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BackgroundObesity and consumption of high-fat diets (HFD) are associated with intestinal permeabilization and increased paracellular transport of endotoxins, which can promote neuroinflammation. Inflammation can affect the hypothalamic pituitary adrenal (HPA) axis, which controls responses to stress and downregulates the brain-derived neurotrophic factor (BDNF), which can promote anxiety and depression, conditions frequently found in obesity. We previously showed that consumption of anthocyanins (AC) mitigate HFD-induced insulin resistance, intestinal permeability, and inflammation.ObjectivesThis study investigated if a dietary supplementation with a cyanidin- and delphinidin-rich extract (CDRE) could counteract HFD/obesity-induced hippocampal inflammation in mice.MethodsC57BL/6J male mice were fed for 14 wk on one of the following diets: 1) a control diet containing 10% total calories from fat (C), 2) a control diet supplemented with 40 mg AC/kg body weight (BW) (CAC), 3) a HFD containing 60% total calories from fat (lard) (HF), or 4) the HFD supplemented with 2, 20, or 40 mg AC/kg BW (HFA2, HFA20, and HFA40, respectively). In plasma and in the hippocampus, parameters of neuroinflammation and the underlying cause (endotoxemia) and consequences (alterations to the HPA and BDNF downregulation) were measured.ResultsConsumption of the HFD caused endotoxemia. Accordingly, hippocampal Tlr4 mRNA levels were 110% higher in the HF group, which were both prevented by CDRE supplementation. Consumption of the HFD also caused: 1) microgliosis and increased expression of genes involved in neuroinflammation, that is, Iba-1, Nox4, Tnfα, and Il-1β, 2) alterations of HPA axis regulation, that is, with low expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors; and 3) decreased Bdnf expression. Supplementation of HFD-fed mice with CDRE mitigated neuroinflammation, microgliosis, and MR and BDNF decreases.ConclusionsCDRE supplementation mitigates the negative effects associated with HFD consumption and obesity in mouse hippocampus, in part by decreasing inflammation, improving glucocorticoid metabolism, and upregulating BDNF.

Background: The primary objective of this study was to advance our understanding of active drug uptake at brain barriers in higher species than rodents, by examining oxycodone brain concentrations in pigs. Methods: This was investigated by a microdialysis study in healthy and endotoxemic conditions to increase the understanding of inter-species translation of putative proton-coupled organic cation (H+/OC) antiporter-mediated central nervous system (CNS) drug delivery in health and pathology, and facilitate the extrapolation to humans for improved CNS drug treatment in patients. Additionally, we sought to evaluate the efficacy of lumbar cerebrospinal fluid (CSF) exposure readout as a proxy for brain unbound interstitial fluid (ISF) concentrations. By simultaneously monitoring unbound concentrations in blood, the frontal cortical area, the lateral ventricle (LV), and the lumbar intrathecal space in healthy and lipopolysaccharide (LPS)-induced inflammation states within the same animal, we achieved exceptional spatiotemporal resolution in mapping oxycodone transport across CNS barriers. Results: Our findings provide novel evidence of higher unbound oxycodone concentrations in brain ISF compared to blood, yielding an unbound brain-to-plasma concentration ratio (Kp,uu,brain) of 2.5. This supports the hypothesis of the presence of the H+/OC antiporter system at the blood–brain barrier (BBB) in pigs. Despite significant physiological changes, reflected in pig Sequential Organ Failure Assessment, pSOFA scores, oxycodone blood concentrations and its active net uptake across the BBB remained nearly unchanged during three hours of i.v. infusion of 4 µg/kg/h LPS from Escherichia coli (O111:B4). Mean Kp,uu,LV values indicated active uptake also at the blood-CSF barrier in healthy and endotoxemic pigs. Lumbar CSF concentrations showed minimal inter-individual variability during the experiment, with a mean Kp,uu,lumbarCSF of 1.5. LPS challenge caused a slight decrease in Kp,uu,LV, while Kp,uu,lumbarCSF remained unaffected. Conclusions: This study enhances our understanding of oxycodone pharmacokinetics and CNS drug delivery in both healthy and inflamed conditions, providing crucial insights for translating these findings to clinical settings. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) is a critical interface that maintains the central nervous system homeostasis by controlling the exchange of substances between the blood and the brain. Disruption of the BBB plays a vital role in the development of neuroinflammation and neurological dysfunction in sepsis, but the mechanisms by which the BBB becomes disrupted during sepsis are not well understood. Here, we induced endotoxemia, a major type of sepsis, in mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS acutely increased BBB permeability, activated microglia, and heightened inflammatory responses in brain endothelium and parenchyma. Concurrently, LPS or proinflammatory cytokines activated the NF-κB pathway, inhibiting Wnt/β-catenin signaling in brain endothelial cells in vitro and in vivo. Cell culture study revealed that NF-κB p65 directly interacted with β-catenin to suppress Wnt/β-catenin signaling. Pharmacological NF-κB pathway inhibition restored brain endothelial Wnt/β-catenin signaling activity and mitigated BBB disruption and neuroinflammation in septic mice. Furthermore, genetic or pharmacological activation of brain endothelial Wnt/β-catenin signaling substantially alleviated LPS-induced BBB leakage and neuroinflammation, while endothelial conditional ablation of the Wnt7a/7b co-receptor Gpr124 exacerbated the BBB leakage caused by LPS. Mechanistically, Wnt/β-catenin signaling activation rectified the reduced expression levels of tight junction protein ZO-1 and transcytosis suppressor Mfsd2a in brain endothelial cells of mice with endotoxemia, inhibiting both paracellular and transcellular permeability of the BBB. Our findings demonstrate that endotoxemia-associated systemic inflammation decreases endothelial Wnt/β-catenin signaling through activating NF-κB pathway, resulting in acute BBB disruption and neuroinflammation. Targeting the endothelial Wnt/β-catenin signaling may offer a promising therapeutic strategy for preserving BBB integrity and treating neurological dysfunction in sepsis. [ABSTRACT FROM AUTHOR]

Endotoxemia is closely related to many diseases. As the largest endotoxin reservoir in the human body, the gut microbiota should be a key target for alleviating endotoxemia. The intestinal microbiota is believed to cause endotoxemia directly or indirectly by modifying the intestinal barrier function through dysbiosis, changing intestinal mucosal permeability and bacterial translocation. Diet is known to be the main environmental factor affecting the intestinal microbiota, and different diets and food components have a large impact on the gut microbiota. The Mediterranean diet, which received much attention in recent years, is believed to be able to regulate the gut microbiota, thereby maintaining the function of the intestinal barrier and alleviating endotoxemia. In this review, we focus on the relationship between the gut microbiota and endotoxemia, and how the Mediterranean dietary (MD) pattern can interfere with endotoxemia through the gut microbiota. [ABSTRACT FROM AUTHOR]

M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Mechanistically, MDM2 triggers the ubiquitination and degradation of E3 ligase, SPSB2, to stabilize iNOS and increases production of NO, which s-nitrosylates and activates HIF-1α for triggering the glycolytic and pro-inflammatory programs in M1 macrophages. Myeloid-specific haplodeletion of MDM2 in mice not only blunts LPS-induced endotoxemia and NO production, but also alleviates obesity-induced adipose tissue-resident macrophage inflammation. By contrast, MDM2 haplodeletion induces higher mortality, tissue damage and bacterial burden, and also suppresses M1 macrophage response, in the cecal ligation and puncture-induced sepsis mouse model. Our findings thus identify MDM2 as an activator of glycolytic and inflammatory responses in M1 macrophages by connecting the iNOS-NO and HIF-1α pathways. Proinflammatory macrophages mediate protective immunity but also contribute to inflammatory diseases. Here the authors show that the E3 ligase, MDM2, induces nitric oxide from macrophage, potentially triggering the s-nitrosylation and activation of HIF-1α for the production of inflammatory cytokines, to protect mice from sepsis but aggravate obesity-induced inflammation. [ABSTRACT FROM AUTHOR]

