Preliminary evidence that blocking the uptake of placenta-derived preeclamptic extracellular vesicles protects the vascular endothelium and prevents vasoconstriction.

Preeclampsia (PE) is a pregnancy syndrome characterized by hypertension and organ damage manifesting after 20 gestational weeks. The etiology is of multifactorial origin, where placental stress causes increased levels of placenta-derived extracellular vesicles (STBEVs) in the maternal circulation, shown to cause inflammation, endothelial activation, vasoconstriction, and anti-angiogenic activity. General endothelial dysfunction is believed to be initiated by endothelial insult during pregnancy that alters vascular function resulting in increased arterial stiffness, cardiac dysfunction, and increased risk of cardiovascular disease later in life.

Short-term exposure to urban PM particles induces histopathological and inflammatory changes in the rat small intestine.

Air pollution and exposure to fine airborne particles with aerodynamic diameter <2.5 μm (PM ) negatively impacts human health. Airways constitute a primary route of exposure but PM -contaminated food, drinks as well as mucociliary and hepatobiliary clearance all constitute potential entry points into the intestine.

Digestion and Absorption of Milk Phospholipids in Newborns and Adults.

Milk polar lipids provide choline, ethanolamine, and polyunsaturated fatty acids, which are needed for the growth and plasticity of the tissues in a suckling child. They may also inhibit cholesterol absorption by interacting with cholesterol during micelle formation. They may also have beneficial luminal, mucosal, and metabolic effects in both the neonate and the adult.

Erenumab (AMG 334), a monoclonal antagonist antibody against the canonical CGRP receptor, does not impair vasodilatory or contractile responses to other vasoactive agents in human isolated cranial arteries.

Background: Calcitonin gene-related peptide (CGRP) is a neuronal transmitter present in intracranial sensory nerves, where it is involved in migraine pathophysiology as well as other biological functions. Recently, the fully human monoclonal antibody erenumab (AMG 334), which targets the canonical calcitonin gene-related peptide receptor, showed significant prophylactic efficacy and favourable safety in phase II and III clinical trials for episodic and chronic migraine and is now approved for migraine prevention in several countries.

Objective: Given that calcitonin gene-related peptide can mediate vasodilation, we investigated the effect of erenumab on vasoactive responses in the presence or absence of various vasodilatory and vasocontractile mediators in a model using isolated human cerebral and meningeal arteries.

Linoleic acid esters of hydroxy linoleic acids are anti-inflammatory lipids found in plants and mammals.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a recently discovered class of biologically active lipids. Here we identify the linoleic acid ester of 13-hydroxy linoleic acid (13-LAHLA) as an anti-inflammatory lipid. An oat oil fraction and FAHFA-enriched extract from this fraction showed anti-inflammatory activity in a lipopolysaccharide-induced cytokine secretion assay.

MEK/ERK/1/2 sensitive vascular changes coincide with retinal functional deficit, following transient ophthalmic artery occlusion.

Retinal ischemia remains a major cause of blindness in the world with few acute treatments available. Recent emphasis on retinal vasculature and the ophthalmic artery's vascular properties after ischemia has shown an increase in vasoconstrictive functionality, as previously observed in cerebral arteries following stroke. Specifically, endothelin-1 (ET-1) receptor-mediated vasoconstriction regulated by the MEK/ERK1/2 pathway.

Expression of Pituitary Adenylate Cyclase-activating Peptide, Calcitonin Gene-related Peptide and Headache Targets in the Trigeminal Ganglia of Rats and Humans.

Neurotransmitter and headache target localization in the trigeminal ganglia (TG) might increase the understanding of sites of action, and mechanisms related to headache therapy. The overall aim of the study was to investigate the presence of migraine targets in the TG with particular emphasis on pituitary adenylate cyclase-activating peptide (PACAP) and calcitonin gene-related peptide (CGRP), known to be involved in cranial pain processing, and selected headache targets. Rat- and human TG were processed for immunohistochemistry.

Fremanezumab blocks CGRP induced dilatation in human cerebral, middle meningeal and abdominal arteries.

