbiota has been increasingly recognized as a vital element in systemic health. However, the precise role of the gut microbiota in severe leptospirosis is still unknown. Here, we aimed to explore the function and potential mechanisms of the gut microbiota in a hamster model of severe leptospirosis. Our study showed that leptospires were able to multiply in the intestine, cause pathological injury, and induce intestinal and systemic inflammatory responses. 16S rRNA gene sequencing analysis revealed that Leptospira infection changed the composition of the gut microbiota of hamsters with an expansion of Proteobacteria. In addition, gut barrier permeability was increased after infection, as reflected by a decrease in the expression of tight junctions. Translocated Proteobacteria were found in the intestinal epithelium of moribund hamsters, as determined by fluorescence in situ hybridization, with elevated lipopolysaccharide (LPS) levels in the serum. Moreover, gut microbiota depletion reduced the survival time, increased the leptospiral load, and promoted the expression of proinflammatory cytokines after Leptospira infection. Intriguingly, fecal filtration and serum from moribund hamsters both increased the transcription of TNF-α, IL-1β, IL-10, and TLR4 in macrophages compared with those from uninfected hamsters. These stimulating activities were inhibited by LPS neutralization using polymyxin B. Based on our findings, we identified an LPS neutralization therapy that significantly improved the survival rates in severe leptospirosis when used in combination with antibiotic therapy or polyclonal antibody therapy. In conclusion, our study not only uncovers the role of the gut microbiota in severe leptospirosis but also provides a therapeutic strategy for severe leptospirosis.

DNMT3A-mutant clonal haematopoiesis and the recovery of patients with acute ST-elevation myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart foundation Background Haematopoietic stem cells can acquire mutations and produce mutant blood cells. When this occurs in the absence of overt blood disease, it is clonal haematopoiesis of indeterminate potential (CHIP). CHIP is a novel, independent risk factor for ischaemic heart disease and heart failure (HF)(1). However, the molecular mechanisms are poorly understood. Myocardial infarction (MI) is a leading cause of HF due to ventricular remodelling and scar formation(2). We postulate CHIP mutations result in aberrant inflammation that contributes to maladaptive ventricular remodelling following MI. We investigated clinical outcomes and immune cell biology in CHIP and non-CHIP patients (pts) with acute ST-segment elevation MI (STEMI). Purpose Identify and quantify mutations with variant allele frequency (VAF)≥1% in STEMI pts. Assess leukocyte mutational burden. Investigate transcription profiles and leukocyte function in CHIP and non-CHIP STEMI pts. Methods 119 pts diagnosed with STEMI were prospectively recruited (REC19/SC/0362). We collected clinical data, including echocardiogram (echo) parameters and isolated plasma and peripheral blood mononucleated cells (PBMCs) from blood collected 48-96 hours post onset of chest pain. PBMCs were screened for mutations and analysed by flow cytometry. We assessed CHIP VAF with digital droplet PCR in flow-sorted monocytes (Mono), T and B-cells. We performed single-cell RNAseq (10x Genomics) on PBMCs. Luminex or ELISA kits were used to measure plasma proteins. Results 59/119 recruited pts had CHIP (VAF≥1%). CHIP pts were significantly older than non-CHIP pts. DNMT3A was the most commonly mutated gene (28%), followed by TET2 (17%) and ASXL1 (5.3%). 53 pts had impaired LV ejection fraction (LVEF) at admission and a follow-up Echo at median 4.6 months (2.5-8 IQR) post STEMI. They were classified as responder (R) n=24, Δ LVEF≥5% or non-responder (NR) n=29, ΔLVEF&amp;lt;5%. Pts with DNMT3A CHIP were 12 times more likely to be NR (p=0.02). Baseline LVEF was similar in CHIP and non-CHIP pts, but ΔLVEF was significantly reduced in DNMT3A vs non-CHIP pts (p&amp;lt;0.01). DNMT3A mutations were highest in Mono (mean VAF 6.3%), present in B cells (3%) but rare in T cells (1.7%). Within the Mono population, DNMT3A mutant pts had significantly higher proportions of classical Mono compared to non-CHIP (p=0.02). Using scRNAseq, we computed Mono trajectories and differential gene expression. Compared to non-CHIP, DNMT3A-mutant samples upregulated receptor for advanced glycation end-products (RAGE) and toll-like receptor signaling gene signatures. Despite this, we did not observe raised leukocyte count or detect increased levels of inflammatory cytokines in DNMT3A-mutant pts plasma samples. Conclusions DNMT3A CHIP is associated with poor LVEF recovery post-STEMI due to a dysregulated inflammatory response to acute myocardial injury. Furthermore, our data suggests that this may occur via different mechanisms than non-CHIP NR.

