Lipid oxidation dysregulation: an emerging player in the pathophysiology of sepsis

Sepsis is a life-threatening organ dysfunction caused by abnormal host response to infection. Millions of people are affected annually worldwide. Derangement of the inflammatory response is crucial in sepsis pathogenesis. However, metabolic, coagulation, and thermoregulatory alterations also occur in patients with sepsis. Fatty acid mobilization and oxidation changes may assume the role of a protagonist in sepsis pathogenesis. Lipid oxidation and free fatty acids (FFAs) are potentially valuable markers for sepsis diagnosis and prognosis. Herein, we discuss inflammatory and metabolic dysfunction during sepsis, focusing on fatty acid oxidation (FAO) alterations in the liver and muscle (skeletal and cardiac) and their implications in sepsis development

Role of Nitric Oxide Synthase in the Function of the Central Nervous System under Normal and Infectious Conditions

Nitric oxide (NO) was discovered as an endothelium‐derived relaxing factor more than two decades ago. Since then, it has been shown to participate in many pathways. NO has been described as a key mediator of different pathways in the central nervous system (CNS) in both healthy and diseased processes. The three isoforms of nitric oxide synthase differ in their activity patterns and expression in different cells. Neuronal nitric oxide synthase (nNOS) is localized in synaptic spines, astrocytes, and the loose connective tissue surrounding blood vessels in the brain; eNOS is present in both cerebral vascular endothelial cells and motor neurons; and iNOS is induced in astrocytes and microglia under pathological conditions. During physiological processes, NO produced by eNOS/nNOS, respectively, controls blood flow activation, and act as a messenger during long‐term potentiation (LTP). However, under pathological conditions, eNOS appears to be impaired, leading to a reduction in blood flow and, consequently, low oxygen/metabolites delivery, efflux of toxicological agents from the brain tissue and disturbance in the blood‐brain barrier. The NO produced by iNOS in glial cells and nNOS, which triggers the NMDA‐excitotoxic pathway, combines with superoxide anion and results in peroxynitrite synthesis, a potent free radical that contributes to tissue damage in the brain. Here, we intend to show the controversial role of the nitric oxide delivered by the three isoforms of the nitric oxide synthase in the CNS, assess its impact under healthy/pathological conditions and speculate on its possible sequela, particularly in long‐term cognitive decline

The Na/K-ATPase role as a signal transducer in lung inflammation

Acute respiratory distress syndrome (ARDS) is marked by damage to the capillary endothelium and alveolar epithelium following edema formation and cell infiltration. Currently, there are no effective treatments for severe ARDS. Pathologies such as sepsis, pneumonia, fat embolism, and severe trauma may cause ARDS with respiratory failure. The primary mechanism of edema clearance is the epithelial cells’ Na/K-ATPase (NKA) activity. NKA is an enzyme that maintains the electrochemical gradient and cell homeostasis by transporting Na+ and K+ ions across the cell membrane. Direct injury on alveolar cells or changes in ion transport caused by infections decreases the NKA activity, loosening tight junctions in epithelial cells and causing edema formation. In addition, NKA acts as a receptor triggering signal transduction in response to the binding of cardiac glycosides. The ouabain (a cardiac glycoside) and oleic acid induce lung injury by targeting NKA. Besides enzymatic inhibition, the NKA triggers intracellular signal transduction, fostering proinflammatory cytokines production and contributing to lung injury. Herein, we reviewed and discussed the crucial role of NKA in edema clearance, lung injury, and intracellular signaling pathway activation leading to lung inflammation, thus putting the NKA as a protagonist in lung injury pathology

Development and validation of liquid chromatography-tandem mass spectrometry method to quantify dasatinib in plasma and its application to a pharmacokinetic study

Dasatinib, a potent oral multi-targeted kinase inhibitor against Src and Bcr-Abl, can decrease inflammatory response in sepsis. A simple and cost-effective method for determination of an effective dose dasatinib was established. This method was validated in human plasma, with the aim of reducing the number of animals used, thus, avoiding ethical problems. Dasatinib and internal standard lopinavir were extracted from 180 uL of plasma using liquid-liquid extraction with methyl tert-butil ether, followed by liquid chromatography coupled to triple quadrupole mass spectrometry in multiple reaction monitoring mode. For the pharmacokinetic study, 1 mg/kg of dasatinib was administered to mice with and without sepsis. The method was linear over the concentration range of 1-98 ng/mL for DAS in mice and human plasma, with r2>0.99 and presented intra- and interday precision within the range of 2.3 - 6.2 and 4.3 - 7.0%, respectively. Further intra- and interday accuracy was within the range of 88.2 - 105.8 and 90.6 - 101.7%, respectively. The mice with sepsis showed AUC0-t = 2076.06 h*ng/mL and Cmax =102.73 ng/mL and mice without sepsis presented AUC0-t = 2128.46 h*ng/mL. Cmax = 164.5 ng/mL. The described analytical method was successfully employed in pharmacokinetic study of DAS in mice

