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Background and Purpose: Lasmiditan is a novel selective 5‐HT1F receptor agonist, recently approved for acute treatment of migraine. 5‐HT1F receptors are widely expressed in the CNS and trigeminovascular system. Here, we have explored the therapeutic effects of 5‐HT1F receptor activation in preclinical models of migraine and cluster headache. Experimental Approach: Electrical stimulation of the dura mater or the superior salivatory nucleus in anaesthetised rats evoked trigeminovascular or trigeminal–autonomic reflex activation at the level of the trigeminocervical complex. Additionally, cranial autonomic manifestations in response to trigeminal–autonomic reflex activation were measured, via anterior choroidal blood flow alterations. These responses were then challenged with lasmiditan. We explored the tissue distribution of mRNA for 5‐HT1F receptors in human post‐mortem tissue and of several 5‐HT1 receptor subtypes in specific tissue beds. Key Results: Lasmiditan dose‐dependently reduced trigeminovascular activation in a preclinical model of migraine. Lasmiditan also reduced superior salivatory nucleus‐evoked activation of the trigeminal–autonomic reflex, but had no effect on cranial autonomic activation. mRNA profiling in human tissue showed expression of the 5‐HT1F receptor in several structures relevant for migraine and cluster headache. Conclusion and Implications: Our data suggest that lasmiditan acts, at least in part, as an anti‐migraine agent by reducing trigeminovascular activation. Furthermore, our results highlight a clear action for lasmiditan in a preclinical model of cluster headache. Given the proven translational efficacy of this model, our data support the potential utility of lasmiditan as a therapeutic option for the acute treatment of cluster headache attacks. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc [ABSTRACT FROM AUTHOR]

Murine NGD5 is a gene identified from NG108-15 cells which is postulated to be involved in opioid receptor function. Here we report the cloning and characterization of a cDNA C20orf9-003 (ACI-1) encoding the human orthologue of the mouse NGD5. Analysis of the genomic structure revealed that C20orf9-003 (ACI-1) contains 13 exons and 12 introns, spanning 52.5 kb of genomic DNA and is a variant of C20orf9. Chromosomal localization of human C20orf9-003 (ACI-1) assigned this gene to chromosome 20q13.12. Genes at this locus have been associated with the progression and possibly the development of various cancers. In addition several linkage studies support the possibility that one or more genes affecting obesity are located in 20q13. No function can be clearly assigned to C20orf9-003 (ACI-1), however, the protein has a cytoplasmic subcellular location and the secondary structure contains a Rossman fold like feature which is found in many nucleotide binding proteins. [ABSTRACT FROM AUTHOR]

We have recently shown that UDP-glucose, and some related UDP-sugars, are potent agonists of the novel G protein-coupled receptor GPR105 (recently re-named P2Y14). GPR105 is widely expressed throughout many brain regions and peripheral tissues of human and rodents, and couples to a pertussis toxin-sensitive G protein. To further characterise the role of GPR105, we demonstrate by immunohistochemistry with receptor-specific antiserum that GPR105 protein is widely distributed throughout the post mortem human brain where it is localised to glial cells, and specifically co-localises with astrocytes. Using quantitative RT-PCR we also show that GPR105 mRNA exhibits a restricted expression profile in an array of human cell lines and primary cells, with prominent expression detected in immune cells including neutrophils, lymphocytes, and megakaryocytic cells. To investigate the G protein selectivity of GPR105, we used chimeric Gα subunits (Gαqi5, Gαqo5, and Gαqs5) and an intracellular Ca2+ mobilisation assay to demonstrate that GPR105 couples to Gα subunits of the Gi/o family but not to Gs family proteins or to endogenous Gq/11 proteins in HEK-293 cells. Finally, we show that expression of GPR105 mRNA in the rat brain is up-regulated by immunologic challenge with lipopolysaccharide. Based on these observations, we propose that Gi/o-coupled GPR105 might play an important role in peripheral and neuroimmune function in response to extracellular UDP-sugars. [Copyright &y& Elsevier]

Peroxisome proliferator-activated receptor γ (PPARγ) is a critical regulator of adipocyte differentiation. Whilst 15-deoxy-Δ12,14-prostaglandin J2 (15-d-PGJ2) has been identified as a putative endogenous ligand for this transcription factor, it is unclear whether the enzymes necessary for 15-d-PGJ2 biosynthesis are co-expressed with PPARγ. Prostaglandin D2 synthase (PGDS) enzymes represent the terminal enzymatic components responsible for 15-d-PGJ2 production. Both glutathione (GSH)-dependent and GSH-independent PGDS isoenzymes exist. We have, therefore, examined the expression of PGDS isoenzymes in mouse 3T3-L1 adipocytes, and various human tissues. The GSH-independent PGDS was found to be expressed in 3T3-L1 cells both before and after their differentiation into adipocytes. By contrast, we were unable to detect expression of the GSH-dependent PGDS at any stage during the adipose conversion of 3T3-L1 cells. Quantitative analysis of mRNA levels for PPARγ and each PGDS isoenzyme revealed their co-expression in a number of human tissues and cell types, including adipose tissue, placenta, prostate, and macrophages. These data reveal the potential for de novo 15-d-PGJ2 synthesis in the context of PPARγ expression, suggesting that this prostaglandin may contribute to PPARγ signalling in vivo. [Copyright &y& Elsevier]

