Integrins (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the 'Catalytic receptors' section of the database until more stringent criteria from NC-IUPHAR allows precise definition of their classification.Integrins are heterodimeric entities, composed of α and β subunits, each 1TM proteins, which bind components of the extracellular matrix or counter-receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its α subunit, and if present (in α1, α2, α10, α11, αD, αE, αL, αM and αX), this I domain contains the ligand binding site. All β subunits possess a similar I-like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an α subunit I domain precludes ligand binding through the β subunit. Integrins provide a link between ligand and the actin cytoskeleton (through typically short intracellular domains). Integrins bind several divalent cations, including a Mg2+ ion in the I or I-like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin-linked kinase. Cellular activation regulates integrin ligand affinity via inside-out signalling and ligand binding to integrins can regulate cellular activity via outside-in signalling.Several drugs that target integrins are in clinical use including: (1) abciximab (αIIbβ3) for short term prevention of coronary thrombosis, (2) vedolizumab (α4β7) to reduce gastrointestinal inflammation, and (3) natalizumab (α4β1) in some cases of severe multiple sclerosis

Integrins in GtoPdb v.2023.1

Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the 'Catalytic receptors' section of the database until more stringent criteria from NC-IUPHAR allows precise definition of their classification.Integrins are heterodimeric entities, composed of α and β subunits, each 1TM proteins, which bind components of the extracellular matrix or counter-receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its α subunit, and if present (in α1, α2, α10, α11, αD, αE, αL, αM and αX), this I domain contains the ligand binding site. All β subunits possess a similar I-like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an α subunit I domain precludes ligand binding through the β subunit. Integrins provide a link between ligand and the actin cytoskeleton (through typically short intracellular domains). Integrins bind several divalent cations, including a Mg2+ ion in the I or I-like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin-linked kinase. Cellular activation regulates integrin ligand affinity via inside-out signalling and ligand binding to integrins can regulate cellular activity via outside-in signalling.Several drugs that target integrins are in clinical use including: (1) abciximab (αIIbβ3) for short term prevention of coronary thrombosis, (2) vedolizumab (α4β7) to reduce gastrointestinal inflammation, and (3) natalizumab (α4β1) in some cases of severe multiple sclerosis

Early embryo mortality in natural human reproduction: What the data say [version 1; referees: 1 approved, 2 approved with reservations]

It is generally accepted that natural human embryo mortality during pregnancy is high – losses of 70% and higher from fertilisation to birth are frequently claimed. The first external sign of pregnancy occurs two weeks after fertilisation with a missed menstrual period. Establishing the fate of embryos before this is challenging, and hampered by a lack of data on the efficiency of fertilisation under natural conditions. Four distinct sources are cited to justify quantitative claims regarding embryo loss: (i) a hypothesis published by Roberts & Lowe in The Lancet  is widely cited but has no quantitative value; (ii) life table analyses give consistent assessments of clinical pregnancy loss, but cannot illuminate losses at earlier stages of development; (iii) studies that measure human chorionic gonadotrophin (hCG) reveal losses in the second week of development and beyond, but not before; and (iv) the classic studies of Hertig and Rock offer the only direct insight into the fate of human embryos from fertilisation under natural conditions. Re-examination of Hertig’s data demonstrates that his estimates for fertilisation rate and early embryo loss are highly imprecise and casts doubt on the validity of his numerical analysis. A recent re-analysis of hCG study data suggests that approximately 40-60% of embryos may be lost between fertilisation and birth, although this will vary substantially between individual women. In conclusion, it is clear that some published estimates of natural embryo mortality are exaggerated. Although available data do not provide a precise estimate, natural human embryo mortality is lower than is often claimed

Noncompetitive Inhibition of 5-HT3 Receptors by Citral, Linalool, and Eucalyptol Revealed by Nonlinear Mixed-Effects Modeling.