Objective: Inulicin is a sesquiterpene lactone in Inulae Flos which is clinically used for the treatment of inflammatory diseases, such as cough, sputum production, and vomiting. This study aimed to demonstrate the anti-inflammatory activity and the underlying mechanism of inulicin by using lipopolysaccharide (LPS)-induced in vitro and in vivo models. Methods: LPS-stimulated RAW264.7 macrophages and mouse peritoneal macrophages (MPMs) were used for evaluating the in vitro anti-inflammatory activity of inulicin, while endotoxemia mice were used for evaluating its in vivo action. Cytokines' levels were determined by ELISA. RT-qPCR and western blot were used for assaying the mRNA and protein levels of target genes. RAW264.7 macrophages transfected with reporter plasmid pNFκB-TA-luc or pAP1-TA-luc were used for assaying the activation of NF-κB or AP-1 signaling. Results: Inulicin significantly inhibited LPS-induced production of NO, IL-6, c-c motif chemokine ligand 2 (CCL2), and IL-1β in both RAW264.7 cells and MPMs. Mechanism study indicated that it could suppress inducible nitric oxide synthase, IL-6, CCL2, and IL-1β mRNA levels in LPS-stimulated RAW264.7 cells. Moreover, inulicin inhibited IκBα phosphorylation and prevented the nuclear translocation of p65, thereby inactivating NF-κB signaling. Concurrently, it also inhibited AP-1 signaling by reducing the phosphorylation of C-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). In endotoxemia mice, a single intraperitoneal administration of inulicin could decrease the production of pro-inflammatory cytokines in serum and peritoneal lavage fluid. Conclusions: The present study demonstrates that inulicin possesses anti-inflammatory effects in vitro and in vivo, which suggests that inulicin might be a promising candidate for the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Objective: To explore the protective effect and the underlying mechanism of silibinin (SIB), one of the active compounds from Silybum marianum (L.) Gaertn in endotoxemia. Methods: Mouse peritoneal macrophage were isolated via intraperitoneally injection of BALB/c mice with thioglycolate medium. Cell viability was assessed using the cell counting kit-8, while cytotoxicity was determined through lactate dehydrogenase cytotoxicity assay. The protein expressions of interleukin (IL)-1 α, IL-1 β, and IL-18 were determined by enzyme-linked immunosorbent assay. Intracellular lipopolysaccharide (LPS) levels were measured by employing both the limulus amoebocyte lysate assay and flow cytometry. Additionally, proximity ligation assay was employed for the LPS and caspase-11 interaction. Mice were divided into 4 groups: the control, LPS, high-dose-SIB (100 mg/kg), and low-dose-SIB (100 mg/kg) groups (n=8). Zebrafish were divided into 4 groups: the control, LPS, high-dose-SIB (200 εmol/L), and low-dose-SIB (100 εmol/L) groups (n=30 for survival experiment and n=10 for gene expression analysis). The expression of caspase-11, gasdermin D (GSDMD), and N-GSDMD was determined by Western blot and the expressions of caspy2, gsdmeb, and IL-1 β were detected using quantitative real-time PCR. Histopathological observation was performed through hematoxylineosin staining, and protein levels in bronchoalveolar lavage fluid were quantified using the bicinchoninicacid protein assay. Results: SIB noticeably decreased caspase-11 and GSDMD-mediated pyroptosis and suppressed the secretion of IL-1 α, IL-1 β, and IL-18 induced by LPS (P<0.05). Moreover, SIB inhibited the translocation of LPS into the cytoplasm and the binding of caspase-11 and intracellular LPS (P<0.05). SIB also attenuated the expression of caspase-11 and N-terminal fragments of GSDMD, inhibited the relative cytokines, prolonged the survival time, and up-regulated the survival rate in the endotoxemia models (P<0.05). Conclusions: SIB can inhibit pyroptosis in the LPS-mediated endotoxemia model, at least in part, by inhibiting the caspase-11-mediated cleavage of GSDMD. Additionally, SIB inhibits the interaction of LPS and caspase-11 and inhibits the LPS-mediated up-regulation of caspase-11 expression, which relieves caspase-11-dependent cell pyroptosis and consequently attenuates LPS-mediated lethality. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) in blood circulation causes endotoxemia and is linked to various disease conditions. Current treatments focus on preventing LPS from interacting with its receptor Toll-like receptor 4 (TLR4) and reducing inflammation. However, our body has a natural defense mechanism: reticuloendothelial cells in the liver rapidly degrade and inactivate much of the circulating LPS within minutes. But this LPS clearance mechanism is not perfect. Excessive LPS that escape this clearance mechanism cause systemic inflammatory damage through TLR4. Despite its importance, the role of reticuloendothelial cells in LPS elimination is not well-studied, especially regarding the specific cells, receptors, and mechanisms involved. This gap hampers the development of effective therapies for endotoxemia and related diseases. This review consolidates the current understanding of LPS clearance, narrates known and explores potential mechanisms, and discusses the relationship between LPS clearance and LPS signaling. It also aims to highlight key insights that can guide the development of strategies to reduce circulating LPS by way of bolstering host defense mechanisms. Ultimately, we seek to provide a foundation for future research that could lead to innovative approaches for enhancing the body's natural ability to clear LPS and thereby lower the risk of endotoxin-related inflammatory diseases, including sepsis. [ABSTRACT FROM AUTHOR]

Targeting NLRP3 inflammasome has been recognized as a promising therapeutic strategy for the treatment of numerous common diseases. UK5099, a long‐established inhibitor of mitochondrial pyruvate carrier (MPC), is previously found to inhibit macrophage inflammatory responses independent of MPC expression. However, the mechanisms by which UK5099 inhibit inflammatory responses remain unclear. Here, it is shown that UK5099 is a potent inhibitor of the NLRP3 inflammasome in both mouse and human primary macrophages. UK5099 selectively suppresses the activation of the NLRP3 but not the NLRC4 or AIM2 inflammasomes. Of note, UK5099 retains activities on NLRP3 in macrophages devoid of MPC expression, indicating this inhibitory effect is MPC‐independent. Mechanistically, UK5099 abrogates mitochondria‐NLRP3 interaction and in turn inhibits the assembly of the NLRP3 inflammasome. Further, a single dose of UK5099 persistently reduces IL‐1β production in an endotoxemia mouse model. Importantly, structure modification reveals that the inhibitory activities of UK5099 on NLRP3 are unrelated to the existence of the activated double bond within the UK5099 molecule. Thus, this study uncovers a previously unknown molecular target for UK5099, which not only offers a new candidate for the treatment of NLRP3‐driven diseases but also confounds its use as an MPC inhibitor in immunometabolism studies. [ABSTRACT FROM AUTHOR]

In dogs, chronic enteropathies, and impaired gut integrity, as well as microbiome imbalances, are a major problem. These conditions may represent a continuous low endotoxin load, which may result in the development of diseases that are attributable to chronic inflammation. Flavonoids are polyphenolic plant compounds with numerous beneficial properties such as antioxidant, anti-inflammatory and antimicrobial effects. For our experiments, we isolated primary white blood cells (peripheral blood mononuclear cells and polymorphonuclear leukocytes) from healthy dogs and induced inflammation and oxidative stress with Escherichia coli and Salmonella enterica serovar Enteritidis lipopolysaccharide (LPS). In parallel, we treated the cell cultures with various flavonoids luteolin, quercetin and grape seed extract oligomeric proanthocyanidins (GSOP) alone and also in combination with LPS treatments. Then, changes in viability, reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-a) levels were measured in response to treatment with quercetin, luteolin and GSOP at 25 and 50 µg/mL concentrations. We found that ROS levels were significantly lower in groups which were treated by flavonoid and LPS at the same time compared to LPS-treated groups, whereas TNF-a levels were significantly reduced only by luteolin and quercetin treatment. In contrast, treatment with lower concentrations of GSOP caused an increase in TNF-a levels, while higher concentrations caused a significant decrease. These results suggest that the use of quercetin, luteolin and GSOP may be helpful in the management of chronic intestinal diseases in dogs with reduced intestinal barrier integrity or altered microbiome composition, or in the mitigation of chronic inflammatory processes maintained by endotoxemia. Further in vitro and in vivo studies are needed before clinical use. [ABSTRACT FROM AUTHOR]