Background: Fremanezumab (TEV-48125) is a fully humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) that has shown positive results in the prevention of episodic migraine and chronic migraine. Previous preclinical studies have revealed CGRP antagonistic effects on intracranial arteries (ICA). The aim of the study was to evaluate the in vitro antagonistic effects of fremanezumab on human arteries.

Faster Protocol for Endogenous Fatty Acid Esters of Hydroxy Fatty Acid (FAHFA) Measurements.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a recently discovered class of endogenous lipids with antidiabetic and anti-inflammatory activities. Interest in these lipids is due to their unique biological activites and the observation that insulin-resistant people have lower palmitic acid esters of hydroxystearic acid (PAHSA) levels, suggesting that a FAHFA deficiency may contribute to metabolic disease. Rigorous testing of this hypothesis will require the measurement of many clinical samples; however, current analytical workflows are too slow to enable samples to be analyzed quickly.

Increased endothelin-1-mediated vasoconstriction after organ culture in rat and pig ocular arteries can be suppressed with MEK/ERK1/2 inhibitors.

Purpose: Even though retinal vascular changes following ischaemia have been poorly understood, the upregulation of vasoconstrictive endothelin-1 (ET-1) receptors (ET /ET ) following global cerebral ischaemia has been described. The aim of this study was to investigate whether or not the MEK/ERK1/2 pathway is involved in the observed upregulation and whether specific MEK/ERK1/2 inhibitors U0126 and trametinib can prevent it.

Methods: The aim was also to localize ET and ET receptors using immunohistochemistry in both fresh rat ophthalmic arteries and after 24-hr organ culture and study the receptors functionally using myography.

Postprandial effects on plasma lipids and satiety hormones from intake of liposomes made from fractionated oat oil: two randomized crossover studies.

Background: The composition and surface structure of dietary lipids influence their intestinal degradation. Intake of liposomes made of fractionated oat oil (LOO) is suggested to affect the digestion process and postprandial lipemia and also induce satiety.

Objective: In the present study, the metabolic effects on plasma lipids and gut hormones related to satiety were investigated in healthy individuals after intake of LOO, with dairy lipids as placebo.

Alkaline sphingomyelinase (NPP7) promotes cholesterol absorption by affecting sphingomyelin levels in the gut: A study with NPP7 knockout mice.

We previously showed that dietary sphingomyelin (SM) inhibited cholesterol absorption in animals. The key enzyme hydrolyzing SM in the gut is alkaline sphingomyelinase (alk-SMase, nucleotide pyrophosphatase/phosphodiesterase 7). Here using the fecal dual-isotope ratio method we compared cholesterol absorption in the wild-type (WT) and alk-SMase knockout (KO) mice.

GLP-1 released to the mesenteric lymph duct in mice: effects of glucose and fat.

Using a newly developed in vivo model measuring glucagon-like peptide-1 (GLP-1) in gut lymphatics in mice, we quantified GLP-1 secretion in vivo after glucose versus fat ingestion with and without concomitant DPP-4 inhibition. The mesenteric lymphatic duct was cannulated in anesthetized C57BL6/J mice and lymph was collected in 30 min intervals. Glucose or fat emulsion (Intralipid®) (0.

Postprandial lipid responses to an alpha-linolenic acid-rich oil, olive oil and butter in women: a randomized crossover trial.

Background: Postprandial lipaemia varies with gender and the composition of dietary fat due to the partitioning of fatty acids between beta-oxidation and incorporation into triacylglycerols (TAGs). Increasing evidence highlights the importance of postprandial measurements to evaluate atherogenic risk. Postprandial effects of alpha-linolenic acid (ALA) in women are poorly characterized.

Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: a study on enzyme knockout mice.

Alkaline sphingomyelinase (alk-SMase) hydrolyses sphingomyelin (SM) to ceramide in the gut. To evaluate the physiological importance of the enzyme, we generated alk-SMase knockout (KO) mice by the Cre-recombinase-Locus of X-over P1(Cre-LoxP) system and studied SM digestion. Both wild-type (WT) and KO mice were fed ³H-palmitic acid labeled SM together with milk SM by gavage.