Citral, eucalyptol, and linalool are widely used as flavorings, fragrances, and cosmetics. Here, we examined their effects on electrophysiological and binding properties of human 5-HT3 receptors expressed in Xenopus oocytes and human embryonic kidney 293 cells, respectively. Data were analyzed using nonlinear mixed-effects modeling to account for random variance in the peak current response between oocytes. The oils caused an insurmountable inhibition of 5-HT-evoked currents (citral IC50 = 120 µM; eucalyptol = 258 µM; linalool = 141 µM) and did not compete with fluorescently labeled granisetron, suggesting a noncompetitive mechanism of action. Inhibition was not use-dependent but required a 30-second preapplication. Compound washout caused a slow (∼180 seconds) but complete recovery. Coapplication of the oils with bilobalide or diltiazem indicated they did not bind at the same locations as these channel blockers. Homology modeling and ligand docking predicted binding to a transmembrane cavity at the interface of adjacent subunits. Liquid chromatography coupled to mass spectrometry showed that an essential oil extracted from Lippia alba contained 75.9% citral. This inhibited expressed 5-HT3 receptors (IC50 = 45 µg ml(-1)) and smooth muscle contractions in rat trachea (IC50 = 200 µg ml(-1)) and guinea pig ileum (IC50 = 20 µg ml(-1)), providing a possible mechanistic explanation for why this oil has been used to treat gastrointestinal and respiratory ailments. These results demonstrate that citral, eucalyptol, and linalool inhibit 5-HT3 receptors, and their binding to a conserved cavity suggests a valuable target for novel allosteric modulators.Our thanks are given to John Peters (University of Dundee) for the 5-HT3A subunit, to Martin Lochner (Bern University) for reviewing our chemical structures and providing G-FL, and to Ruth Murrell-Lagnado for hosting the experimental work. AJT was supported by the British Heart Foundation (PG/13/39/30293).This is the final version of the article. It first appeared from the American Society for Pharmacology and Experimental Therapeutics via https://doi.org/10.1124/jpet.115.230011

Editors’ Moral Obligations – Profit, Regulation and Virtue

Ethics is the branch of knowledge or study dealing with moral principles. These principles guide actions and choices made by individuals. A moral obligation is a constraint on action and choice that may arise from legal or ethical considerations. Underlying principles that impose obligations on journal editors arise from considerations of profit, regulation and virtue. To profit is to gain. Why might a journal exist? What do those responsible, e.g., learned societies and publishers, hope to gain from publishing a journal? What is their interest: financial reward, prestige, impact, social good? Journals and editors function within regulatory frameworks that may be internally or externally imposed. Most journals have ‘guidelines for authors’, which may be extensive and detailed or relatively light-touch. External frameworks include the Committee on Publication Ethics (COPE), founded in 1997. There are many other guidelines of relevance to journal editors that address specific issues: ARRIVE, CASP, FAIR, PREPARE, PRISMA, TOP to name but a few. Where do these regulations come from? Why are there so many and do they make journals better? Dr Ed Pellegrino argued that any professional (doctor, lawyer, scientist, editor) should be both competent and virtuous. Such an editor embodies habits and instincts that inform choices that promote fundamental goods, irrespective of regulations or interests. A competent and virtuous editor does not require regulations to know that published science should be conducted ethically and be of a good quality. These three dimensions of moral obligation must function harmoniously and not in competition. Clarity as to whether ‘Open Science’ and ‘Transparency’ are interests, regulations or fundamental goods is essential and perhaps not so obvious. To act effectively and ethically, an editor must have clearly defined objectives and follow a transparent regulatory framework. However, these must be built on a secure foundation of personal and institutional virtue

Evidence for an effect of receptor density on ligand occupancy and agonist EC 50

Abstract: Drug-receptor interaction theory predicts that proportional receptor occupancy is a function of ligand concentration as defined by a ligand-receptor affinity constant, and is independent of receptor density. However, we previously observed that the EC50 of 5-HT reduced as the density of 5-HT3 receptors increased, suggesting an effect of receptor density on occupancy. The current study was designed to maximise variability in experimentally observed currents and confirm this apparent contradiction prospectively. Xenopus oocytes were injected with RNA encoding 5-HT3A receptors under conditions designed to achieve varying receptor expression levels and 5-HT-evoked currents measured using two electrode voltage clamp. Results from 99 oocytes showed that as the maximal peak current increased from 0.05 µA to 12.1 µA there was a 3.7-fold reduction in EC50. Since occupancy and conductance are directly related in this system, this indicates that for a given concentration of 5-HT, proportional occupancy increases with increased receptor density. We conclude that normalising data masks this correlation, and can result in reduced accuracy of pharmacological measurements. We propose a mechanistic explanation for our observations

The role of the angle of the fibularis longus tendon in foot arch support.