Background: Cognitive dysfunction caused by infection frequently emerges as a complication in sepsis survivor patients. However, a comprehensive understanding of its pathogenesis remains elusive. Methods: In our in vivo experiments, an animal model of endotoxemia was employed, utilizing the Novel Object Recognition Test and Morris Water Maze Test to assess cognitive function. Various techniques, including immunofluorescent staining, Western blotting, blood‒brain barrier permeability assessment, Limulus Amebocyte Lysate (LAL) assay, and Proximity-ligation assay, were employed to identify brain pathological injury and neuroinflammation. To discern the role of Caspase-11 (Casp11) in hematopoietic or non-hematopoietic cells in endotoxemia-induced cognitive decline, bone marrow chimeras were generated through bone marrow transplantation (BMT) using wild-type (WT) and Casp11-deficient mice. In vitro studies involved treating BV2 cells with E. coli-derived outer membrane vesicles to mimic in vivo conditions. Results: Our findings indicate that the deficiency of Casp11-GSDMD signaling pathways reverses infection-induced cognitive dysfunction. Moreover, cognitive dysfunction can be ameliorated by blocking the IL-1 effect. Mechanistically, the absence of Casp11 signaling significantly mitigated blood‒brain barrier leakage, microglial activation, and synaptic damage in the hippocampal CA3 region, ultimately leading to improved cognitive function. Conclusion: This study unveils the crucial contribution of Casp11 and GSDMD to cognitive impairments and spatial memory loss in a murine sepsis model. Targeting Casp11 signaling emerges as a promising strategy for preventing or treating cognitive dysfunction in patients with severe infections. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Pre‐left ventricular assist device (LVAD) pectoralis muscle assessment, an estimate of sarcopenia, has been associated with postoperative mortality and gastrointestinal bleeding, though its association with inflammation, endotoxemia, length‐of‐stay (LOS), and readmissions remains underexplored.This was a single‐center cohort study of LVAD patients implanted 1/2015–10/2018. Preoperative pectoralis muscle area was measured on chest computed tomography (CT), adjusted for height squared to derive pectoralis muscle area index (PMI). Those with PMI in the lowest quintile were defined as low‐PMI cohort; all others constituted the reference cohort. Biomarkers of inflammation (interleukin‐6, adiponectin, tumor necrosis factor‐α [TNFα]) and endotoxemia (soluble (s)CD14) were measured in a subset of patients.Of the 254 LVAD patients, 95 had a preoperative chest CT (median days pre‐LVAD: 7 [IQR 3–13]), of whom 19 (20.0%) were in the low‐PMI cohort and the remainder were in the reference cohort. Compared with the reference cohort, the low‐PMI cohort had higher levels of sCD14 (2594 vs. 1850 ng/mL; p = 0.04) and TNFα (2.9 vs. 1.9 pg/mL; p = 0.03). In adjusted analyses, the low‐PMI cohort had longer LOS (incidence rate ratio 1.56 [95% confidence interval 1.16–2.10], p = 0.004) and higher risk of 90‐day and 1‐year readmissions (subhazard ratio 5.48 [1.88–16.0], p = 0.002; hazard ratio 1.73 [1.02–2.94]; p = 0.04, respectively).Pre‐LVAD PMI is associated with inflammation, endotoxemia, and increased LOS and readmissions. [ABSTRACT FROM AUTHOR]

Alcohol is the most widely abused substance in the world, the leading source of mortality in 15–49‐year‐olds, and a major risk factor for heart disease, liver disease, diabetes, and cancer. Despite this, alcohol is regularly misused in wider society. Consumers of excess alcohol often note a constellation of negative symptoms, known as the alcohol hangover. However, the alcohol hangover is not considered to have long‐term clinical significance by clinicians or consumers. We undertook a critical review of the literature to demonstrate the pathophysiological mechanisms of the alcohol hangover. Hereafter, the alcohol hangover is re‐defined as a manifestation of sickness behavior secondary to alcohol‐induced inflammation, using the Bradford‐Hill criteria to demonstrate causation above correlation. Alcohol causes inflammation through oxidative stress and endotoxemia. Alcohol metabolism is oxidative and increased intake causes relative tissue hypoxia and increased free radical generation. Tissue damage ensues through lipid peroxidation and the formation of DNA/protein adducts. Byproducts of alcohol metabolism such as acetaldehyde and congeners, sleep deprivation, and the activation of nonspecific inducible CYP2E1 in alcohol‐exposed tissues exacerbate free radical generation. Tissue damage and cell death lead to inflammation, but in the intestine loss of epithelial cells leads to intestinal permeability, allowing the translocation of pathogenic bacteria to the systemic circulation (endotoxemia). This leads to a well‐characterized cascade of systemic inflammation, additionally activating toll‐like receptor 4 to induce sickness behavior. Considering the evidence, it is suggested that hangover frequency and severity may be predictors of the development of later alcohol‐related diseases, meriting formal confirmation in prospective studies. In light of the mechanisms of alcohol‐mediated inflammation, research into gut permeability and the gut microbiome may be an exciting future therapeutic avenue to prevent alcohol hangover and other alcohol‐related diseases. [ABSTRACT FROM AUTHOR]

We aimed to systematize the results of published studies on the use of Saccharomyces boulardii (SB) for the treatment of various liver disorders (CRD42022378050). Searches were conducted using PubMed and Scopus on 1 August 2022. The PubMed search was updated on 15 June 2024. The review included sixteen studies: ten experimental animal studies (EASs) and six randomized controlled trials (RCTs). The CNCM I-745 strain was used in 68.8% of the included studies. SB reduced the severity of many manifestations of cirrhosis, and lowered the Child–Pugh scores in RCT. SB reduced the serum concentrations of TNF-α, IL-1β, IL-6, and IL-4 in animals with metabolic dysfunction-associated steatotic liver disease (MASLD); lowered the serum TNF-α and IL-6 levels in experimental cirrhosis in rats; and reduced the CRP levels in decompensated cirrhosis. The EAS of MASLD revealed that SB reduced liver steatosis and inflammation and lowered the liver expression of genes of TNF-α, IL-1β, interferon-γ, and IL-10. In studies on experimental cirrhosis and MASLD, SB reduced the liver expression of genes of TGF-β, α-SMA, and collagen as well as liver fibrosis. SB reduced the abundance of Escherichia (Proteobacteria), increased the abundance of Bacteroidetes in the gut microbiota, prevented an increase in intestinal barrier permeability, and reduced bacterial translocation and endotoxemia. [ABSTRACT FROM AUTHOR]

Abstract The blood-brain barrier (BBB) is a critical interface that maintains the central nervous system homeostasis by controlling the exchange of substances between the blood and the brain. Disruption of the BBB plays a vital role in the development of neuroinflammation and neurological dysfunction in sepsis, but the mechanisms by which the BBB becomes disrupted during sepsis are not well understood. Here, we induced endotoxemia, a major type of sepsis, in mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS acutely increased BBB permeability, activated microglia, and heightened inflammatory responses in brain endothelium and parenchyma. Concurrently, LPS or proinflammatory cytokines activated the NF-κB pathway, inhibiting Wnt/β-catenin signaling in brain endothelial cells in vitro and in vivo. Cell culture study revealed that NF-κB p65 directly interacted with β-catenin to suppress Wnt/β-catenin signaling. Pharmacological NF-κB pathway inhibition restored brain endothelial Wnt/β-catenin signaling activity and mitigated BBB disruption and neuroinflammation in septic mice. Furthermore, genetic or pharmacological activation of brain endothelial Wnt/β-catenin signaling substantially alleviated LPS-induced BBB leakage and neuroinflammation, while endothelial conditional ablation of the Wnt7a/7b co-receptor Gpr124 exacerbated the BBB leakage caused by LPS. Mechanistically, Wnt/β-catenin signaling activation rectified the reduced expression levels of tight junction protein ZO-1 and transcytosis suppressor Mfsd2a in brain endothelial cells of mice with endotoxemia, inhibiting both paracellular and transcellular permeability of the BBB. Our findings demonstrate that endotoxemia-associated systemic inflammation decreases endothelial Wnt/β-catenin signaling through activating NF-κB pathway, resulting in acute BBB disruption and neuroinflammation. Targeting the endothelial Wnt/β-catenin signaling may offer a promising therapeutic strategy for preserving BBB integrity and treating neurological dysfunction in sepsis.

