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Introduction: Placental infection and inflammation are risk factors for adverse pregnancy outcomes, including preterm labor. However, the mechanisms underlying these outcomes are poorly understood.Methods: To study this response, we have employed a pregnant mouse model of placental infection caused by the bacterial pathogen Listeria monocyogenes, which infects the human placenta. Through in vivo bioluminescence imaging, we confirm the presence of placental infection and quantify relative infection levels. Infected and control placentas were collected on embryonic day 18 for RNA sequencing to evaluate gene expression signatures associated with infection by Listeria.Results: We identified an enrichment of genes associated with eicosanoid biosynthesis, suggesting an increase in eicosanoid production in infected tissues. Because of the known importance of eicosanoids in inflammation and timing of labor, we quantified eicosanoid levels in infected and uninfected placentas using semi-targeted mass spectrometry. We found a significant increase in the concentrations of several key eicosanoids: leukotriene B4, lipoxin A4, prostaglandin A2, prostaglandin D2, and eicosatrienoic acid.Discussion: Our study provides a likely explanation for dysregulation of the timing of labor following placental infection. Further, our results suggest potential biomarkers of placental pathology and targets for clinical intervention. [ABSTRACT FROM AUTHOR]

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. Anti-ceramide antibodies abolish these events. Furthermore, intravitreal and systemic anti-ceramide antibodies protect from diabetic retinopathy in standardized rodent ischemia reperfusion and streptozotocin models. These data support (1) retinal endothelial ceramide as a diabetic retinopathy treatment target, (2) early-stage therapy of non-proliferative diabetic retinopathy to prevent progression, and (3) systemic diabetic retinopathy treatment; and they characterize diabetic retinopathy as a "ceramidopathy" reversible by anti-ceramide immunotherapy. [Display omitted] • Vitreous C16:0/26:0 ceramide ratio is increased in proliferative diabetic retinopathy • C16-ceramide forms pro-inflammatory and pro-apoptotic ceramide-rich platforms • Cytokines induce ceramide-rich platform formation on retinal endothelial cells • Retinal microvascular injury in diabetes is reversed by anti-ceramide immunotherapy Diabetic metabolic abnormalities cause retinal "ceramidopathy," with sphingolipid imbalance leading to pathological ceramide-rich platform formation on the surface of retinal endothelial cells. Anti-ceramide antibodies targeting ceramide-rich platforms inhibit diabetes-induced endothelial cell apoptosis, dysfunction, and increased permeability. Intravitreal and systemic anti-ceramide immunotherapy reverse retinal microvascular injury in diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the role of liver-specific CPT1a on hepatic lipid metabolism. Male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (60% kcal fat) for 15 weeks. Mice were necropsied after a 16 h fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging, kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis (Plin2 , Cidec , G0S2) and in polyunsaturated fatty acid metabolism (Elovl5, Fads1, Elovl2), while only female LKO mice increased genes involved in inflammation (Ly6d, Mmp12, Cxcl2). Kinase profiling showed decreased protein kinase A activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice. Liver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury. [Display omitted] • Sexually dimorphic NAFLD is driven, in part, by CPT1a-mediated fatty acid oxidation. • CPT1a-deficiency drives microvesicular steatosis in periportal hepatocytes. • DHA-containing phospholipids are selectively reduced in lipid droplets from CPT1a LKO mice. • PKA activity and triglyceride turnover is impaired in CPT1a LKO mice. [ABSTRACT FROM AUTHOR]

An automated tandem mass spectrometry–based analysis using precursor ion and neutral loss scans in a triple quadrupole (QqQ) mass spectrometer has been used to identify and quantify changes in the abundances of glycerophospholipids extracted from retina and erythrocytes in a rat streptozotocin model of type 1 diabetes, 6 and 36 weeks after the induction of diabetes, compared with age-matched nondiabetic controls. The utility of an “internal standard” method compared with an “internal standard free” method for quantification of differences in the abundances of specific lipid ions was evaluated in both retina and erythrocyte lipid extracts. In retina, equivalent results were obtained by using the internal standard and internal standard free methods for quantification. In erythrocytes, the two methods of analysis yielded significantly different results, suggesting that factors intrinsic to particular sample types may influence the outcome of label-free lipidome quantification approaches. Overall increases (∼25–35%) in the abundances of major retina glycerophospholipid classes were demonstrated in rats at 6 weeks of diabetes, relative to control animals. However, at 36 weeks of diabetes, subsequent overall decreases in retina glycerophosphatidylcholine (GPCho) and glycerophosphatidylethanolamine (GPEtn) abundances of 16% and 33%, respectively, were observed. Additionally, retina and erythrocyte GPCho lipids at both 6 and 36 weeks of diabetes exhibited increased incorporation of linoleic acid(18:2n6) and a decrease in docosahexaenoic acid (DHA(22:6n3)) content. Finally, an approximately fivefold increase in the abundances of specific glycated GPEtn (Amadori-GPEtn) lipids were observed in the retina of 36-week diabetic rats, with a corresponding 1.6-fold increase of Amadori-GPEtn lipids in diabetic erythrocytes. [Copyright &y& Elsevier]

The article presents a study that assesses the mediation capability of insulin-like growth factor binding protein (IGFBP)-3 for cytoprotection after vascular injury. It notes the administration of IGFBP-3 into the 2 vascular injury models which are oxygen-induced retinopathy (OIR) in mouse pups and the laser-injured retinal vessel of green fluorescent protein (GFP) chimeric mice. It shows that IGFBP-3 among GFP mice reduces macrophages and prevents vascular endothelial cell death among OIRs.