Dairy products and plasma cholesterol levels.

Cholesterol synthesized in the body or ingested is an essential lipid component for human survival from our earliest life. Newborns ingest about 3-4 times the amount per body weight through mother's milk compared to the dietary intake of adults. A birth level of 1.

Curcumin inhibits cholesterol uptake in Caco-2 cells by down-regulation of NPC1L1 expression.

Background: Curcumin is a polyphenol and the one of the principle curcuminoids of the spice turmeric. Its antioxidant, anti-cancer and anti-inflammatory effects have been intensively studied. Previous in vivo studies showed that administration of curcumin also decreased cholesterol levels in the blood, and the effects were considered to be related to upregulation of LDL receptor.

Generating ceramide from sphingomyelin by alkaline sphingomyelinase in the gut enhances sphingomyelin-induced inhibition of cholesterol uptake in Caco-2 cells.

Background Sphingomyelin (SM) is present in dietary products and cell plasma membranes. We previously showed that dietary SM inhibited cholesterol absorption in rats. In the intestinal tract, SM is mainly hydrolyzed by alkaline sphingomyelinase (alk-SMase) to ceramide.

Sphingolipids in human ileostomy content after meals containing milk sphingomyelin.

Background: Sphingomyelin occurs in modest amounts in the diet, in sloughed mucosal cells, and in bile. It is digested by the mucosal enzymes alkaline sphingomyelinase and ceramidase. In humans, alkaline sphingomyelinase is also secreted in bile.

Long term effects on human plasma lipoproteins of a formulation enriched in butter milk polar lipid.

Background: Sphingolipids (SL), in particular sphingomyelin (SM) are important components of milk fat polar lipids. Dietary SM inhibits cholesterol absorption in rats (Nyberg et al. J Nutr Biochem.

Expression of intestinal and lung alkaline sphingomyelinase and neutral ceramidase in cystic fibrosis f508del transgenic mice.

Objectives: The intestinal brush border enzymes alkaline sphingomyelinase (alk-SMase) and neutral ceramidase (CDase) digest milk sphingomyelin in suckling neonates. In addition, alk-SMase, CDase, and acid sphingomyelinase (acid-SMase) have been implicated in sphingolipid signaling, which exhibits abnormalities in cystic fibrosis (CF). In this study, we tested the hypothesis that the expression of these enzymes is different in CF.

Curcumin decreases acid sphingomyelinase activity in colon cancer Caco-2 cells.

Curcumin has been shown to inhibit cell growth and induce apoptosis in colon cancer cells. The metabolism of sphingomyelin has implications in the development of colon cancert. We examined whether curcumin affects the enzymes that hydrolyse sphingomyelin in Caco-2 cells.

Purification and characterization of human intestinal neutral ceramidase.

Sphingolipids are degraded by sphingomyelinase and ceramidase in the gut to ceramide and sphingosine, which may inhibit cell proliferation and induce apoptosis, and thus have anti-tumour effects in the gut. Although previous rodent studies including experiments on knockout mice indicate a role of neutral ceramidase in ceramide digestion, the human enzyme has never been purified and characterized in its purified form. We here report the purification and characterization of neutral ceramidase from human ileostomy content, using octanoyl-[(14)C]sphingosine as substrate.

Human meconium contains significant amounts of alkaline sphingomyelinase, neutral ceramidase, and sphingolipid metabolites.

Intestinal alkaline sphingomyelinase (Alk-SMase) and neutral ceramidase may catalyze the hydrolysis of endogenous sphingomyelin (SM) and milk SM in human-milk fed infants. The enzymes generate sphingolipid metabolites that may influence gut maturation. Alk-SMase also inactivates platelet-activating factor (PAF) that is involved in the pathogenesis of necrotizing enterocolitis (NEC).

Rat intestinal ceramidase: purification, properties, and physiological relevance.

Neutral ceramidase activity has previously been identified in the intestinal mucosa and gut lumen and postulated to be important in the digestion of sphingolipids. It is found throughout the intestine but has never been fully characterized. We have purified rat intestinal neutral ceramidase from an eluate obtained by perfusing the intestinal lumen with 0.