Impact of Resolvin-E1 and Maresin-1 on Bone Marrow Stem Cell Osteogenesis under Inflammatory Stress.

Periodontal disease is characterized by inflammation and bone loss. Central to its pathogenesis is the dysregulated inflammatory response, complicating regenerative therapies. Mesenchymal stem cells (MSCs) hold significant promise in tissue repair and regeneration. This study investigated the effects of specialized pro-resolving mediators (SPMs), Resolvin E1 (RvE1) and Maresin 1 (MaR1), on the osteogenic differentiation of human bone marrow-derived MSCs under inflammatory conditions. The stem cells were treated with SPMs in the presence of lipopolysaccharide (LPS) to simulate an inflammatory environment. Osteogenic differentiation was assessed through alkaline phosphatase activity and alizarin red staining. Proteomic analysis was conducted to characterize the protein expression profile changes, focusing on proteins related to osteogenesis and osteoclastogenesis. Treatment with RvE1 and MaR1, both individually and in combination, significantly enhanced calcified deposit formation. Proteomic analysis revealed the differential expression of proteins associated with osteogenesis and osteoclastogenesis, highlighting the modulatory impact of SPMs on bone metabolism. RvE1 and MaR1 promote osteogenic differentiation of hBMMSCs in an inflammatory environment, with their combined application yielding synergistic effects. This study provides insights into the therapeutic potential of SPMs in enhancing bone regeneration, suggesting a promising avenue for developing regenerative therapies for periodontal disease and other conditions characterized by inflammation-induced bone loss.

CD5L as a promising biological therapeutic for treating sepsis

Sepsis results from systemic, dysregulated inflammatory responses to infection, culminating in multiple organ failure. Here, we demonstrate the utility of CD5L for treating experimental sepsis caused by cecal ligation and puncture (CLP). We show that CD5L’s important features include its ability to enhance neutrophil recruitment and activation by increasing circulating levels of CXCL1, and to promote neutrophil phagocytosis. CD5L-deficient mice exhibit impaired neutrophil recruitment and compromised bacterial control, rendering them susceptible to attenuated CLP. CD5L-/- peritoneal cells from mice subjected to medium-grade CLP exhibit a heightened pro-inflammatory transcriptional profile, reflecting a loss of control of the immune response to the infection. Intravenous administration of recombinant CD5L (rCD5L) in immunocompetent C57BL/6 wild-type (WT) mice significantly ameliorates measures of disease in the setting of high-grade CLP-induced sepsis. Furthermore, rCD5L lowers endotoxin and damage-associated molecular pattern (DAMP) levels, and protects WT mice from LPS-induced endotoxic shock. These findings warrant the investigation of rCD5L as a possible treatment for sepsis in humans.

Diagnostic accuracy of pancreatic stone protein in patients with sepsis: a systematic review and meta-analysis

BackgroundSepsis is a common syndrome of multiorgan system dysfunction secondary to the dysregulated inflammatory response to infection. The role of pancreatic stone protein (PSP) in diagnosing sepsis has been investigated in previous studies. The meta-analysis aimed to comprehensively investigate the diagnostic value of PSP in identifying sepsis.MethodsPubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI), were systematically searched. Studies investigating the diagnostic performance of PSP were included. Pooled sensitivity, specificity, positive Likelihood Ratio (+ LR) and negative Likelihood Ratio (-LR), diagnostic odds ratio (DOR), and area under the curve (AUC) of summary receiver operating characteristic (SROC) were calculated.ResultsThe sensitivity of PSP was 0.88 (95% CI: 0.77–0.94), and the pooled specificity was 0.78 (95% CI: 0.65–0.87). Pooled + LR, -LR, and DOR were 4.1 (2.3, 7.3), 0.16 (0.07, 0.34), and 26 (7, 98). The AUC value for the SROC of PSP was 0.90 (0.87, 0.92). The pooled sensitivity, specificity, + LR and - LR, and DOR for PSP among neonates were 0.91 (95% CI: 0.84, 0.96), 0.66 (95% CI: 0.58, 0.74), 3.97 (95% CI: 0.53, 29.58), 0.13 (95% CI: 0.02, 1.00), and 31.27 (95% CI: 0.97, 1004.60).ConclusionsThis study indicates that PSP demonstrated favorable diagnostic accuracy in detecting sepsis. Well-designed studies are warranted to ascertain the value of PSP measurement to guide early empirical antibiotic treatment, particularly in neonates.