The aim of review. Analysis of literature data on the possible causes of fever at patients with disorders of liver function. Article presents pathophysiological mechanisms of development of fever. The algorithm of assessment of patient with disorder of liver function and fever is submitted.Original positions. Fever in patients with liver failure can be caused both by infectious and non-infectious causes. Infections are the most frequent causes of fever at disorder of the liver function, that accounts for immunodeficiency state at this category of patients. An important role in development of fever at patients with liver cirrhosis is bacterial overgrowth syndrome, bacterial translocation processes and, as a consequence, endotoxemia. If the site of infection is not detected, it is necessary to keep in mind the option of development of non-infectious fever within acute phase reaction, neoplastic process or reaction to applied pharmaceutical agents.Conclusion. At development of fever at patients with liver failure carrying out differential diagnostics of the causes of body temperature elevation is necessary that allows more differentiated approaches to treatment.

AIM OF THE STUDY. To establish the incidence of acute thrombosis of the veins of the lower extremities and the activity of the most significant trigger agents that led to this complication in patients with a new coronavirus infection. MATERIAL AND METHODS. The clinical section of the work is presented by observations of 123 patients with acute surgical pathology and thrombosis of the veins of the lower extremities. The first group (comparison) (n = 48) included patients with thrombosis of the veins of the lower extremities, the second (studied) group (n = 87) included patients with a similar problem that arose against the background of coronavirus infection. All patients underwent surgical interventions: thrombectomy and plication. Before surgery, on the 1st, 4th and 7th days after surgery, disorders of the hemostasis system, the severity of endogenous intoxication syndrome, and lipid metabolism were assessed. RESULTS. Damage to the veins of the lower extremities in patients with acute surgical pathology and new coronavirus infection occurs much more often, in 8.04 % of cases, than in such patients without COVID-19, in 0.76% (χ2 = 252.5, p < 0.001). Of the 87 patients with acute venous thrombosis of the inferior vena cava system and COVID-19, 63 patients (72.41 %) were operated on. In the early postoperative period, venous rethmbosis occurred in 11 (17.5 %) patients. The mortality rate was 6.3 %. According to thromboelastography, in the main group the values of such parameters as reactive time, the growth rate of the fibrin network and its structure formation and the maximum strength of the clot were statistically significantly higher than in the control group, which indicates the predominance of hypercoagulation in these patients. Patients in this group showed more significant phenomena of endotoxemia, oxidative stress and activation of phospholipases. CONCLUSION. With a new coronavirus infection, surgical patients have a high probability of developing threatening thrombohemorrhagic complications. The most important trigger for their occurrence is significant disturbances in the hemostatic system, which are generally characterized by an increased ability of the blood to form thrombosis against the background of a decrease in its fibrinolytic activity. Disturbances in the hemostatic system occurred against the background of oxidative stress, activation of phospholipases and endotoxemia. The obtained material is proof of the significance of the new coronavirus COVID-19 infection worsens coagulopathy, which plays an important role in the pathogenesis of the disease in general and the development of complications.

Abstract Background Cognitive dysfunction caused by infection frequently emerges as a complication in sepsis survivor patients. However, a comprehensive understanding of its pathogenesis remains elusive. Methods In our in vivo experiments, an animal model of endotoxemia was employed, utilizing the Novel Object Recognition Test and Morris Water Maze Test to assess cognitive function. Various techniques, including immunofluorescent staining, Western blotting, blood‒brain barrier permeability assessment, Limulus Amebocyte Lysate (LAL) assay, and Proximity-ligation assay, were employed to identify brain pathological injury and neuroinflammation. To discern the role of Caspase-11 (Casp11) in hematopoietic or non-hematopoietic cells in endotoxemia-induced cognitive decline, bone marrow chimeras were generated through bone marrow transplantation (BMT) using wild-type (WT) and Casp11-deficient mice. In vitro studies involved treating BV2 cells with E. coli-derived outer membrane vesicles to mimic in vivo conditions. Results Our findings indicate that the deficiency of Casp11-GSDMD signaling pathways reverses infection-induced cognitive dysfunction. Moreover, cognitive dysfunction can be ameliorated by blocking the IL-1 effect. Mechanistically, the absence of Casp11 signaling significantly mitigated blood‒brain barrier leakage, microglial activation, and synaptic damage in the hippocampal CA3 region, ultimately leading to improved cognitive function. Conclusion This study unveils the crucial contribution of Casp11 and GSDMD to cognitive impairments and spatial memory loss in a murine sepsis model. Targeting Casp11 signaling emerges as a promising strategy for preventing or treating cognitive dysfunction in patients with severe infections.

Maintenance of autonomic homeostasis is continuously calibrated by sensory fibers of the vagus nerve and sympathetic chain that convey compound action potentials (CAPs) to the central nervous system. Lipopolysaccharide (LPS) intravenous challenge reliably elicits a robust inflammatory response that can resemble systemic inflammation and acute endotoxemia. Here, we administered LPS intravenously in nine healthy subjects while recording ventral cervical magnetoneurography (vcMNG)-derived CAPs at the rostral Right Nodose Ganglion (RNG) and the caudal Right Carotid Artery (RCA) with optically pumped magnetometers (OPM). We observed vcMNG RNG and RCA neural firing rates that tracked changes in TNF-α levels in the systemic circulation. Further, endotype subgroups based on high and low IL-6 responders segregate RNG CAP frequency (at 30-120 min) and based on high and low IL-10 response discriminate RCA CAP frequency (at 0-30 min). These vcMNG tools may enhance understanding and management of the neuroimmune axis that can guide personalized treatment based on an individual's distinct endophenotype. Ventral cervical magnetoneurography responses after LPS administration temporally aligned with the changes in TNF-α levels, making it a potential sensitive bioindicator of the neuroimmune axis for clinical use. [ABSTRACT FROM AUTHOR]

Tyloxapol is a surfactant which increases the concentration of lipoproteins in humans and animals. These lipoproteins are the natural scavengers of the lipopolysaccharides, also known as endotoxins, secreted by outer membrane of the gram-negative bacterium and responsible for morbidity and mortality of the diseases associated with gram-negative bacterium. Therefore, the present study was designed to evaluate the therapeutic effects of tyloxapol in Pasteurella multocida-induced infection in water buffaloes. For this purpose, 12 healthy buffalo calves, 8-10 months old, were procured and experimentally induced with Pasteurella multocida infection after acclimatization period of 7 days. The buffalo calves were randomly divided into two groups (n=6) A & B. Group A was treated with ceftiofur HCl and flunixin meglumine @ 6 and 2 mg/kg BW, respectively. This treatment continued for 5 days. Group B was administered with tyloxapol @ 150 mg/kg BW IV QD continuously for 3 days. Efficacy of the treatment was evaluated through cardinal parameters, lipoproteins and concentrations of cytokines and endotoxins. The data obtained was analyzed statistically. Results of the study depicted that no untoward or allergic reaction was observed after intravenous administration of tyloxapol to the buffalo calves. Tyloxapol significantly elevated lipoprotein concentrations to the normal in group B and differed significantly (P<0.05) from its counterpart. It significantly (P<0.05) reduced the concentration of pro-inflammatory cytokines and endotoxins than its counterpart, thereby successfully ameliorated their deleterious effects. We concluded from findings of the study that tyloxapol is safe to administer in buffalo calves and could successfully resuscitate the calves suffering from hemorrhagic septicemia thus improving survival. It showed anti-endotoxic effects and enhanced natural scavengers of endotoxins i.e., HDL & LDL and successfully ameliorated cytokine concentration. Tyloxapol can be useful in clinical settings to contravene the effects of endotoxemia/septicemia in animals. [ABSTRACT FROM AUTHOR]

