2,163 research outputs found
Combined targeting of fatty acid amide hydrolase and melatonin receptors promotes neuroprotection and stimulates inflammation resolution in rats
No full textBackground and purpose: Devising novel strategies to therapeutically favour inflammation resolution and provide neuroprotection is an unmet clinical need. Enhancing endocannabinoid tone by inhibiting the catabolic enzyme fatty acid amide hydrolase (FAAH), or stimulating melatonin receptors has therapeutic potential to treat neuropathological states in which neuroinflammation plays a central role. Experimental approach: A rodent hippocampal explant model of inflammatory injury was used to assess the effects of UCM1341, a dual-acting compound with FAAH inhibitory action and agonist activity at melatonin receptors, against neuroinflammatory damage. FAAH activity was measured by a radiometric assay, and N-acylethanolamine levels were assessed by HPLC-MS/MS methods. FAAH distribution, evolution of inflammation and the contribution of UCM1341 to the expression of proteins controlling macrophage behaviour were investigated by biochemical and confocal analyses. Key results: UCM1341 exhibited greater neuroprotection against neuroinflammatory degeneration, compared with the reference compounds URB597 (FAAH inhibitor) and melatonin. During neuroinflammation, UCM1341 augmented the levels of anandamide and N-oleoylethanolamine, but not N-palmitoylethanolamine, up-regulated PPAR-α levels, attenuated demyelination and prevented the release of TNF-α. UCM1341 modulated inflammatory responses by contributing to microglia/macrophage polarization, stimulating formation of lipid-laden macrophages and regulating expression of proteins controlling cholesterol metabolism and efflux. The neuroprotective effects of UCM1341 were prevented by PPARα, TRPV1 and melatonin receptor antagonists. Conclusion and implications: UCM1341, by enhancing endocannabinoid and melatoninergic signalling, benefits neuroprotection and stimulates inflammation resolution pathways. Our findings provide an encouraging prospect of therapeutically targeting endocannabinoid and melatoninergic systems in inflammatory demyelinating states in the CNS
Enhancement of peripheral fatty acyl ethanolamide signaling prevents stress‐induced social avoidance and anxiety‐like behaviors in male rats
No full text"The love that made hell, paradise." Ouida re-writing the Paolo and Francesca theme in Held in Bondage
No full textThe bestselling Victorian author Ouida reveals in her novels, and, in particular, Held in Bondage, an extraordinary knowledge od Dante, by using characters and themes from the Commedia. The Paolo and Francesca theme actually constitutes part of the plot of the novel and is to be found in many of her other works, short stories and non-fiction writing
Antidepressant-like effects of pharmacological inhibition of FAAH activity in socially isolated female rats
No full textPharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid N-arachidonoylethanolamine (or anandamide, AEA), exerts favourable effects in rodent models of stress-related depression. Yet although depression seems to be more common among women than men and in spite of some evidence of sex differences in treatment efficacy, preclinical development of FAAH inhibitors for the pharmacotherapy of stress-related depression has been predominantly conducted in male animals. Here, adult female rats were exposed to six weeks of social isolation and, starting from the second week, treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle. Compared to pair-housed females, socially isolated female rats treated with vehicle developed behavioral (mild anhedonia, passive stress coping) and physiological (reduced body weight gain, elevated plasma corticosterone levels) alterations. Moreover, prolonged social isolation provoked a reduction in brain-derived neurotrophic factor (BDNF) and AEA levels within the hippocampus. Together, these changes are indicative of an increased risk of developing a depressive-like state. Conversely, pharmacological inhibition of FAAH activity with URB694 restored both AEA and BDNF levels within the hippocampus of socially isolated rats and prevented the development of behavioral and physiological alterations. These results suggest a potential interplay between AEA-mediated signaling and hippocampal BDNF in the pathogenesis of depression-relevant behaviors and physiological alterations and antidepressant action of FAAH inhibition in socially isolated female rats
HERStory Makers 2023: Francesca Fotheringham