Reduced Plasma Nonesterified Fatty Acid Levels and the Advent of an Acute Lung Injury in Mice after Intravenous or Enteral Oleic Acid Administration

Although exerting valuable functions in living organisms, nonesterified fatty acids (NEFAs) can be toxic to cells. Increased blood concentration of oleic acid (OLA) and other fatty acids is detected in many pathological conditions. In sepsis and leptospirosis, high plasma levels of NEFA and low albumin concentrations are correlated to the disease severity. Surprisingly, 24 h after intravenous or intragastric administration of OLA, main NEFA levels (OLA inclusive) were dose dependently decreased. However, lung injury was detected in intravenously treated mice, and highest dose killed all mice. When administered by the enteral route, OLA was not toxic in any tested conditions. Results indicate that OLA has important regulatory properties on fatty acid metabolism, possibly lowering circulating fatty acid through activation of peroxisome proliferator-activated receptors. The significant reduction in blood NEFA levels detected after OLA enteral administration can contribute to the already known health benefits brought about by unsaturated-fatty-acid-enriched diets

Reduced Plasma Nonesterified Fatty Acid Levels and the Advent of an Acute Lung Injury in Mice after Intravenous or Enteral Oleic Acid Administration

Although exerting valuable functions in living organisms, nonesterified fatty acids (NEFAs) can be toxic to cells. Increased blood concentration of oleic acid (OLA) and other fatty acids is detected in many pathological conditions. In sepsis and leptospirosis, high plasma levels of NEFA and low albumin concentrations are correlated to the disease severity. Surprisingly, 24 h after intravenous or intragastric administration of OLA, main NEFA levels (OLA inclusive) were dose dependently decreased. However, lung injury was detected in intravenously treated mice, and highest dose killed all mice. When administered by the enteral route, OLA was not toxic in any tested conditions. Results indicate that OLA has important regulatory properties on fatty acid metabolism, possibly lowering circulating fatty acid through activation of peroxisome proliferator-activated receptors. The significant reduction in blood NEFA levels detected after OLA enteral administration can contribute to the already known health benefits brought about by unsaturatedfatty-acid-enriched diets

Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life

Abstract: Background: The term sepsis is used to designate a systemic condition of infection and inflammation associated with hemodynamic changes that result in organic dysfunction. Gestational sepsis can impair the development of the central nervous system and may promote permanent behavior alterations in the offspring. The aim of our work was to evaluate the effects of maternal sepsis on inflammatory cytokine levels and synaptic proteins in the hippocampus, neocortex, frontal cortex, and cerebellum of neonatal, young, and adult mice. Additionally, we analyzed the motor development, behavioral features, and cognitive impairments in neonatal, young and adult offspring. Methods: Pregnant mice at the 14th embryonic day (E14) were intratracheally instilled with saline 0.9% solution (control group) or Klebsiella spp. (3 × 108 CFU) (sepsis group) and started on meropenem after 5 h. The offspring was sacrificed at postnatal day (P) 2, P8, P30, and P60 and samples of liver, lung, and brain were collected for TNF-α, IL-1β, and IL-6 measurements by ELISA. Synaptophysin, PSD95, and β-tubulin levels were analyzed by Western blot. Motor tests were performed at all analyzed ages and behavioral assessments were performed in offspring at P30 and P60. Results: Gestational sepsis induces a systemic pro-inflammatory response in neonates at P2 and P8 characterized by an increase in cytokine levels. Maternal sepsis induced systemic downregulation of pro-inflammatory cytokines, while in the hippocampus, neocortex, frontal cortex, and cerebellum an inflammatory response was detected. These changes in the brain immunity were accompanied by a reduction of synaptophysin and PSD95 levels in the hippocampus, neocortex, frontal cortex, and cerebellum, in all ages. Behavioral tests demonstrated motor impairment in neonates, and depressive-like behavior, fear-conditioned memory, and learning impairments in animals at P30 and P60, while spatial memory abilities were affected only at P60, indicating that gestational sepsis not only induces an inflammatory response in neonatal mouse brains, but also affects neurodevelopment, and leads to a plethora of behavioral alterations and cognitive impairments in the offspring. Conclusion: These data suggest that maternal sepsis may be causatively related to the development of depression, learning, and memory impairments in the litter

