Oleoylethanolamide (OEA) is a lipid mediator that inhibits food intake by activating the nuclear receptor peroxisome proliferator-activated receptor-␣. In the rodent small intestine OEA levels decrease during food deprivation and increase upon refeeding, suggesting that endogenous OEA may participate in the regulation of satiety. Here we show that feeding stimulates OEA mobilization in the mucosal layer of rat duodenum and jejunum but not in the serosal layer from the same intestinal segments in other sections of the gastrointestinal tract (stomach, ileum, colon) or in a broad series of internal organs and tissues (e.g. liver, brain, heart, plasma). Feeding also increases the levels of other unsaturated fatty acid ethanolamides (FAEs) (e.g. linoleoylethanolamide) without affecting those of saturated FAEs (e.g. palmitoylethanolamide). Feeding-induced OEA mobilization is accompanied by enhanced accumulation of OEA-generating N-acylphosphatidylethanolamines (NAPEs) increased activity and expression of the OEA-synthesizing enzyme NAPE-phospholipase D, and decreased activity and expression of the OEAdegrading enzyme fatty acid amide hydrolase. Immunostaining studies revealed that NAPE-phospholipase D and fatty acid amide hydrolase are expressed in intestinal enterocytes and lamina propria cells. Collectively, these results indicate that nutrient availability controls OEA mobilization in the mucosa of the proximal intestine through a concerted regulation of OEA biosynthesis and degradation.The gastrointestinal tract controls key aspects of feeding behavior through both neuronal and humoral mechanisms. Among the regulatory signals released by the gut, peptides such as cholecystokinin (CCK), 3 glucagon-like peptide-1, and ghrelin have attracted the most attention (1), but recent evidence indicates that lipid-derived messengers such as oleoylethanolamide (OEA) may also be involved (2). OEA is synthesized in the small intestine of various vertebrate species, where its levels decrease during food deprivation and increase upon refeeding (3-5). The possibility that these fluctuations represent a satiety signal is suggested by experiments in rodents which show that pharmacological administration of OEA delays meal initiation and prolongs the interval between successive meals, resulting in a persistent inhibition of food intake (3, 6 -8). These anorexiant effects are strikingly different from those elicited by traditional satiety factors such as CCK, which reduce meal size without affecting the interval between meals (9). Moreover, the hypophagic actions of OEA differ from those exerted by glucagon-like peptide-1 (10) and corticotropin-releasing factor (11) in that they are not accompanied by behavioral signs of malaise and anxiety or by changes in circulating corticosterone levels (3, 12). The molecular mechanism through which OEA inhibits feeding has been partially elucidated. In vitro studies have shown that OEA is a high affinity agonist of peroxisome proliferator-activated receptor-␣ (PPAR-␣) (13), a nuclear receptor pres...
Activation of group I metabotropic glutamate (mGlu) receptors drives the endocannabinoid system to cause both shortand long-term changes of synaptic strength in the striatum, hippocampus, and other brain areas. Although there is strong electrophysiological evidence for a role of endocannabinoid release in mGlu receptor-dependent plasticity, the identity of the endocannabinoid transmitter mediating this phenomenon remains undefined. In this study, we show that activation of group I mGlu receptors triggers the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG), but not anandamide, in primary cultures of corticostriatal and hippocampal slices prepared from early postnatal rat brain.Pharmacological studies suggest that 2-AG biosynthesis is initiated by activation of mGlu5 receptors, is catalyzed by phospholipase C (PLC) and 1,2-diacylglycerol lipase (DGL) activities, and is dependent on intracellular Ca 2ϩ ions. Realtime polymerase chain reaction and immunostaining analyses indicate that DGL- is the predominant DGL isoform expressed in corticostriatal and hippocampal slices and that this enzyme is highly expressed in striatal neurons, where it is colocalized with PLC-1. The results suggest that 2-AG is a primary endocannabinoid mediator of mGlu receptor-dependent neuronal plasticity.
