Ceramide

Derangement of the epidermal barrier lipids and dysregulated immune responses are key pathogenic features of atopic dermatitis (AD). The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signaling axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D epidermal equivalents. Tofacitinib, a low-molecular-mass JAK inhibitor, was used to screen for JAK/STAT-mediated deregulation of lipid metabolism...

In this study, we used the LC-ESI-MS/MS technique to elucidate the effects of stir-frying on the lipidomics of oat flour before and after storage. We detected 1540 lipids in 54 subclasses; triglycerides were the most abundant, followed by diacylglycerol, ceramide (Cer), digalactosyldiacylglycerol, cardiolipin, and phosphatidylcholine. Principal component analysis and orthogonal least squares discriminant analysis analyses showed that oat flour lipids were significantly different before and after storage in stir-fried oat flour and raw oat flour...

BACKGROUND: Cancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and ongoing skeletal muscle loss resulting in weakness, poor quality of life, and decreased survival. Whereas lipid accumulation in skeletal muscle is associated with cancer cachexia as well as the prognosis of cancer patients, surprisingly little is known about the nature of the lipids that accumulate in the muscle during cachexia, and whether this is related to inflammation. We aimed to identify the types and distributions of intramyocellular lipids in patients with and without cancer cachexia...

The pathogenesis of atopic dermatitis (AD) is complex and multifactorial. However, recent advancements in the genetics and pathophysiology of AD suggest that epidermal barrier dysfunction is paramount in the development and progression of the condition (Boguniewicz M, Leung DYM, Immunol Rev 242(1):233-246, 2011). In addition to standard therapy for AD, there are a plethora of nonprescription treatment modalities which may be employed. Over-the-counter treatments for atopic dermatitis can come in the form of topical corticosteroids, moisturizers/emollients, and oral antihistamines...

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies with a median 5 year-survival rate of 12%. Cannabidiol (CBD) has been found to exhibit antineoplastic potential and may potentiate the anticancer effects of cytotoxic's such as gemcitabine. CBD therapy has been linked to de novo synthesis of ceramide. The sphingolipid ceramide is a potent tumour suppressor lipid with roles in apoptosis and autophagy. One of the key players involved is ceramide synthase, an enzyme with six isoforms (CerS1-CerS6), reported to have disease prognostic value...

Dietary sphingomyelin (SM) has been reported to favorably modulate postprandial lipemia. Mechanisms underlying these beneficial effects on cardiovascular risk markers are not fully elucidated. Rodent studies showed that tritiated SM was hydrolyzed in the intestinal lumen into ceramides (Cer), and further to sphingosine (SPH) and fatty acids (FA) that were absorbed by the intestine. Our objective was to investigate in Caco-2/TC7 cells cultured on semi-permeable inserts the uptake and metabolism of SPH and/or C23:0, the main FA of milk SM, as well as lipid secretion...

Niemann-Pick type C1 (NPC1) disease is rare neurodegenerative cholesterol and sphingolipid storage disorder primarily due to mutations in the cholesterol-trafficking protein NPC1. In addition to catabolic-derived sphingolipids, NPC1 dysfunction also leads to an increase in de novo sphingolipid biosynthesis, yet little is known of the cellular mechanism involved. Although deletion of NPC1 or inhibition of the NPC1 sterol binding domain enhanced de novo sphingolipid biosynthesis, surprisingly levels of the ORMDLs, the regulatory subunits of serine palmitoyltransferase (SPT), the rate-limiting step in sphingolipid biosynthesis, were also greatly increased...

Inflammation is a key mechanism underlying the adverse health effects of exposure to fine particulate matter (PM2.5 ). Bioactive lipids in the arachidonic acid (ARA) pathway are important in the regulation of inflammation and are reportedly altered by PM2.5 exposure. Ceramide-1-phosphate (C1P), a class of sphingolipids, is required to initiate ARA metabolism. We examined the role of C1P in the alteration of ARA metabolism after PM2.5 exposure and explored whether changes in the ARA pathway promoted systemic inflammation based on a panel study involving 112 older adults in Beijing, China...

Diabetic retinopathy is a microvascular disease that causes blindness. Using acid sphingomyelinase knockout mice, we reported that ceramide generation is critical for diabetic retinopathy development. Here, in patients with proliferative diabetic retinopathy, we identify vitreous ceramide imbalance with pathologic long-chain C16-ceramides increasing and protective very long-chain C26-ceramides decreasing. C16-ceramides generate pro-inflammatory/pro-apoptotic ceramide-rich platforms on endothelial surfaces. To geo-localize ceramide-rich platforms, we invented a three-dimensional confocal assay and showed that retinopathy-producing cytokines TNFα and IL-1β induce ceramide-rich platform formation on retinal endothelial cells within seconds, with volumes increasing 2-logs, yielding apoptotic death...

AIMS: The aim of this study was to better understand how the chemotherapy drug doxorubicin contributes to the development of β-cell dysfunction and to explore its relationship with mitochondrial aldehyde dehydrogenase-2 (ALDH2). MATERIALS AND METHODS: In order to investigate this hypothesis, doxorubicin was administered to INS-1 cells, a rat insulinoma cell line, either with or without several target protein activators and inhibitors. ALDH2 activity was detected with a commercial kit and protein levels were determined with western blot...