Acute Respiratory Distress Syndrome: Role of Oleic Acid-Triggered Lung Injury and Inflammation

Submitted by sandra infurna ([email protected]) on 2016-02-22T15:05:28Z No. of bitstreams: 1 cassiano_albuquerque_etal_IOC_2015.pdf: 2378904 bytes, checksum: 36787e7d0e6457e85ecc64b7b9ff7a1c (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-02-22T15:15:50Z (GMT) No. of bitstreams: 1 cassiano_albuquerque_etal_IOC_2015.pdf: 2378904 bytes, checksum: 36787e7d0e6457e85ecc64b7b9ff7a1c (MD5)Made available in DSpace on 2016-02-22T15:15:50Z (GMT). No. of bitstreams: 1 cassiano_albuquerque_etal_IOC_2015.pdf: 2378904 bytes, checksum: 36787e7d0e6457e85ecc64b7b9ff7a1c (MD5) Previous issue date: 2015Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Universidade Federal Fluminense. Instituto de Biologia. Departamento de Biologia Celular e Molecular. Niterói, RJ, Brasil.Universidade do Estado do Rio de Janeiro. Faculdade de Ciências Médicas. Departamento de Medicina Interna. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Lung injury especially acute respiratory distress syndrome (ARDS) can be triggered by diverse stimuli, including fatty acids and microbes. ARDS affects thousands of people worldwide each year, presenting high mortality rate and having an economic impact. One of the hallmarks of lung injury is edema formation with alveoli flooding. Animal models are used to study lung injury. Oleic acid-induced lung injury is a widely used model resembling the human disease. The oleic acid has been linked to metabolic and inflammatory diseases; here we focus on lung injury. Firstly, we briefly discuss ARDS and secondly we address the mechanisms by which oleic acid triggers lung injury and inflammation

Na/K Pump and Beyond: Na/K-ATPase as a Modulator of Apoptosis and Autophagy

Submitted by Sandra Infurna ([email protected]) on 2017-11-21T16:24:49Z No. of bitstreams: 1 cassiano_albuquerque_etal_IOC_2017.pdf: 1297250 bytes, checksum: 52adfdd10a39f6337dba261eb5a5d466 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2017-11-21T16:36:33Z (GMT) No. of bitstreams: 1 cassiano_albuquerque_etal_IOC_2017.pdf: 1297250 bytes, checksum: 52adfdd10a39f6337dba261eb5a5d466 (MD5)Made available in DSpace on 2017-11-21T16:36:33Z (GMT). No. of bitstreams: 1 cassiano_albuquerque_etal_IOC_2017.pdf: 1297250 bytes, checksum: 52adfdd10a39f6337dba261eb5a5d466 (MD5) Previous issue date: 2017Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ. Brasil / Universidade Federal do Estado do Rio de Janeiro. Departamento de Bioquímica. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ. Brasil.Universidade Federal Fluminense. Instituto de Biologia. Departamento de Biologia Celular e Molecular. Laboratório de Enzimologia e Sinalização Celular. Niterói, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ. Brasil.Universidade Federal Fluminense. Instituto de Biologia. Departamento de Biologia Celular e Molecular. Laboratório de Enzimologia e Sinalização Celular. Niterói, RJ, Brasil.Lung cancer is a leading cause of global cancer deaths. Na/K-ATPase has been studied as a target for cancer treatment. Cardiotonic steroids (CS) trigger intracellular signalling upon binding to Na/K-ATPase. Normal lung and tumour cells frequently express different pump isoforms. Thus, Na/K-ATPase is a powerful target for lung cancer treatment. Drugs targeting Na/K-ATPase may induce apoptosis and autophagy in transformed cells. We argue that Na/K-ATPase has a role as a potential target in chemotherapy in lung cancer treatment. We discuss the effects of Na/K-ATPase ligands and molecular pathways inducing deleterious effects on lung cancer cells, especially those leading to apoptosis and autophagy