Lipedema is a poorly understood disorder of adipose tissue characterized by abnormal symmetrical deposition of subcutaneous white adipose tissue (WAT) in proximal extremities. Here we show that the underlying cause for lipedema should be a selective accumulation of bacterial lipopolysaccharides (LPS, also known as endotoxins) in gluteofemoral WAT (gfWAT) that, together with a malfunctioning complement system, can induce low-grade inflammation in this depot and raise its uncontrollable expansion. Increased appearance of LPS in circulation and expansion of gfWAT are typical over the course of pregnancy. However, even in a non-pregnant individual, from a gfWAT perspective, increased LPS levels could be viewed as a "pseudo-pregnancy", which should lead to an induced expansion of gfWAT. In accordance with this pathophysiology, proper management of endotoxemia (especially in early stages of lipedema) should decelerate progression and even improve the state of disease. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a metabolic chronic disease in which insulin resistance and insufficient insulin production lead to elevated blood glucose levels. The prevalence of T2D is growing worldwide, mainly due to obesity and the adoption of Western diets. Replacing animal foods with healthy plant foods is associated with a lower risk of T2D in prospective studies. In randomized controlled trials, the consumption of healthy plant foods in place of animal foods led to cardiometabolic improvements in patients with T2D or who were at high risk of the disease. Dietary patterns that limit or exclude animal foods and focus on healthy plant foods (eg, fruits, vegetables, whole grains, nuts, legumes), known as healthy, plant-based diets, are consistently associated with a lower risk of T2D in cohort studies. The aim of this review is to examine the differential effects of plant foods and animal foods on T2D risk and to describe the existing literature about the role of healthy, plant-based diets, particularly healthy vegan diets, in T2D prevention and management. The evidence from cohort studies and randomized controlled trials will be reported, in addition to the potential biological mechanisms that seem to be involved. [ABSTRACT FROM AUTHOR]

• We assessed if experimental sickness affected perception of unknown caregivers. • We developed the Caregiver Perception task (CgPT), in which participants watch and rate caregivers. • Twenty-six participants were injected with lipopolysaccharide (0.8 ng/kg body weight) and placebo. • Healthcare professionals providing care were rated more positively than those not providing care. • Experimental sickness led to increased willingness to receive care from caregivers who provided care. Social withdrawal is a well-established part of sickness behavior, but in some contexts sick animals might gain from keeping close instead of keeping away. For instance, sick individuals are more willing to be near known individuals who can provide care and safety (close others) compared to when healthy. Yet, interactions with some strangers might also be beneficial (i.e., healthcare professionals), but it is not known how sickness interplay with social behavior towards such individuals. Here, we assessed if sickness affects perception of caregivers, and developed a new task, the Caregiver Perception Task (CgPT). Twenty-six participants performed the CgPT, once after an injection of lipopolysaccharide (LPS, 0.8 ng/kg body weight, n = 24), and once after an injection of saline (n = 25), one hour and forty-five minutes post-injection. During the task, participants watched short video clips of three types of caregivers: a healthcare professional taking care of a sick individual, a healthcare professional not taking care of a sick individual, and a non-healthcare professional taking care of their sick adult child or partner. After each video clip, the likability, trustworthiness, professionalism, and willingness to interact with and receive care from the caregiver were rated on visual analogue scales. Results showed that participants injected with saline rated healthcare professionals who did not take care of a sick individual less positively on all aspects compared to healthcare professionals who took care of a sick individual. Moreover, compared to saline, LPS increased the participants' willingness to receive care from healthcare professionals and non-healthcare professionals providing care, but not from healthcare professionals not providing care. Thus, our results indicate that sick individuals may approach unknown individuals with potential to provide care and support. [ABSTRACT FROM AUTHOR]

Background Thrombomodulin (TM) exerts anticoagulant and anti-inflammatory effects to improve the survival of patients with septic shock. Heat stroke resembles septic shock in many aspects. We tested whether TM would improve cognitive deficits and related causative factors in heat-stressed (HS) mice. Methods Adult male mice were exposed to HS (33°C for 2 hours daily for 7 consecutive days) to induce cognitive deficits. Recombinant human soluble TM (1 mg/kg, i.p.) was administered immediately after the first HS trial and then once daily for 7 consecutive days. We performed the Y-maze, novel objective recognition, and passive avoidance tests to evaluate cognitive function. Plasma levels of lipopolysaccharide (LPS), high-mobility group box 1 (HMGB1), coagulation parameters, and both plasma and tissue levels of inflammatory and oxidative stress markers were biochemically measured. The duodenum and hippocampus sections were immunohistochemically stained. The intestinal and blood-brain barrier permeability were determined. Results Compared with controls, HS mice treated with TM had lesser extents of cognitive deficits, exacerbated stress reactions, gut barrier disruption, endotoxemia, blood-brain barrier disruption, and inflammatory, oxidative, and coagulatory injury to heart, duodenum, and hippocampal tissues, and increased plasma HMGB1. In addition to reducing cognitive deficits, TM therapy alleviated all the abovementioned complications in heat-stressed mice. Conclusions The findings suggest that HS can lead to exacerbated stress reactions, endotoxemia, gut barrier disruption, blood-brain barrier disruption, hippocampal inflammation, coagulopathy, and oxidative stress, which may act as causative factors for cognitive deficits. TM, an anti-inflammatory, antioxidant, and anti-coagulatory agent, inhibited heat stress-induced cognitive deficits in mice. [ABSTRACT FROM AUTHOR]

Sugar beverages are discussed as critical in the development of metabolic endotoxemia. Here, employing a cross-over design study we assessed the effect of diluted cloudy apple juice (AJ), an iso-caloric and -sweetened placebo (P), or water (W) on post-prandial endotoxemia in healthy, normal weight adults. After obtaining fasting blood, 19 healthy men and women consumed 500 mL AJ, P, or W in a randomized order and blood was taken 120 and 180 min later. Caco-2 cells were incubated with the beverages. Markers of intestinal barrier function were assessed. The intake of P but not of AJ or W was associated with a significant increase in TLR2 ligands and bacterial endotoxin in serum after 120 min and 180 min, respectively. P but not AJ significantly increased bacterial toxin permeation in Caco-2 cells. Our results suggest that the effects of sugar-sweetened beverages on markers of intestinal barrier function markedly differ from those of fruit juices. [ABSTRACT FROM AUTHOR]

Purpose: In this study, we compared the effects of a single patient dialysis fluid delivery system (SPDDS) against a central dialysis fluid delivery system (CDDS) on inflammatory markers and endotoxemia in a population of patients receiving routine hemodialysis (HD). Materials & methods: 80 prevalent HD patients, aged from 18 to 60 years old, who were clinically stable and receiving thrice weekly dialysis treatments via an arteriovenous fistula were the subjects of a cross-sectional research. group I underwent HD using a CDDS water purification system that was implemented at El Demerdash Hospital two years prior, and group II underwent HD using an SPDDS water purification system at Ain Shams Specialized Hospital. Results: Pre-dialysis endotoxin levels were significantly lower in the CDDS group (0.07±0.05) compared to the SPDDS group (0.20±0.07), p-value<0.001, post-dialysis serum endotoxin levels were significantly lower in CDDS group (0.04±0.02) compared to SDDPS (0.15±0.03), p-value<0.001. Conclusions: CDDS group's circulating endotoxins had significantly decreased. [ABSTRACT FROM AUTHOR]