NLRP6 negatively regulates host defense against polymicrobial sepsis.

Sepsis remains a major cause of death in Intensive Care Units. Sepsis is a life-threatening multi-organ dysfunction caused by a dysregulated systemic inflammatory response. Pattern recognition receptors, such as TLRs and NLRs contribute to innate immune responses. Upon activation, some NLRs form multimeric protein complexes in the cytoplasm termed "inflammasomes" which induce gasdermin d-mediated pyroptotic cell death and the release of mature forms of IL-1β and IL-18. The NLRP6 inflammasome is documented to be both a positive and a negative regulator of host defense in distinct infectious diseases. However, the role of NLRP6 in polymicrobial sepsis remains elusive. We have used NLRP6 KO mice and human septic spleen samples to examine the role of NLRP6 in host defense in sepsis. NLRP6 KO mice display enhanced survival, reduced bacterial burden in the organs, and reduced cytokine/chemokine production. Co-housed WT and KO mice following sepsis show decreased bacterial burden in the KO mice as observed in singly housed groups. NLRP6 is upregulated in CD3, CD4, and CD8 cells of septic patients and septic mice. The KO mice showed a higher number of CD3, CD4, and CD8 positive T cell subsets and reduced T cell death in the spleen following sepsis. Furthermore, administration of recombinant IL-18, but not IL-1β, elicited excessive inflammation and reversed the survival advantages observed in NLRP6 KO mice. These results unveil NLRP6 as a negative regulator of host defense during sepsis and offer novel insights for the development of new treatment strategies for sepsis.

Clomiphene Citrate Administered in Periconception Phase Causes Fetal Loss and Developmental Impairment in Mice.

Clomiphene citrate is a common treatment for ovulation induction in subfertile women, but its use is associated with elevated risk of adverse perinatal outcomes and birth defects. To investigate the biological plausibility of a causal relationship, this study investigated the consequences in mice for fetal development and pregnancy outcome of periconception clomiphene citrate administration at doses approximating human exposures. A dose-dependent adverse effect of clomiphene citrate given twice in the 36 hours after mating was seen, with a moderate dose of 0.75 mg/kg sufficient to cause altered reproductive outcomes in 3 independent cohorts. Viable pregnancy was reduced by 30%, late gestation fetal weight was reduced by 16%, and ∼30% of fetuses exhibited delayed development and/or congenital abnormalities not seen in control dams, including defects of the lung, kidney, liver, eye, skin, limbs, and umbilicus. Clomiphene citrate also caused a 30-hour average delay in time of birth, and elevated rate of pup death in the early postnatal phase. In surviving offspring, growth trajectory tracking and body morphometry analysis at 20 weeks of age showed postweaning growth and development similar to controls. A dysregulated inflammatory response in the endometrium was observed and may contribute to the underlying pathophysiological mechanism. These results demonstrate that in utero exposure to clomiphene citrate during early pregnancy can compromise implantation and impact fetal growth and development, causing adverse perinatal outcomes. The findings raise the prospect of similar iatrogenic effects in women where clomiphene citrate may be present in the periconception phase unless its use is well-supervised.

Recent alcohol intake impacts microbiota in adult burn patients

Alcohol use is associated with an increased incidence of negative health outcomes in burn patients due to biological mechanisms that include a dysregulated inflammatory response and increased intestinal permeability. This study used phosphatidylethanol (PEth) in blood, a direct biomarker of recent alcohol use, to investigate associations between a recent history of alcohol use and the fecal microbiota, short chain fatty acids, and inflammatory markers in the first week after a burn injury for nineteen participants. Burn patients were grouped according to PEth levels of low or high and differences in the overall fecal microbial community were observed between these cohorts. Two genera that contributed to the differences and had higher relative abundance in the low PEth burn patient group were Akkermansia, a mucin degrading bacteria that improves intestinal barrier function, and Bacteroides, a potentially anti-inflammatory bacteria. There was no statistically significant difference between levels of short chain fatty acids or intestinal permeability across the two groups. To our knowledge, this study represents the first report to evaluate the effects of burn injury and recent alcohol use on early post burn microbiota dysbiosis, inflammatory response, and levels of short chain fatty acids. Future studies in this field are warranted to better understand the factors associated with negative health outcomes and develop interventional trials.