Alzheimer's disease (AD) is a neurodegenerative pathology with relevant unmet therapeutic needs. Both natural aging and AD have been associated with a significant decline in the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA), and accordingly, administration of DHA has been proposed as a possible treatment for this pathology. However, recent clinical trials in mild-to-moderately affected patients have been inconclusive regarding the real efficacy of DHA in halting this disease. Here, we show that the novel hydroxyl-derivative of DHA (2-hydroxydocosahexaenoic acid - OHDHA) has a strong therapeutic potential to treat AD. We demonstrate that OHDHA administration increases DHA levels in the brain of a transgenic mouse model of AD (5xFAD), as well as those of phosphatidylethanolamine (PE) species that carry long polyunsaturated fatty acids (PUFAs). In 5xFAD mice, administration of OHDHA induced lipid modifications that were paralleled with a reduction in amyloid-β (Αβ) accumulation and full recovery of cognitive scores. OHDHA administration also reduced Aβ levels in cellular models of AD, in association with alterations in the subcellular distribution of secretases and reduced Aβ-induced tau protein phosphorylation as well. Furthermore, OHDHA enhanced the survival of neuron-like differentiated cells exposed to different insults, such as oligomeric Aβ and NMDA-mediated neurotoxicity. These results were supported by model membrane studies in which incorporation of OHDHA into lipid-raft-like vesicles was shown to reduce the binding affinity of oligomeric and fibrillar Aβ to membranes. Finally, the OHDHA concentrations used here did not produce relevant toxicity in zebrafish embryos in vivo. In conclusion, we demonstrate the pleitropic effects of OHDHA that might prove beneficial to treat AD, which suggests that an upstream event, probably the modulation of the membrane lipid composition and structure, influences cellular homeostasis reversing the neurodegenerative process. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

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The hormone PYY is released from the distal gut in response to nutrient ingestion. Numerous studies have shown that PYY3-36, the most abundant circulating isoform of PYY, reduces food intake when given to obese rodents and humans. Its infusion to mimic postprandial levels in fasting subjects inhibits appetite, suggesting a physiological role in postprandial satiety. However, the mechanisms underlying this effect remain unclear. Neuronal activity within several brain areas appears to be modified following peripheral administration of PYY3-36 and a direct effect on the central nervous system is possible. Several studies suggest that PYY3-36 levels are reduced in obesity and are elevated following gastric bypass surgery, possibly contributing to the increased feelings of satiety following this procedure. Whether PYY has a role in the regulation of energy expenditure is currently unclear. However, due to the clear appetite-inhibitory effect of PYY, this hormone continues to be investigated as a potential therapeutic agent in the treatment of obesity.

Primary central nervous system lymphoma (PCNSL) is a rare aggressive variant of diffuse large B-cell lymphoma with a poor prognosis and no defined optimal therapeutic strategies. Our aim was to compare the role of intrathecal chemotherapy with current high-dose methotrexate (HDMTX) treatments. Clinicopathologic characteristics, therapy, and outcomes of patients with PCNSL at Moffitt Cancer Center were reviewed in 89 patients identified over an 11-year period. Patients treated initially with HDMTX-based therapy showed improved overall and progression-free survival, with no improvement shown with added radiation or intrathecal therapy. Age and performance status were also important prognostic indicators. Our conclusion is that initial therapy in PCNSL should include an HDMTX backbone. The use of intrathecal chemotherapy or radiation therapy initially likely does not improve outcomes. Future multicenter phase III clinical trials are needed to better establish the superior initial treatment in PCNSL.

AimsTo investigate the effect of Glu-3 OXM-like analogues on food intake and bodyweight in male rats.BackgroundOxyntomodulin (OXM) is a natural agonist at both the glucagon receptor (GCGr) and the glucagon-like peptide 1 receptor (GLP-1r), and peripheral administration reduces food intake and increases energy expenditure in rodents and humans. Substituting the native glutamine (Gln) at amino acid position 3 of OXM for glutamate (Glu) has previously been shown to diminish GCGr activity without affecting GLP-1r activity. The effects of Glu-3 OXM analogues have not been investigated in rats.MethodsThe effect of 2 Glu-3-substituted OXM-like analogues (eg, OXM14E3 and OXM15E3) on food intake and body weight was investigated in male Wistar rats during 6 days of daily subcutaneous (SC) administration. The effects of Glu-3 substitution on analogue binding and activity at the rat GCGr and rat GLP-1 receptor were investigated in vitro using Chinese hamster ovary or Chinese hamster lung cells.ResultsWe report the novel finding that 2 5-nmol/kg Glu-3 OXM-like analogues (OXM14E3 and OXM15E3) significantly increased rat body weight by up to 4% compared with the equivalent non-Glu-3 analogues (OXM14 and OXM15), without affecting food intake. The effect of OXM15E3 on body weight was dose–dependent. Glu-3 analogues, including Glu-3 OXM, decreased glucagon-mediated cyclic adenosine monophosphate accumulation in Chinese hamster ovary cells expressing the rat GCGr, suggesting they may be acting as antagonists.ConclusionsThe results indicate Glu-3 OXM-like analogues might not be suitable tools to investigate the mechanism of OXM analogue action in a rat model because they significantly increase body weight independent of food intake. Glu-3 OXM analogues are partial agonists at the rat GCGr and may also act as antagonists, possibly resulting in the observed increase in body weight.