This paper explores the potentialities of an empowered public services/technical services interface as a liberating and exhilarating vehicle for change, improvement, understanding, and access in the online subject catalog. [ABSTRACT FROM PUBLISHER]

No abstract available for this article. [ABSTRACT FROM PUBLISHER]

Background and Purpose: Lasmiditan is a novel selective 5-HT 1F receptor agonist, recently approved for acute treatment of migraine. 5-HT 1F receptors are widely expressed in the CNS and trigeminovascular system. Here, we have explored the therapeutic effects of 5-HT 1F receptor activation in preclinical models of migraine and cluster headache., Experimental Approach: Electrical stimulation of the dura mater or the superior salivatory nucleus in anaesthetised rats evoked trigeminovascular or trigeminal-autonomic reflex activation at the level of the trigeminocervical complex. Additionally, cranial autonomic manifestations in response to trigeminal-autonomic reflex activation were measured, via anterior choroidal blood flow alterations. These responses were then challenged with lasmiditan. We explored the tissue distribution of mRNA for 5-HT 1F receptors in human post-mortem tissue and of several 5-HT 1 receptor subtypes in specific tissue beds., Key Results: Lasmiditan dose-dependently reduced trigeminovascular activation in a preclinical model of migraine. Lasmiditan also reduced superior salivatory nucleus-evoked activation of the trigeminal-autonomic reflex, but had no effect on cranial autonomic activation. mRNA profiling in human tissue showed expression of the 5-HT 1F receptor in several structures relevant for migraine and cluster headache., Conclusion and Implications: Our data suggest that lasmiditan acts, at least in part, as an anti-migraine agent by reducing trigeminovascular activation. Furthermore, our results highlight a clear action for lasmiditan in a preclinical model of cluster headache. Given the proven translational efficacy of this model, our data support the potential utility of lasmiditan as a therapeutic option for the acute treatment of cluster headache attacks., Linked Articles: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc., (© 2021 The British Pharmacological Society.)

We have recently shown that UDP-glucose, and some related UDP-sugars, are potent agonists of the novel G protein-coupled receptor GPR105 (recently re-named P2Y(14)). GPR105 is widely expressed throughout many brain regions and peripheral tissues of human and rodents, and couples to a pertussis toxin-sensitive G protein. To further characterise the role of GPR105, we demonstrate by immunohistochemistry with receptor-specific antiserum that GPR105 protein is widely distributed throughout the post mortem human brain where it is localised to glial cells, and specifically co-localises with astrocytes. Using quantitative RT-PCR we also show that GPR105 mRNA exhibits a restricted expression profile in an array of human cell lines and primary cells, with prominent expression detected in immune cells including neutrophils, lymphocytes, and megakaryocytic cells. To investigate the G protein selectivity of GPR105, we used chimeric Galpha subunits (Galpha(qi5), Galpha(qo5), and Galpha(qs5)) and an intracellular Ca(2+) mobilisation assay to demonstrate that GPR105 couples to Galpha subunits of the G(i/o) family but not to G(s) family proteins or to endogenous G(q/11) proteins in HEK-293 cells. Finally, we show that expression of GPR105 mRNA in the rat brain is up-regulated by immunologic challenge with lipopolysaccharide. Based on these observations, we propose that G(i/o)-coupled GPR105 might play an important role in peripheral and neuroimmune function in response to extracellular UDP-sugars.

Resistin is a cysteine-rich protein postulated to be a molecular link between obesity and type 2 diabetes. The aim of this study was to investigate the role of PPAR gamma in the regulation of resistin expression in human primary macrophages. Fluorescent real-time PCR (Taqman) analysis of resistin expression across a range of human tissues showed that resistin is highly expressed in bone marrow compared to other tissues. Taqman analysis and Western blotting showed that rosiglitazone decreased resistin expression at both the mRNA and protein levels in human primary monocyte-derived macrophages in vitro. Resistin expression was reduced by up to 80% after exposure to 100 nM rosiglitazone for 96 h. Bioinformatics analysis of the genomic sequence upstream of the resistin coding sequence identified several putative PPAR response elements of which one was shown to bind PPAR gamma using electrophoretic mobility shift assays. Our data support a direct role for PPAR gamma in the regulation of resistin expression.