Purpose: Gut barrier dysfunction is a pivotal pathophysiological alteration in cirrhosis and end-stage liver disease, which is further aggravated during and after the operational procedures for liver transplantation (LT). In this review, we analyze the multifactorial disruption of all major levels of defense of the gut barrier (biological, mechanical, and immunological) and correlate with clinical implications. Methods: A narrative review of the literature was performed using PubMed, PubMed Central and Google from inception until November 29th, 2023. Results: Systemic translocation of indigenous bacteria through this dysfunctional barrier contributes to the early post-LT infectious complications, while endotoxin translocation, through activation of the systemic inflammatory response, is implicated in non-infectious complications including renal dysfunction and graft rejection. Bacterial infections are the main cause of early in-hospital mortality of LT patients and unraveling the pathophysiology of gut barrier failure is of outmost importance. Conclusion: A pathophysiology-based approach to prophylactic or therapeutic interventions may lead to enhancement of gut barrier function eliminating its detrimental consequences and leading to better outcomes for LT patients. [ABSTRACT FROM AUTHOR]

Background: Virtually the entire spectrum of liver disease is observed in association with type 2 diabetes mellitus (T2DM); indeed, T2DM is now the most common cause of liver disease in the U.S. We conducted a pilot study to investigate the relevance of increased microbial translocation and systemic inflammation in the development of liver injury in patients with T2DM. Methods: Patients with T2DM (n = 17) and non-diabetic controls (NDC; n = 11) aged 25–80 yrs. participated in this study. Serum levels of endotoxin, calprotectin, soluble CD14 and CD163, and several inflammatory cytokines were measured. In addition to standard liver injury markers, ALT and AST, novel serum markers of liver injury, keratin 18 (K-18) M30 (apoptosis-associated caspase-cleaved keratin 18), and M65 (soluble keratin 18) were evaluated. Statistical analyses were performed using the Mann–Whitney test to assess differences between study groups. Pearson's correlation analysis was performed to determine the strength of association between two variables using GraphPad Prism 9.5.0 software. Results: Patients with T2DM had significantly higher levels of sCD14 in comparison to NDC, suggesting an increase in gut permeability, microbial translocation, and monocyte/macrophage activation. Importantly, relevant to the ensuing inflammatory responses, the increase in sCD14 in patients with T2DM was accompanied by a significant increase in sCD163, a marker of hepatic Kupffer cell activation and inflammation. Further, a positive correlation was observed between sCD163 and endotoxin and sCD14 in T2DM patients but not in NDC. In association with these changes, keratin 18 (K-18)-based serum markers (M65 and M30) that reflect hepatocyte death were significantly higher in the T2DM group indicating ongoing liver injury. Notably, both M65 and M30 levels correlated with sCD14 and sCD163, suggesting that immune cell activation and hepatic inflammation may be linked to the development of liver injury in T2DM. Conclusions: These findings suggest that the pathogenic changes in the gut–liver axis, marked by increased microbial translocation, may be a major component in the etiology of hepatocyte inflammation and injury in patients with T2DM. However, larger longitudinal studies, including histological evidence, are needed to confirm these observations. [ABSTRACT FROM AUTHOR]

Objective: The experiment aimed to determine the effects of lipopolysaccharide (LPS), polymyxin B, and honey on survival rates, hematological parameters, liver and kidney biomarkers, blood glucose levels, serum insulin levels, and histopathology of the liver, kidney, lungs, brain, and pancreas in LPS-challenged mice. Materials and Methods: 50 male Swiss Albino mice (Mus musculus), aged 3 weeks, were randomly assigned into 5 groups (10 mice per group): Control group (A), LPS (2 mg/kg bwt/day IP in NS) treated group (B), polymyxin B (1.2 mg/kg bwt/day IM) pre-treated plus LPS (2 mg/kg bwt/day IP in NS) treated group (C), honey (10 gm/kg bwt/day PO) pre-treated plus LPS (2 mg/kg bwt/day IP in NS) treated group (D), both polymyxin B (1.2 mg/kg bwt/day IM) and honey (10 gm/kg bwt/day PO) pre-treated plus LPS (2 mg/kg bwt/day IP in NS) treated group (E). The LPS was administered intraperitoneally (IP) at 80 µg/mice/day, diluting in normal saline. After 16 weeks, the mice were sacrificed, and blood samples and organs (liver, kidney, lung, brain, and pancreas) were collected for laboratory tests. Results: The results revealed that in LPS-treated mice, the mortality rate was the highest, and hemato-biochemical parameters were altered. Histopathological examination in the group treated with LPS showed disarrangement of hepatocytes, cellular infiltrations in the glomerulus, alveolar congestion in the lungs, several nerve fiber degenerations in the brain, and degenerative changes in pancreatic islets. The mortality rate and hemato-biochemical and histopathological changes were restored by the combined treatment of polymyxin B and honey. Conclusion: LPS has detrimental effects on survival rate and hemato-biochemistry, which are lessened by taking honey and polymyxin B supplements. [ABSTRACT FROM AUTHOR]

Severe infection and sepsis are medical emergencies. High morbidity and mortality are linked to CNS dysfunction, excessive inflammation, immune compromise, coagulopathy and multiple organ dysfunction. Males appear to have a higher risk of mortality than females. Currently, there are few or no effective drug therapies to protect the brain, maintain the blood brain barrier, resolve excessive inflammation and reduce secondary injury in other vital organs. We propose a major reason for lack of progress is a consequence of the treat-as-you-go, single-nodal target approach, rather than a more integrated, systems-based approach. A new revolution is required to better understand how the body responds to an infection, identify new markers to detect its progression and discover new system-acting drugs to treat it. In this review, we present a brief history of sepsis followed by its pathophysiology from a systems' perspective and future opportunities. We argue that targeting the body's early immune-driven CNS-response may improve patient outcomes. If the barrage of PAMPs and DAMPs can be reduced early, we propose the multiple CNS-organ circuits (or axes) will be preserved and secondary injury will be reduced. We have been developing a systems-based, small-volume, fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat sepsis and endotoxemia. Our early studies indicate that ALM therapy shifts the CNS from sympathetic to parasympathetic dominance, maintains cardiovascular-endothelial glycocalyx coupling, reduces inflammation, corrects coagulopathy, and maintains tissue O2 supply. Future research will investigate the potential translation to humans. [ABSTRACT FROM AUTHOR]

Community-acquired respiratory infection is the commonest cause of sepsis presenting to emergency departments. Yet current experimental animal models simulate peritoneal sepsis with intraperitoneal (I.P.) injection of lipopolysaccharide (LPS) as the predominant route. We aimed to compare the progression of organ injury between I.P. LPS and intranasal (I.N.) LPS in order to establish a better endotoxemia murine model of respiratory sepsis. Eight weeks old male BALB/c mice received LPS-Escherichia coli doses at 0.15, 1, 10, 20, 40 and 100 mg per kg body weight (e.g. LPS-10 is a dose of 10 mg/kg body weight). Disease severity was monitored by a modified Mouse Clinical Assessment Score for Sepsis (M-CASS; range 0–21). A M-CASS score ≥ 10 or a weight reduction of ≥ 20%, was used as a criterion for euthanasia. The primary outcome was the survival rate (either no death or no need for euthanasia). The progression of disease was specified as M-CASS, body weight, blood glucose, histopathological changes to lung, liver, spleen, kidney, brain and heart tissues. Survival rate in I.P. LPS-20 mice was 0% (2/3 died; 1/3 euthanized with M-CASS > 10) at 24 h. Survival rate in all doses of I.N. LPS was 100% (20/20; 3–4 per group) at 96 h. 24 h mean M-CASS post-I.P. LPS-10 was 6.4/21 significantly higher than I.N. LPS-10 of 1.7/21 (Unpaired t test, P < 0.05). Organ injury was present at 96 h in the I.P. LPS-10 group: lung (3/3; 100%), spleen (3/3; 100%) and liver (1/3; 33%). At 24 h in the I.P. LPS-20 group, kidney injury was observed in the euthanized mouse. At 96 h in the post-I.N. LPS-20 group, only lung injury was observed in 2/3 (67%) mice (Kruskal-Wallis test with Dunn's, P < 0.01). At 24 h in the post-I.N. LPS-100 group all (4/4) mice had evidence of lung injury. Variable doses of I.N. LPS in mice produced lung injury but did not produce sepsis. Higher doses of I.P. LPS induced multi-organ injury but not respiratory sepsis. Lethal models of respiratory virus, e.g., influenza A, might provide alternative avenues that can be explored in future research. [ABSTRACT FROM AUTHOR]

