,8-IMINAZOLYLETHYLAMINE is the amine which is produced when carbon dioxide is split off from histidine. It was first prepared synthetically by Windaus and Vogt'. Recently Ackermann2 obtained a large yield of the base by submitting histidine to the action of putrefactive organisms. It has been shown that several of the amines thus related to amino-acids possess marked physiological activity. The activity of j8-iminazolylethylamine was discovered in the course of the investigation of ergot and its extracts by G. Barger and one of us3, who attributed this structure to a base which they obtained, and which in minute doses produced tonic contraction of the uterus. The synthetic substance, and the base produced by splitting off carbon dioxide from histidine by bacterial action or by chemical means, were found to have an identical action. Meanwhile Kutscher4 had simultaneously and independently described the isolation from ergot of a base having this action and presumably identical with that obtained by Barger and Dale. By its chemical properties this first ergot base of Kutscher was not distinguishable from 8-iminazolylethylamine; but certain apparent differences in the physiological action of the two bases, observed by Ackermann and Kutscber-5, led them to the conclusion that the ergot base, though closely related to 8-iminazolylethylamine, is not identical with it. The alleged difference in action, on the existence and cause of which our experiments throw light, was as follows: the

The physiological action of β-iminazolylethylamine

https://link.springer.com/content/pdf/10.1016%2Fj.nurt.2010.07.002.pdf

Role of microglia in neurotrauma

Alternatively activated microglia and macrophages in the central nervous system.

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation.

/pdf/iron-behaving-badly-inappropriate-iron-chelation-as-a-major-229l082exr.pdf

Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is not fully understood. As the liver is both a major target of insulin signalling and critically involved in glucose metabolism, the aim of this study was to examine the role of GPR21 in the regulation of glucose uptake and production in human hepatocytes. In particular, HepG2 cells, which express GPR21, were adopted as cellular models. Compared with untreated cells, a significant increase in glucose uptake was measured in cells treated with siRNA to downregulate GPR21 expression or with the GPR21-inverse agonist, GRA2. Consistently, a significantly higher membrane translocation of GLUT-2 was measured under these conditions. These effects were accompanied by an increased ratio of phAKT(Ser473)/tot-AKT and phGSK-3β(Ser9)/tot-GSK-3β, thus indicating a marked activation of the insulin signalling pathway. Moreover, a significant reduction in ERK activation was observed with GPR21 inhibition. Collectively, these results indicate that GPR21 mediates the negative effects on glucose uptake by the liver cells. In addition, they suggest that the pharmacological inhibition of GPR21 could be a novel strategy to improve glucose homeostasis and counteract hepatic insulin resistance.

GPR21 Inhibition Increases Glucose-Uptake in HepG2 Cells

Histamine and the Kidney: In Vivo Animal Models

Methodological Approaches to Study Histamine Pharmacology in the Kidney: From Cell Culture and Cell Imaging to Functional Assays and Electron Microscopy

In light of the recent worldwide emergency caused by the coronavirus disease (COVID-19), it has become even more urgent that we solve unmet medical needs (UMNs). The COVID-19 pandemic has placed national health systems, as well as scientific research communities under enormous pressures in terms of drug repositioning, which is considered to be the quickest possible transition from bench to bedside for UMNs (Singh et al., 2020). Conceived before the pandemic occurred, this Research Topic is topical and relevant to this context but does not fully address the pitfalls of COVID-19 management. As many working in this area are aware, the larger the disease burden, the greater the degree to which important needs are not met. Consistently, clinical testing and the approval of new medicines involves an accelerated authorization procedure. According to the article 4 paragraph 2 of the Commission Regulation EC (No. 507/2006 of 29 March 2006), the conditional authorization of medicinal products for human use (falling within the scope of Regulation, EC No. 726/2004 of the European Parliament and the Council UMN) takes place when there is “a condition for which there exists no satisfactory method of diagnosis, prevention or treatment in the Union or, even if such a method exists, in relation to which the medicinal product concerned will be of major therapeutic advantage to those affected”. This topic is focused around a review by Scavone et al. entitled “The New Paradigms in Clinical Research: From Early Access Programs to the Novel Therapeutic Approaches for Unmet Medical Needs”, an extended review which describes the regulatory framework and the more importantly, criticism of new drugs covering UMNs. The other 16 papers in this Research Topic include reviews and research papers which cover an apparent and high heterogeneity of subjects. This collection aims to reflect on a number of important UMNs in different medical areas, to address the lack of a real consensus on the definition and interpretation of UMN (Vreman et al., 2019). Consistently, a search on PubMed.gov using the keyword “unmet therapeutic needs” retrieves 5,100 results, with a variety of specific therapeutic areas that reflect the complexity of the topic. The above definition of UMN includes the concept of “satisfactory method” or, in other words, “adequate treatment” and “major therapeutic advantage”, also meaning “significant benefit”. This implies: (i) a degree of disease severity or burden; (ii) a lack of effective drugs; (iii) the existence of non-responders among the treated patients; (iv) poor adherence to the prescribed regimen affecting the extent of

/pdf/editorial-the-challenge-of-new-therapeutic-approaches-for-2b1ulevsif.pdf

Arianna Carolina Rosa

Papers

GPR21 Inhibition Increases Glucose-Uptake in HepG2 Cells

Histamine and the Kidney: In Vivo Animal Models

Methodological Approaches to Study Histamine Pharmacology in the Kidney: From Cell Culture and Cell Imaging to Functional Assays and Electron Microscopy

Editorial: The Challenge of New Therapeutic Approaches for Unmet Therapeutic Needs.