INTRODUCTION: Understanding the contribution of the fibularis longus tendon to the support of the midfoot arches has potential therapeutic applications. This cadaveric study sought to quantify this support across both the transverse arch and medial longitudinal arch and to establish whether a correlation exists between this support and the angle at which the tendon enters the sole. MATERIALS AND METHODS: Markers placed in 11 dissected cadaveric foot specimens defined the arch boundaries. Incremental weights up to 150 N were applied to the fibularis longus tendon to simulate progressive muscle contraction, and associated changes in the transverse and medial longitudinal arch boundaries were recorded. RESULTS: A force of 150 N reduced the transverse arch distance by 4.6 (1.7) mm (mean [SD]) and medial longitudinal arch distance by 6.8 (1.4) mm. The angle of the fibularis longus tendon on the sole correlated well with changes in the transverse arch distance (slope ± s.e. = 0.56 ± 0.13 mm/degree, Pearson r = .83, p = .002) but only weakly with the medial longitudinal arch (0.18 ± 0.18 mm/degree, r = .32, p = .33). CONCLUSIONS: The results of this preliminary study raise the possibility that physical therapies targeting the fibularis longus tendon may be valuable in the management of midfoot arch collapse. The correlation observed with the transverse arch suggests the possibility that surgical modification of the angle of the fibularis longus tendon on the sole may benefit patients with transverse arch collapse

Intrasynovial triamcinolone treatment is not associated with incidence of acute laminitis

Background: Intra-synovial corticosteroid injections are commonly used in the treatment of equine orthopaedic disease, but corticosteroid administration is widely considered a risk factor for the development of laminitis. Despite a list of putative mechanisms and a number of case reports of steroid-induced laminitis, no case-control or cohort studies investigating the association between use of intra-synovial corticosteroids and acute laminitis have been published. Objectives: To quantify the risk of laminitis posed by intra-synovial triamcinolone acetonide (TA) administration in a mixed population of horses. Study design: Retrospective observational cohort study. Methods: Clinical records of horses registered with one large UK equine practice were reviewed retrospectively to identify all horses receiving intra-synovial TA treatment between 1 January 2007 and 31 December 2017. 1,510 horses were selected and records investigated for incidence of laminitis over a 4-month period following treatment. For each TA-treated horse, an untreated horse, individually matched by age, sex, date of treatment and client type, was selected from the clinical records. Untreated horses were then investigated for laminitis over the same 4-month period. Data was analysed in a 2×2 contingency table using Fisher’s exact test. Results: 489 horses were lost to follow-up and 55 horses were excluded, leaving 966 treated and matched, untreated horses. The incidence of laminitis over the 4-month study period in both groups was identical: 3/966 horses (0.31%) (95% C.I. [0.08%, 0.91%]), equivalent to 0.93 cases per 100 horses per year (P >0.9). Main limitations: Retrospective study; large proportion (489/1510) of horses lost to follow-up; large proportion of study population were racehorses; selection method resulted in disproportionate selection of horses born before 2013; similar incidence between groups may reflect existing risk-based selection by clinicians. Conclusions: Intra-synovial triamcinolone acetonide administration does not increase the risk of laminitis in this study population

Intrasynovial triamcinolone treatment is not associated with incidence of acute laminitis

Background: Intra-synovial corticosteroid injections are commonly used in the treatment of equine orthopaedic disease, but corticosteroid administration is widely considered a risk factor for the development of laminitis. Despite a list of putative mechanisms and a number of case reports of steroid-induced laminitis, no case-control or cohort studies investigating the association between use of intra-synovial corticosteroids and acute laminitis have been published. Objectives: To quantify the risk of laminitis posed by intra-synovial triamcinolone acetonide (TA) administration in a mixed population of horses. Study design: Retrospective observational cohort study. Methods: Clinical records of horses registered with one large UK equine practice were reviewed retrospectively to identify all horses receiving intra-synovial TA treatment between 1 January 2007 and 31 December 2017. 1,510 horses were selected and records investigated for incidence of laminitis over a 4-month period following treatment. For each TA-treated horse, an untreated horse, individually matched by age, sex, date of treatment and client type, was selected from the clinical records. Untreated horses were then investigated for laminitis over the same 4-month period. Data was analysed in a 2×2 contingency table using Fisher’s exact test. Results: 489 horses were lost to follow-up and 55 horses were excluded, leaving 966 treated and matched, untreated horses. The incidence of laminitis over the 4-month study period in both groups was identical: 3/966 horses (0.31%) (95% C.I. [0.08%, 0.91%]), equivalent to 0.93 cases per 100 horses per year (P >0.9). Main limitations: Retrospective study; large proportion (489/1510) of horses lost to follow-up; large proportion of study population were racehorses; selection method resulted in disproportionate selection of horses born before 2013; similar incidence between groups may reflect existing risk-based selection by clinicians. Conclusions: Intra-synovial triamcinolone acetonide administration does not increase the risk of laminitis in this study population