Pharmacological administration of the natural lipid amide, oleoylethanolamide (OEA), inhibits food intake in free-feeding rodents by prolonging latency to feed and postmeal interval. This anorexic effect is mediated by activation of type-α peroxisome proliferator-activated receptors (PPAR-α). Food intake stimulates mucosal cells in duodenum and jejunum to generate OEA, suggesting that this lipid-derived messenger may act as a local satiety hormone. As a test of this hypothesis, here, we examined whether targeted enhancement of OEA production in the small intestine affects feeding behavior in rats. We constructed an adenoviral vector (Ad-NPLD) that directs overexpression of the enzyme N-acylphosphatidylethanolamine (NAPE)-phospholipase D (PLD), which catalyzes the hydrolysis of NAPE to generate OEA. Intraduodenal injection of the Ad-NPLD vector resulted in a time-dependent increase in NAPE-PLD expression and OEA production, which was restricted to the proximal small intestine. No such effect was observed after administration of a control adenoviral vector. Enhanced OEA production in Ad-NPLD-injected animals was temporally associated with increased expression of two PPAR-α target genes (PPAR-α and CD36) and with decreased food intake. The hypophagic phenotype of Ad-NPLD-injected rats was attributable to increase feeding latency and postmeal interval, rather than decreased meal size. The results suggest that localized changes in OEA production in the small intestine, such as those produced by food intake, are sufficient to induce in rats a state of across-meal satiety similar to that elicited by systemic administration of exogenous OEA.
Immune checkpoint inhibitor (ICI) immunotherapy improved the survival of head and neck squamous cell carcinoma (HNSCC) patients. However, more than 80% of the patients are still resistant to this therapy. To test whether the efficacy of ICI therapy can be improved by vaccine-induced immunity, we investigated the efficacy of a tumor membrane-based vaccine immunotherapy in murine models of HNSCC. The tumors, grown subcutaneously, are used to prepare tumor membrane vesicles (TMVs). TMVs are then incorporated with glycolipid-anchored immunostimulatory molecules GPI-B7-1 and GPI-IL-12 by protein transfer to generate the TMV vaccine. This TMV vaccine inhibited tumor growth and improved the survival of mice challenged with SCCVII tumor cells. The tumor-free mice survived for several months, remained tumor-free, and were protected following a secondary tumor cell challenge, suggesting that the TMV vaccine induced an anti-tumor immune memory response. However, no synergy with anti-PD1 mAb was observed in this model. In contrast, the TMV vaccine was effective in inhibiting MOC1 and MOC2 murine oral cancer models and synergized with anti-PD1 mAb in extending the survival of tumor-bearing mice. These observations suggest that tumor tissue based TMV vaccines can be harnessed to develop an effective personalized immunotherapy for HNSCC that can enhance the efficacy of immune checkpoint inhibitors.
Objective: To document health care providers' views regarding treatments for symptoms associated with menopause and discussions with patients about symptoms and treatment decisions. Results informed development of a data collection form for a retrospective medical record review (reported separately).Methods: Registered US gynecologists or primary care providers from all US regions were identified from local association directories and an in-house database and were invited to participate in a qualitative interview if they consulted with three or more patients per week presenting with menopausal symptoms. Participants provided demographic data, information about patients' symptoms, and health care provider and patient views on prescription and nonprescription therapies. Key concepts/themes from interviews were identified.Results: Participating health care providers (10 gynecologists, 10 primary care providers) agreed there are effective treatment options for menopausal symptoms, particularly vasomotor symptoms and vaginal dryness and/or atrophy. Health care providers reported that treatment was generally dictated by symptoms that interfered with quality of life and/or daily activities, although patients often had symptoms for months before presentation. All health care providers said they prescribe hormone and/or nonhormone therapies for treatment of menopausal symptoms; half stated that they typically inquire about patients' nonprescription therapy use, and 45% recommend specific nonprescription therapies. The most commonly cited barriers to initiation of any therapy for menopausal symptoms were patient concerns about risks and financial considerations (ie, insurance or cost).Conclusions: US health care providers reported prescribing therapies for menopausal symptoms and noted that these therapies were perceived as generally effective; however, barriers to initiation of prescription therapy exist, and new treatment options are needed.
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