Targeted rescue of synaptic plasticity improves cognitive decline in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a frequent complication of severe systemic infection resulting in delirium, premature death, and long-term cognitive impairment. We closely mimicked SAE in a murine peritoneal contamination and infection (PCI) model. We found long-lasting synaptic pathology in the hippocampus including defective long-term synaptic plasticity, reduction of mature neuronal dendritic spines, and severely affected excitatory neurotransmission.

Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis.

Sepsis is defined by life-threatening organ dysfunction mediated by the host’s response to infection. This can result in septic dyslipidemia, which is involved in the neutralization of pathogen-related lipids. Knowledge of the regulatory mechanisms of septic dyslipidemia is incomplete.

Aβ-Induced Alterations in Membrane Lipids Occur before Synaptic Loss Appears.

Loss of active synapses and alterations in membrane lipids are crucial events in physiological aging as well as in neurodegenerative disorders. Both are related to the abnormal aggregation of amyloid-beta (Aβ) species, generally known as amyloidosis. There are two major known human Aβ species: Aβ and Aβ.

Altered Serum Phospholipids in Atopic Dermatitis and Association with Clinical Status.

Circulating phospholipids have been considered as biomarkers and therapeutic targets in multiple disorders. Atopic dermatitis (AD) is the most common inflammatory skin disease. Although there are numerous studies having addressed stratum corneum lipids in the context of epidermal barrier, little is known about the circulating lipids in patients with AD.

Endoplasmic reticulum stress and the unfolded protein response in skeletal muscle of subjects suffering from peritoneal sepsis.

We provide a descriptive characterization of the unfolded protein response (UPR) in skeletal muscle of human patients with peritoneal sepsis and a sepsis model of C57BL/6J mice. Patients undergoing open surgery were included in a cross-sectional study and blood and skeletal muscle samples were taken. Key markers of the UPR and cluster of differentiation 68 (CD68) as surrogate of inflammatory injury were evaluated by real-time PCR and histochemical staining.

Activation of Sphingomyelinase-Ceramide-Pathway in COVID-19 Purposes Its Inhibition for Therapeutic Strategies.

Effective treatment strategies for severe coronavirus disease (COVID-19) remain scarce. Hydrolysis of membrane-embedded, inert sphingomyelin by stress responsive sphingomyelinases is a hallmark of adaptive responses and cellular repair. As demonstrated in experimental and observational clinical studies, the transient and stress-triggered release of a sphingomyelinase, SMPD1, into circulation and subsequent ceramide generation provides a promising target for FDA-approved drugs.

Erythrocytes increase endogenous sphingosine 1-phosphate levels as an adaptive response to SARS-CoV-2 infection.

Low plasma levels of the signaling lipid metabolite sphingosine 1-phosphate (S1P) are associated with disrupted endothelial cell (EC) barriers, lymphopenia and reduced responsivity to hypoxia. Total S1P levels were also reduced in 23 critically ill patients with coronavirus disease 2019 (COVID-19), and the two main S1P carriers, serum albumin (SA) and high-density lipoprotein (HDL) were dramatically low. Surprisingly, we observed a carrier-changing shift from SA to HDL, which probably prevented an even further drop in S1P levels.

Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock.

Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune response. We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines.

Sphingolipidomics in Translational Sepsis Research-Biomedical Considerations and Perspectives.

Sphingolipids are a highly diverse group of lipids with respect to physicochemical properties controlling either structure, distribution, or function, all of them regulating cellular response in health and disease. Mass spectrometry, on the other hand, is an analytical technique characterizing ionized molecules or fragments thereof by mass-to-charge ratios, which has been prosperingly developed for rapid and reliable qualitative and quantitative identification of lipid species. Parallel to best performance of in-depth chromatographical separation of lipid classes, preconditions of precise quantitation of unique molecular species by preprocessing of biological samples have to be fulfilled.

Keep Your Friends Close, but Your Enemies Closer: Role of Acid Sphingomyelinase During Infection and Host Response.

Breakdown of the inert and constitutive membrane building block sphingomyelin to the highly active lipid mediator ceramide by extracellularly active acid sphingomyelinase is tightly regulated during stress response and opens the gate for invading pathogens, triggering the immune response, development of remote organ failure, and tissue repair following severe infection. How do one enzyme and one mediator manage all of these affairs? Under physiological conditions, the enzyme is located in the lysosomes and takes part in the noiseless metabolism of sphingolipids, but following stress the protein is secreted into circulation. When secreted, acid sphingomyelinase (ASM) is able to hydrolyze sphingomyelin present at the outer leaflet of membranes to ceramide.

Inactivation of the tyrosine phosphatase SHP-2 drives vascular dysfunction in Sepsis.

Background: Sepsis, the most severe form of infection, involves endothelial dysfunction which contributes to organ failure. To improve therapeutic prospects, elucidation of molecular mechanisms underlying endothelial vascular failure is of essence.

Methods: Polymicrobial contamination induced sepsis mouse model and primary endothelial cells incubated with sepsis serum were used to study SHP-2 in sepsis-induced endothelial inflammation.

Acid Sphingomyelinase Inhibition Stabilizes Hepatic Ceramide Content and Improves Hepatic Biotransformation Capacity in a Murine Model of Polymicrobial Sepsis.