Hyperproduction of mediators of LPS-induced inflammatory process (endotoxicosis, sepsis) initiates the development of acute respiratory failure (ARF), impaired gas exchange, progressive hypoxemia and hypercapnia, hypotension, respiratory arrest and death. Severe sepsis associated with hypoxemia remains the main cause of death, and therefore the development of methods to increase resistance to acute hypoxia in septic patients is an urgent task. The aim of the work was to study the effectiveness of preconditioning with short-term intermittent moderate hypoxia to increase tolerance to subsequent severe hypoxia in rats with LPS-induced endotoxicosis. The experiments were carried out on anesthetized and traheostomized male Wistar rats. Endotoxicosis was modeled by administration of a lipopolysaccharide solution (Escherichia coli) in an amount of 7 mg/kg. To assess resistance to severe hypoxia, the rebreathing method of (RM) with a gradual decrease in oxygen in the rebreather from 21% to the onset of apnea was used. Hypoxic preconditioning (hypoxic training, HT) was also created by the method of RM in the mode of 3 cycles: reduction of the oxygen fraction in the rebreather to 12%—3 min, 5 min—normoxia. 3 groups of animals were studied: I-control-NaCl, II-LPS, III-LPS+HT. The following parameters were recorded: external respiration, mean arterial pressure (MAP), saturation (SpO2), fraction of inhaled O2, time of onset of apnea, the amount of spontaneous respiratory recovery (autoresuscitation) in the posthypoxic period. It was shown that the administration of LPS under normoxic conditions was accompanied by hyperventilation, hypoxemia and hypotension. The maximum deterioration in resistance to severe hypoxia was observed in rats with LPS, which was manifested by a decrease in MAP, SpO2 and a decrease in the possibility of autoresuscitation after hypoxic apnea. The effect of HT prevented a decrease in arterial pressure, SpO2 increased by 1.4 times, survival increased by 2 times, which is comparable to the level of normoxia before the introduction of LPS. It is assumed that the effectiveness of hypoxic preconditioning is due to the inhibition of the inflammatory response. [ABSTRACT FROM AUTHOR]

The study aimed to investigate the vitality of ovarian granulosa cells (GCs), metabolic activity of neutrophils, as well as the antioxidant system state in aging female mice subjected to experimental endotoxemia, as well as the influence of germanium (Ge) citrate on the studied parameters under these conditions. Treatment with Gramm-negative bacteria lipopolysaccharide caused pathological changes in mouse ovaries: a decrease in GCs viability by increasing necrosis, an enhancement of metabolic activity of peripheral blood neutrophils, an increase in lipid peroxidaxion products and a violation of the antioxidant defense system (as evidenced by an elevation of the content of reactive products of 2-thiobarbituric acid and a reduction of reduced glutathione in liver homogenate, as well as a decrease in the concentration of ceruloplasmin in blood serum of aging female mice). Pretreatment of mice with Ge citrate was effective to reduce GCs death and improve their viability, decrease the degree of disruption of the redox balance and weaken the activity of cells of non-specific immune protection in aging endotoxemic animals. Our results suggest that Ge citrate may offer promising therapeutic benefits. Its cytoprotective effects and regulatory role in the antioxidant defense system, combined with its potential to reduce the intensity of gram-negative bacterial toxins induced inflammation, imply its usefulness. This multifaceted action may help prevent ovarian cell aging and, consequently, improve reproductive function. [ABSTRACT FROM AUTHOR]

Objective: To explore the role and mechanism of heat shock protein A12A (HSPA12A) in hepatic injury induced by endotoxemia. Methods: ①The mRNA expression changes of Hspa12a and multiple apolipoproteins were analyzed by bioinformatics using a public database of RNA sequencing results from septic mice liver tissue. ② Endotoxemia was induced by intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) using 6-8⁃week-old Hspa12a knockout (Hspa12a-/-) mice and wild-type (WT) mice. Mice treated with normal saline (NS) served as controls. Animals were divided into four groups, NS⁃WT group, NS⁃Hspa12a-/- group, LPS⁃WT group, and LPS⁃Hspa12a-/- group. Six hours after LPS treatment, liver tissues were collected to evaluate the tissue damage by HE and analyze the expression levels of HSPA12A, ApoA1, ApoB, and ApoM by immunoblotting and RT⁃PCR. Serum was separated for measuring the levels of liver function markers (alanine aminotransferase, ALT；aspartate aminotransferase, AST) and lipoproteins (high- density lipoprotein cholesterol, HDL- C；low- density lipoprotein cholesterol, LDL-C). ③Primary hepatocytes overexpressed Hspa12a were treated with LPS (500 ng/mL) to emulate endotoxemia induced liver injury. Six hours after LPS treatment, culture medium was collected for measuring levels of ALT and AST. ④Patients were divided into the sepsis induced liver injury group and the control group according to whether the septic liver injury occurred. ALT, AST, HDL⁃C and LDL⁃C levels were collected and compared between the two groups. Results: ①Bioinformatic analysis showed that the levels of Hspa12a, Apoa1, Apob and Apom mRNA were decreased in livers of septic mice. ②Compared with NS-WT mice, LPS-WT mice displayed obvious histopathological injury in liver tissues (P < 0.001) and the number of inflammatory foci was increased (P < 0.01) along with the elevated serum ALT (P < 0.05) and AST (P < 0.01) activiaties. At the same time, the expression of HSPA12A protein in liver was decreased (P < 0.05). However, compared with LPS-WT mice, LPS-Hspa12a-/- mice showed more severe pathological damage of liver tissues (P < 0.05), along with higher ALT (P < 0.01) and AST (P < 0.05) levels and lower HDL⁃C and LDL⁃C levels (P < 0.01). At the same time, the expression levels of hepatic apolipoproteins (ApoA1, ApoB, ApoM) were reduced (P < 0.05, P < 0.01). ③In vitro, ALT and AST levels in culture medium of hepatocytes were signaficantly increased after LPS treatment (P < 0.001). However, overexpression of Hspa12a alleviated the increases of ALT and AST levels (P < 0.01). ④Clinical results suggested that compared with the control group, the sepsis induced liver injury group showed signaficantly higher serum ALT and AST levels (P < 0.001). In contrast, HDL-C and LDL-C levels were signaficantly lower (P < 0.001). Conclusion: Endotoxemia leads to downregulation of hepatic HSPA12A expression, which mediates the development of endotoxemic liver injury. However, overexpression of Hspa12a can protect liver injury induced by endotoxemia. The action of HSPA12A may involve the regulation of hepatic apolipoprotein expression and serum lipoprotein cholesterol levels. [ABSTRACT FROM AUTHOR]

Background: Recent studies suggest gut-derived lipopolysaccharide (LPS)-translocation to play a role in both systemic inflammation and in inflammatory adipose tissue. We aimed to investigate whether circulating LPS-related inflammatory markers and corresponding genetic expression in adipose tissue were associated with obesity, cardiometabolic risk factors, and dietary habits in patients with coronary artery disease. Methods: Patients (n=382) suffering a myocardial infarction 2– 8 weeks prior to inclusion were enrolled in this cross-sectional study. Subcutaneous adipose tissue (SAT), taken from the gluteal region, and fasting blood samples were collected at inclusion for determination of genetic expression of LPS-binding protein (LBP), CD14, toll-like receptor 2 (TLR2), and TLR4 in SAT, and LPS, LBP, and soluble cluster of differentiation 14 (sCD14) in the circulation. All patients filled out a dietary registration form. Results: Patients (median age 74 years, 25% women), had a median body mass index (BMI) of 25.9 kg/m2. Circulating levels of LBP correlated to BMI (p=0.02), were significantly higher in overweight or obese (BMI≥ 25 kg/m2) compared to normal- or underweight patients (BMI< 25 kg/m2), and were significantly elevated in patients with T2DM, hypertension, and MetS, compared to patients without (p≤ 0.04, all). In SAT, gene expression of CD14 and LBP correlated significantly to BMI (p≤ 0.001, both), and CD14 and TLR2 expressions were significantly higher in patients with T2DM and MetS compared to patients without (p≤ 0.001, both). Circulating and genetically expressed CD14 associated with use of n-3 PUFAs (p=0.008 and p=0.003, respectively). No other significant associations were found between the measured markers and dietary habits. Conclusion: In patients with established CAD, circulating levels of LBP and gene expression of CD14 and TLR2 in SAT were related to obesity, MetS, T2DM, and hypertension. This suggests that the LPS–LBP–CD14 inflammatory axis is activated in the chronic low-grade inflammation associated with cardiometabolic abnormalities, whereas no significant associations with dietary habits were observed. [ABSTRACT FROM AUTHOR]

