THE CONCISE GUIDE TO PHARMACOLOGY 2021/22:Transporters

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15543. Transporters are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

Parallel Changes in Mood and Melatonin Rhythm Following an Adjunctive Multimodal Chronobiological Intervention With Agomelatine in People With Depression: A Proof of Concept Open Label Study

Background: Agomelatine is a melatonin agonist and 5HT antagonist developed for the treatment of major depressive disorder which also has some effects on the circadian system. Since circadian dysfunctions are thought to play a role in the pathophysiology of depression, some of the mechanism of action of this drug may relate to improvements in circadian rhythms.Objective: This proof of concept open-label study sought to determine if improvements in depressive symptoms following an adjunctive multimodal intervention including agomelatine intake are associated with the magnitude of circadian realignment. This was investigated in young people with depression, a subgroup known to have high rates of delayed circadian rhythms.Methods: Young people with depression received a psychoeducation session about sleep and circadian rhythms, were asked to progressively phase advance their wake up time, and completed an 8 weeks course of agomelatine (25–50 mg). Participants underwent semi-structured psychological assessments, ambulatory sleep-wake monitoring and measurement of melatonin circadian phase before and after the intervention.Results: Twenty-four young adults with depression (17–28 years old; 58% females) completed the study. After the intervention, depressive symptoms were significantly reduced [t(23) = 6.9, p < 0.001] and, on average, the timing of dim light melatonin onset (DLMO) shifted 3.6 h earlier [t(18) = 4.4, p < 0.001]. On average, sleep onset was phase shifted 28 min earlier [t(19) = 2.1, p = 0.047] and total sleep time increased by 24 min [t(19) = –2.6, p = 0.018]. There was no significant change in wake-up times. A strong correlation (r = 0.69, p = 0.001) was found between the relative improvements in depression severity and the degree of phase shift in DLMO.Conclusion: Although this needs to be replicated in larger randomized controlled trials, these findings suggest that the degree of antidepressant response to a multimodal intervention including psychoeducation and agomelatine intake may be associated with the degree of change in evening melatonin release in young people with depression. This offers promising avenues for targeted treatment based on the prior identification of objective individual characteristics

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Ion channels

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15539. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

Bioprocessing of grains

A method of treating a crop kernel prior to milling to improve millability, which includes the step of exposing the crop kernel to one or more plant hormones is provided. Typically, the crop kernel is a cereal such as wheat. The plant hormone is selected from the group consisting of auxins, gibberellins and abscisic acid. The method further includes the step of exposing the crop kernel to an enzyme. Typically the enzyme is a plant cell-wall degrading enzyme such as xylanase, lipase and cellulase. Also provided are methods of production of flour, food products and compositions. A particular application of this method is the optimisation of milling performance for the production of high quality flour

Cell-derived apolipoprotein E (ApoE) particles inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in human endothelial cells

Sub-endothelial infiltration of monocytes occurs early in atherogenesis and is facilitated by cell adhesion molecules that are up-regulated on activated endothelium. Apolipoprotein E (apoE) helps protect against atherosclerosis, in part, because apoE particles secreted by macrophages have local beneficial effects at lesion sites. Here, we hypothesize that such protection includes anti-inflammatory actions and investigate whether cell-derived apoE can inhibit tumor necrosis factor-alpha-mediated up-regulation of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). Two models were used to mimic endothelial exposure to macrophage-derived apoE. In the first, HUVECs were transiently transfected to secrete apoE; VCAM-1 induction inversely correlated with secretion of apoE into the media (r = -0.76, p < 0.001). In the second, incubation of HUVECs with media from recombinant Chinese hamster ovary (CHO) cells expressing apoE (CHO(apoE)) also reduced VCAM-1 in a dose-dependent manner (r = -0.70, p < 0.001). Characterization of CHO(apoE) cell-derived apoE revealed several similarities to apoE particles secreted by human blood monocyte-derived macrophages. The suppression of endothelial activation by apoE most likely occurs via stimulation of endothelial nitric oxide synthase; apoE increased levels of intracellular nitric oxide and its surrogate marker, cyclic guanosine monophosphate, while the nitric oxide synthase inhibitor, ethyl-isothiourea, blocked its effect. We propose that apoE secreted locally at lesion sites by macrophages may be anti-inflammatory by stimulating endothelium to release NO and suppress VCAM-1 expression

Apolipoprotein E (apoE) isoforms differentially induce nitric oxide production in endothelial cells

Although apolipoprotein E3 (apoE3) is atheroprotective, two common isoforms, apoE2 and apoE4, produce recessive and dominant hyperlipidaemias, respectively. Using a fluorescent assay, we report herein that apoE3 particles secreted from recombinant cells stimulate more nitric oxide release in cultured human EA.hy926 endothelial cells than apoE2 or apoE4 (141% more than controls vs. 61 or 11%). Phosphatidylinositol (PI) 3-kinase inhibitors suppressed the apoE effect, while apoE receptor 2 (apoER2) was tyrosine phosphorylated. We conclude that apoE stimulates endothelial nitric oxide release in an isoform-dependent manner, and propose that tyrosine phosphorylation of apoER2 initiates PI3-kinase signalling and activation of nitric oxide synthase

Human complement factor I glycosylation: structural and functional characterisation of the N-linked oligosaccharides.

Factor I (fI) is a key serine protease that modulates the complement cascade by regulating the levels of C3 convertases. Human fI circulates in plasma as a heavily N-glycosylated (25-27% w/w) heterodimer composed of two disulphide linked chains, each carrying three N-linked oligosaccharide chains. It had been suggested that the oligosaccharides may have both structural and functional roles in the interactions with the natural substrate and the cofactor during a catalysis. The N-linked glycans of each fI chain were characterised in detail and the analysis revealed a similar composition of the glycan pools with both chains heavily sialylated. Disialylated structures were in excess over monosialylated ones: 55% over 40% for the heavy chain and 62% over 35% for the light chain. The dominant type of glycan identified on both chains was A(2)G(2)S(2), a biantennary structure with chains terminating in sialic acid linked to galactose. The glycan characterisation facilitated a strategy for the partial deglycosylation of the enzyme. Assessment of the proteolytic activities of the native and partially deglycosylated forms of fI showed that both forms of the enzyme have very similar proteolytic activities against C3(NH(3)) indicating that the charged glycans of fI do not influence the fI-cofactor-substrate interactions