Liver dysfunction during sepsis is an independent risk factor leading to increased mortality rates. Specifically, dysregulation of hepatic biotransformation capacity, especially of the cytochrome P450 (CYP) system, represents an important distress factor during host response. The activity of the conserved stress enzyme sphingomyelin phosphodiesterase 1 (SMPD1) has been shown to be elevated in sepsis patients, allowing for risk stratification.

Low-dose hydrocortisone prolongs survival in a lethal sepsis model in adrenalectomized rats.

Background: Controversial clinical findings of low-dose hydrocortisone supplementation in septic shock led us to investigate the impact of administration in lethal septic shock in adrenalectomized rats.

Materials And Methods: After preliminary experiments, to define the intravenous dose of hydrocortisone delivered in bilaterally adrenalectomized rats with serum cortisol level similar to sham rats, survival experiments were run in 75 rats after intraperitoneal challenge with Escherichia coli. Rats were treated with placebo, ertapenem, hydrocortisone, and a combination.

Corrigendum: Monocyte-induced recovery of inflammation-associated hepatocellular dysfunction in a biochip-based human liver model.

This corrects the article DOI: 10.1038/srep21868.

Combination of Classifiers Identifies Fungal-Specific Activation of Lysosome Genes in Human Monocytes.

Blood stream infections can be caused by several pathogens such as viruses, fungi and bacteria and can cause severe clinical complications including sepsis. Delivery of appropriate and quick treatment is mandatory. However, it requires a rapid identification of the invading pathogen.

NB 06: From a simple lysosomotropic aSMase inhibitor to tools for elucidating the role of lysosomes in signaling apoptosis and LPS-induced inflammation.

Ceramide generation is involved in signal transduction of cellular stress response, in particular during stress-induced apoptosis in response to stimuli such as minimally modified Low-density lipoproteins, TNFalpha and exogenous C-ceramide. In this paper we describe 48 diverse synthetic products and evaluate their lysosomotropic and acid sphingomyelinase inhibiting activities in macrophages. A stimuli-induced increase of C-ceramide in macrophages can be almost completely suppressed by representative compound NB 06 providing an effective protection of macrophages against apoptosis.

Acid Sphingomyelinase Inhibition Prevents Development of Sepsis Sequelae in the Murine Liver.

The molecular mechanisms of maladaptive response in liver tissue with respect to the acute and post-acute phase of sepsis are not yet fully understood. Long-term sepsis survivors might develop hepatocellular/hepatobiliary injury and fibrosis. Here, we demonstrate that acid sphingomyelinase, an important regulator of hepatocyte apoptosis and hepatic stellate cell (HSC) activation, is linked to the promotion of liver dysfunction in the acute phase of sepsis as well as to fibrogenesis in the long-term.

Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction.

Cardiac dysfunction, in particular of the left ventricle, is a common and early event in sepsis, and is strongly associated with an increase in patients' mortality. Acid sphingomyelinase (SMPD1)-the principal regulator for rapid and transient generation of the lipid mediator ceramide-is involved in both the regulation of host response in sepsis as well as in the pathogenesis of chronic heart failure. This study determined the degree and the potential role to which SMPD1 and its modulation affect sepsis-induced cardiomyopathy using both genetically deficient and pharmacologically-treated animals in a polymicrobial sepsis model.

Increased lipogenesis in spite of upregulated hepatic 5'AMP-activated protein kinase in human non-alcoholic fatty liver.

Aims: Molecular adaptations in human non-alcoholic fatty liver disease (NAFLD) are incompletely understood. This study investigated the main gene categories related to hepatic de novo lipogenesis and lipid oxidation capacity.

Methods: Liver specimens of 48 subjects were histologically classified according to steatosis severity.

Differential Biphasic Transcriptional Host Response Associated with Coevolution of Hemagglutinin Quasispecies of Influenza A Virus.

Severe influenza associated with strong symptoms and lung inflammation can be caused by intra-host evolution of quasispecies with aspartic acid or glycine in hemagglutinin position 222 (HA-222D/G; H1 numbering). To gain insights into the dynamics of host response to this coevolution and to identify key mechanisms contributing to copathogenesis, the lung transcriptional response of BALB/c mice infected with an A(H1N1)pdm09 isolate consisting HA-222D/G quasispecies was analyzed from days 1 to 12 post infection (p.i).

Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis.

The pathophysiology of sepsis involves activation of acid sphingomyelinase (SMPD1) with subsequent generation of the bioactive mediator ceramide. We herein evaluated the hypothesis that the enzyme exerts biological effects in endothelial stress response. Plasma-secreted sphingomyelinase activity, ceramide generation and lipid raft formation were measured in human microcirculatory endothelial cells (HMEC-1) stimulated with serum obtained from sepsis patients.

Preconditioned suppression of prolyl-hydroxylases attenuates renal injury but increases mortality in septic murine models.

Background: Septic conditions contribute to tissue hypoxia, potentially leading to multiple organ failure, including acute kidney injury. The regulation of cellular adaptation to low oxygen levels is regulated by hypoxia-inducible transcription factors (HIFs). While the role of HIFs in ischaemia/reperfusion is more studied, their function in sepsis-induced renal injury is not well characterized.

Monocyte-induced recovery of inflammation-associated hepatocellular dysfunction in a biochip-based human liver model.

Liver dysfunction is an early event in sepsis-related multi-organ failure. We here report the establishment and characterization of a microfluidically supported in vitro organoid model of the human liver sinusoid. The liver organoid is composed of vascular and hepatocyte cell layers integrating non-parenchymal cells closely reflecting tissue architecture and enables physiological cross-communication in a bio-inspired fashion.