Periodontitis is associated with an increased risk of ischemic stroke, and the risk may be particularly high among young people with unexplained stroke etiology. Thus, we investigated in a case-control study whether periodontitis or recent invasive dental treatments are associated with young-onset cryptogenic ischemic stroke (CIS). We enrolled participants from a multicenter case-control SECRETO study including adults aged 18 to 49 y presenting with an imaging-positive first-ever CIS and stroke-free age- and sex-matched controls. Thorough clinical and radiographic oral examination was performed. Furthermore, we measured serum lipopolysaccharide (LPS) and lipotechoic acid (LTA) levels. Multivariate conditional regression models were adjusted for stroke risk factors, regular dentist visits, and patent foramen ovale (PFO) status. We enrolled 146 case-control pairs (median age 41.9 y; 58.2% males). Periodontitis was diagnosed in 27.5% of CIS patients and 20.1% of controls (P < 0.001). In the fully adjusted models, CIS was associated with high periodontal inflammation burden (odds ratio [OR], 95% confidence interval) with an OR of 10.48 (3.18–34.5) and severe periodontitis with an OR of 7.48 (1.24–44.9). Stroke severity increased with the severity of periodontitis, having an OR of 6.43 (1.87–23.0) in stage III to IV, grade C. Invasive dental treatments performed within 3 mo prestroke were associated with CIS, with an OR of 2.54 (1.01–6.39). Association between CIS and invasive dental treatments was especially strong among those with PFO showing an OR of 6.26 (1.72–40.2). LPS/LTA did not differ between CIS patients and controls but displayed an increasing trend with periodontitis severity. Periodontitis and recent invasive dental procedures were associated with CIS after controlling for multiple confounders. However, the role of bacteremia as a mediator of this risk was not confirmed. [ABSTRACT FROM AUTHOR]

Background: Sepsis-induced myocardial injury, as one of the important complications of sepsis, can significantly increase the mortality of septic patients. Our previous study found that nucleolin affected mitochondrial function in energy synthesis and had a protective effect on septic cardiomyopathy in mice. During sepsis, glucose metabolism disorders aggravated myocardial injury and had a negative effect on septic patients. Objectives: We investigated whether nucleolin could regulate glucose metabolism during endotoxemia-induced myocardial injury. Methods: The study tested whether the nucleolin cardiac-specific knockout in the mice could affect glucose metabolism through untargeted metabolomics, and the results of metabolomics were verified experimentally in H9C2 cells. The ATP content, lactate production, and oxygen consumption rate (OCR) were evaluated. Results: The metabolomics results suggested that glycolytic products were increased in endotoxemia-induced myocardial injury, and that nucleolin myocardial-specific knockout altered oxidative phosphorylation-related pathways. The experiment data showed that TNF-α combined with LPS stimulation could increase the lactate content and the OCR values by about 25%, and decrease the ATP content by about 25%. However, interference with nucleolin expression could further decrease ATP content and OCR values by about 10–20% and partially increase the lactate level in the presence of TNF-α and LPS. However, nucleolin overexpression had the opposite protective effect, which partially reversed the decrease in ATP content and the increase in lactate level. Conclusion: Down-regulation of nucleolin can exacerbate glucose metabolism disorders in endotoxemia-induced myocardial injury. Improving glucose metabolism by regulating nucleolin was expected to provide new therapeutic ideas for patients with septic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background: One of the most prevalent causes of death in sepsis is sepsis-induced cardiomyopathy (SICM). Circadian disruption is involved in the progress of sepsis. However, the molecular mechanism remains unclear. Methods: Here, we built LPS-induced SICM in-vivo and in-vitro models. LPS was administrated at the particular Zeitgeber times (ZT), ZT4-ZT10-ZT16-ZT22 and ZT10-ZT22 in vivo and vitro experiments, respectively. Results: In vivo experiment, injection of LPS at ZT10 induced higher infiltration of inflammatory cells and content of intracellular Fe2+, and lower level of Glutathione peroxidase 4 (GPX4) and cardiac function than other ZTs (P

In dogs, chronic enteropathies, and impaired gut integrity, as well as microbiome imbalances, are a major problem. These conditions may represent a continuous low endotoxin load, which may result in the development of diseases that are attributable to chronic inflammation. Flavonoids are polyphenolic plant compounds with numerous beneficial properties such as antioxidant, anti-inflammatory and antimicrobial effects. For our experiments, we isolated primary white blood cells (peripheral blood mononuclear cells and polymorphonuclear leukocytes) from healthy dogs and induced inflammation and oxidative stress with Escherichia coli and Salmonella enterica serovar Enteritidis lipopolysaccharide (LPS). In parallel, we treated the cell cultures with various flavonoids luteolin, quercetin and grape seed extract oligomeric proanthocyanidins (GSOP) alone and also in combination with LPS treatments. Then, changes in viability, reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α) levels were measured in response to treatment with quercetin, luteolin and GSOP at 25 and 50 μg/mL concentrations. We found that ROS levels were significantly lower in groups which were treated by flavonoid and LPS at the same time compared to LPS-treated groups, whereas TNF-α levels were significantly reduced only by luteolin and quercetin treatment. In contrast, treatment with lower concentrations of GSOP caused an increase in TNF-α levels, while higher concentrations caused a significant decrease. These results suggest that the use of quercetin, luteolin and GSOP may be helpful in the management of chronic intestinal diseases in dogs with reduced intestinal barrier integrity or altered microbiome composition, or in the mitigation of chronic inflammatory processes maintained by endotoxemia. Further in vitro and in vivo studies are needed before clinical use.

Objective: In response to bacterial inflammation, anorexia of acute illness is protective and is associated with the induction of fasting metabolic programs such as ketogenesis. Forced feeding during the anorectic period induced by bacterial inflammation is associated with suppressed ketogenesis and increased mortality. As ketogenesis is considered essential in fasting adaptation, we sought to determine the role of ketogenesis in illness-induced anorexia. Methods: A mouse model of inducible hepatic specific deletion of the rate limiting enzyme for ketogenesis (HMG-CoA synthase 2, Hmgcs2) was used to investigate the role of ketogenesis in endotoxemia, a model of bacterial inflammation, and in prolonged starvation. Results: Mice deficient of hepatic Hmgcs2 failed to develop ketosis during endotoxemia and during prolonged fasting. Surprisingly, hepatic HMGCS2 deficiency and the lack of ketosis did not affect survival, glycemia, or body temperature in response to endotoxemia. Mice with hepatic ketogenic deficiency also did not exhibit any defects in starvation adaptation and were able to maintain blood glucose, body temperature, and lean mass compared to littermate wild-type controls. Mice with hepatic HMGCS2 deficiency exhibited higher levels of plasma acetate levels in response to fasting. Conclusions: Circulating hepatic-derived ketones do not provide protection against endotoxemia, suggesting that alternative mechanisms drive the increased mortality from forced feeding during illness-induced anorexia. Hepatic ketones are also dispensable for surviving prolonged starvation in the absence of inflammation. Our study challenges the notion that hepatic ketogenesis is required to maintain blood glucose and preserve lean mass during starvation, raising the possibility of extrahepatic ketogenesis and use of alternative fuels as potential means of metabolic compensation.