thermozymocidin and Inflammation

Heart disease is widely believed to develop from two pathological processes. Circulating lipoproteins containing the nondegradable lipid, cholesterol, accumulate within the arterial wall and perhaps are oxidized to more toxic lipids. Both lipid accumulation and vascular reaction to the lipids lead to the gradual thickening of the vascular wall. A second major process that in some circumstances is a primary event is the development of a local inflammatory reaction. This might be a reaction to vessel wall injury that accompanies infections, immune disease, and perhaps diabetes and renal failure. In this chapter, we will focus on the relationship between de novo synthesis of sphingolipids and lipid metabolism, atherosclerosis, and cardiomyopathy.

Topics: Animals; Apoptosis; Atherosclerosis; Cardiomyopathies; Cardiovascular Diseases; Cholesterol; Coronary Disease; Endothelium, Vascular; Fatty Acids; Fatty Acids, Monounsaturated; Humans; Inflammation; Lipoproteins; MAP Kinase Signaling System; Models, Cardiovascular; Serine C-Palmitoyltransferase; Sphingolipids; Transferases (Other Substituted Phosphate Groups)

Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and immune response. Intracellular lipid accumulation favors microbial infection, and autophagy deficiency impairs internalized pathogen clearance. Myriocin, an inhibitor of sphingolipid synthesis, significantly reduces inflammation, promotes microbial clearance in the lungs, and induces autophagy and lipid oxidation. RNA-seq was performed in

Topics: Antifungal Agents; Aspergillosis; Autophagy; Cell Line; Cystic Fibrosis; Epithelial Cells; Fatty Acids, Monounsaturated; Gene Expression; Humans; Inflammation; Leukocytes, Mononuclear; Lipid Metabolism; Sphingolipids

Our aim was to use quantitative and qualitative analyses to gain further insight into the role of ceramide in cystic fibrosis (CF). Sphingolipid ceramide is a known inflammatory mediator, and its accumulation in inflamed lung has been reported in different types of emphysema, chronic obstructive pulmonary disease and CF. CF is caused by a mutation of the chloride channel and associated with hyperinflammation of the respiratory airways and high susceptibility to ongoing infections. We have previously demonstrated that de novo ceramide synthesis is enhanced in lung inflammation and sustains Pseudomonas aeruginosa pulmonary infection in a CF murine model. We used liquid chromatography and matrix-assisted laser desorption/ionization (MALDI) imaging coupled with mass spectrometry, confocal laser scan microscopy and histology analyses to reveal otherwise undecipherable information. We demonstrated that (i) upregulated ceramide synthesis in the alveoli is strictly related to alveolar infection and inflammation, (ii) alveolar ceramide (C16) can be specifically targeted by nanocarrier delivery of the ceramide synthesis inhibitor myriocin (Myr) and (iii) Myr is able to downmodulate pro-inflammatory lyso-PC, favouring an increase in anti-inflammatory PCs. We concluded that Myr modulates alveolar lipids milieu, reducing hyperinflammation and favouring anti-microbial effective response in CF mouse model.

Topics: Animals; Ceramides; Cystic Fibrosis; Fatty Acids, Monounsaturated; Female; Inflammation; Lung; Male; Mice, Knockout; Nanoparticles; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections

Cardiovascular disease (CVD) is a serious comorbidity in nonalcoholic fatty liver disease (NAFLD). Since plasma ceramides are increased in NAFLD and sphingomyelin, a ceramide metabolite, is an independent risk factor for CVD, the role of ceramides in dyslipidemia was assessed using LDLR(-/-) mice, a diet-induced model of NAFLD and atherosclerosis. Mice were fed a standard or Western diet (WD), with or without myriocin, an inhibitor of ceramide synthesis. Hepatic and plasma ceramides were profiled and lipid and lipoprotein kinetics were quantified. Hepatic and intestinal expression of genes and proteins involved in insulin, lipid and lipoprotein metabolism were also determined. WD caused hepatic oxidative stress, inflammation, apoptosis, increased hepatic long-chain ceramides associated with apoptosis (C16 and C18) and decreased very-long-chain ceramide C24 involved in insulin signaling. The plasma ratio of ApoB/ApoA1 (proteins of VLDL/LDL and HDL) was increased 2-fold due to increased ApoB production. Myriocin reduced hepatic and plasma ceramides and sphingomyelin, and decreased atherosclerosis, hepatic steatosis, fibrosis, and apoptosis without any effect on oxidative stress. These changes were associated with decreased lipogenesis, ApoB production and increased HDL turnover. Thus, modulation of ceramide synthesis may lead to the development of novel strategies for the treatment of both NAFLD and its associated atherosclerosis.

Topics: Animals; Apolipoproteins B; Apoptosis; Atherosclerosis; Biological Transport; Body Weight; Ceramides; Cholesterol, HDL; Diet, Western; Fasting; Fatty Acids, Monounsaturated; Feeding Behavior; Gene Expression Regulation; Glucose; Inflammation; Insulin; Liver Cirrhosis; Mice; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Receptors, LDL; RNA, Messenger