No full textFrancesca Fotheringham is a postdoctoral research associate at the University of Edinburgh studying educational psychology with a focus on neurodiversity. She took part in HERStory Makers 2023.What is HERStory Makers?HERStory Makers is a social media competition for female-identifying early career researchers to share their research, their career journeys, and to inspire the next generation. Winners are selected by public vote. HERStory Makers is also part of EXPLORATHON, Scotland's contribution to European Researchers' Night.In 2022-23, EXPLORATHON Francescasupported by the Engineering & Physical Sciences Research Council [grant number EP/X020762/1].Author contributions to contentFrancesca conceived, planned, and recorded the video content. Kirsty Ross edited the video content to insert HERStory Maker credits, added subtitles, and reduce video length to below Twitter/X limit of 2 mins and 20 secs.</p
Identification of Human Alanine–Glyoxylate Aminotransferase Ligands as Pharmacological Chaperones for Variants Associated with Primary Hyperoxaluria Type 1
No full text[Image: see text] Primary hyperoxaluria type I (PH1) is a rare kidney disease due to the deficit of alanine:glyoxylate aminotransferase (AGT), a pyridoxal-5′-phosphate-dependent enzyme responsible for liver glyoxylate detoxification, which in turn prevents oxalate formation and precipitation as kidney stones. Many PH1-associated missense mutations cause AGT misfolding. Therefore, the use of pharmacological chaperones (PCs), small molecules that promote correct folding, represents a useful therapeutic option. To identify ligands acting as PCs for AGT, we first performed a small screening of commercially available compounds. We tested each molecule by a dual approach aimed at defining the inhibition potency on purified proteins and the chaperone activity in cells expressing a misfolded variant associated with PH1. We then performed a chemical optimization campaign and tested the resulting synthetic molecules using the same approach. Overall, the results allowed us to identify a promising hit compound for AGT and draw conclusions about the requirements for optimal PC activity
(2S,4R)-4-fluoroglutamine is converted into (2S,4R)-4-fluoroglutamate by glutaminase activity and may be exploited as a PET tracer in glutamine-addicted cancers
No full textMedicina illuminata. La Biblioteca Lancisiana di Roma
No full textL'articolo presenta i codici miniati della Biblioteca Lancisiana di Roma. La prima parte, del coautore, è dedicata alla Biblioteca. La seconda parte, di F. Manzari, tratta dei manoscritti miniati, costituiti da due codici con le opere di Avicenna e dal Liber fraternitatis della Confraternita dell'Ospedale di Santo Spirito in Sassia a Roma.The article introduces the illuminated manuscripts of the Biblioteca Lancisiana in Rome. The first part of the article, by the co-author, is dedicated to the Library. The second part, by Francesca Manzari, illustrates the manuscipts; these are two manuscripts with the works of Avicenna and the Liber fraternitatis of the Confraternity of the Hospital of Santo Spirito in Sassia in Rome
A DH-Leavened Musicological Toolbox
No full textGraduate-level training in music research methodologies tends to ignore digital humanities work and overlook the use of digital tools created in support of new forms of reading. Training instead focuses on source material in the student’s area of interest. This material includes secondary and primary (archival) resources, as well as information resources, such as: monuments of music and critical editions; indexes; bibliographies and thematic catalogs; dictionaries and encyclopedias; digital libraries of scores or editions; and databases of period-specific newspapers or journals. Graduate students taking research methods courses already have a toolbox built from their experiences as musicians and students of music, including the ability to read and interpret music notation, to understand theoretical and analytical concepts in music, as well as a command of music history, including the canon of musical works.
Digital humanities has become a major area of academic endeavor at the “interface of technological development, epistemological change and methodological concerns." An important characteristic of digital humanities research has been its interdisciplinarity. We argue that graduate training in musicology needs to include coverage of methodologies applied by digital humanists in support of new forms of reading, not only to broaden the canon of research topics in musicology, but also to build common ground with researchers of other disciplines. We propose that librarians are well positioned to provide this expertise and training
Social stress-induced depressive-like symptoms and changes in gut microbial and lipidomic profiles are prevented by pharmacological inhibition of FAAH activity in male rats
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