Atopic dermatitis is a multi-pathogenic disease characterized by chronic skin inflammation and barrier dysfunction. Therefore, improving the skin's ability to form an epidermal barrier and suppressing the production of cytokines that induce type 2 inflammatory responses are important for controlling atopic dermatitis symptoms. (-)-Blebbistatin, a non-muscle myosin II inhibitor, has been suggested to improve pulmonary endothelial barrier function and control inflammation by suppressing immune cell migration; however, its efficacy in atopic dermatitis is unknown...

Sphingomyelin synthase (SMS) is a sphingolipid-metabolizing enzyme involved in the de novo synthesis of sphingomyelin (SM) from ceramide (Cer). Recent studies have indicated that SMS is a key therapeutic target for metabolic diseases such as fatty liver, type 2 diabetes, atherosclerosis, and colorectal cancer. However, very few SMS inhibitors have been identified because of the limited sensitivity and selectivity of the current fluorescence-based screening assay. In this study, we developed a simple cell-based assay coupled with liquid chromatography/tandem mass spectrometry (LC-MS/MS) to screen for SMS inhibitors...

AIM: - New tools are required to better assess cardiovascular risk in individuals with type 2 diabetes mellitus (T2DM). Plasma ceramides emerge as promising candidates, given their substantial influence on the pathogenesis of both T2DM and atherosclerosis. The current study aimed to investigate whether plasma ceramides in patients with T2DM are a predictive factor for carotid intima-media thickness (CIMT), a well-established noninvasive marker for atherosclerosis that predicts adverse cardiovascular outcomes...

Sphingolipids are ubiquitous lipids, present in the membranes of all cell types, the stratum corneum and the circulating lipoproteins. Autosomal recessive as well as dominant diseases due to disturbed sphingolipid biosynthesis have been identified, including defects in the synthesis of ceramides, sphingomyelins and glycosphingolipids. In many instances, these gene variants result in the loss of catalytic function of the mutated enzymes. Additional gene defects implicate the subcellular localization of the sphingolipid-synthesizing enzyme, the regulation of its activity, or even the function of a sphingolipid-transporter protein...

BACKGROUND: Being implicated during tumor migration, invasion, clonogenicity, and proliferation, the nicotinamide adenine dinucleotide (NAD) / -phosphate (NADP)-dependent dehydrogenase / reductase member 2 (DHRS2) has been considered to be induced upon inhibition of histone deacetylases (HDACi). In this brief report, we evaluated the current knowledge on the underlying mechanisms of the (epi)genetic regulation of DHRS2, as well as its function during tumor progression. METHODS: DHRS2 was evaluated on mRNA- and protein-level upon treatment with HDACi by means of qRT-PCR and western blot analyses, respectively...

Circulating ceramide levels are dysregulated in kidney disease. However their associations with rapid decline in kidney function (RDKF) and end-stage kidney disease (ESKD) in patients with type 2 diabetes (T2D) are unknown. In this prospective study of 1746 T2D participants, we examined the association of plasma ceramide Cer16:0, Cer18:0, Cer24:0 and Cer24:1 with RDKF, defined as an estimated glomerular filtration rate (eGFR) decline of 5ml/min/1.73m2 /yr or greater, and ESKD defined as eGFR <15/min/1.73m2 for at least three months, on dialysis, or renal death at follow-up...

Multiple isozymes are encoded in the C. elegans genome for the various sphingolipid biosynthesis reactions, but the contributions of individual isozymes are characterized only in part. We developed a simple but effective reversed-phase liquid chromatography-tandem mass spectrometry (RPLC-MS/MS) method that enables simultaneous identification and quantification of ceramides (Cer), glucosylceramides (GlcCer), and sphingomyelins (SM), three important classes of sphingolipids from the same MS run. Validating this sphingolipid profiling method, we show that nearly all 47 quantifiable sphingolipid species found in young adult worms were reduced upon RNA interference (RNAi) of sptl-1 or elo-5, which are required for synthesis of the id17:1 sphingoid base...

Human pluripotent stem cell-derived β cells (hPSC-β cells) show the potential to restore euglycemia. However, the immature functionality of hPSC-β cells has limited their efficacy in application. Here, by deciphering the continuous maturation process of hPSC-β cells post transplantation via single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), we show that functional maturation of hPSC-β cells is an orderly multistep process during which cells sequentially undergo metabolic adaption, removal of negative regulators of cell function, and establishment of a more specialized transcriptome and epigenome...

Lipids in the stratum corneum play an important role in the formation of the skin permeability barrier. The causative gene for congenital ichthyosis, NIPAL4, encodes a Mg2+ transporter and is involved in increases in intracellular Mg2+ concentrations that depend on keratinocyte differentiation. However, the role of this increased Mg2+ concentration in skin barrier formation and its effect on the lipid composition of the stratum corneum has remained largely unknown. Therefore, in the present study, we performed a detailed analysis of epidermal lipids in Nipal4 KO mice via TLC and MS...

BACKGROUND: Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder. These variants have been identified in a group of children with neurodevelopmental disorders with microcephaly, arthrogryposis, and structural brain anomalies. SMPD4 encodes a sphingomyelinase that hydrolyzes sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope and interacts with nuclear pore complexes...