A pharmacological organization of G protein–coupled receptors

Protein classification typically uses structural, sequence, or functional similarity. Here we introduce an orthogonal method that organizes proteins by ligand similarity, focusing here on the class A G protein-coupled receptor (GPCR) protein family. Comparing a ligand-based dendogram to a sequence-based one, we sought examples of GPCRs that were distantly linked by sequence but neighbors by ligand similarity. Experimental testing of compounds predicted to link three of these new pairs confirmed the predicted association, with potencies ranging from the low-nanomolar to low-micromolar. We then identified hundreds of non-GPCRs closely related to GPCRs by ligand similarity, including the CXCR2 chemokine receptor to Casein kinase I, the cannabinoid receptors to epoxide hydrolase 2, and the α2 adrenergic receptor to phospholipase D. These, too, were confirmed experimentally. Ligand similarities among these targets may reflect a chemical integration in the time domain of molecular signaling

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...Comment: 159 pages, including 9 Figs and 2184 reference

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Cardiovascular depression secondary to ionic hypocalcemia during hepatic transplantation in humans

Cardiovascular function, serum ionized calcium (Ca2+), and serum citrate were measured intraoperatively in patients (n = 9) undergoing orthotopic hepatic homotransplantation. Serum citrate increased 20-fold (P < 0.0006) following transfusion of citrated blood products in the absence of a functional liver. Serum ionized calcium decreased (P < 0.003) with concomitant decreases in cardiac index (P < 0.005), stroke index (P < 0.004), and left ventricular stroke work index (P < 0.001). Hemodynamic depression and ionic hypocalcemia were reversed following the administration of CaCl2. In contrast to patients with normal hepatic function, who may tolerate large amounts of citrated blood, patients with end-stage liver disease demonstrate acute ionic hypocalcemia with concomitant hemodynamic depression when receiving citrated blood products during the course of hepatic transplantation

Biomass composition of Arthrospira platensis during cultivation on industrial process water and harvesting

Microalgae have the ability to utilize nutrients from wastewater and use it for biomass production. The effluent from a biogas process was tested as a nutrient source for blue-green microalga Arthrospira platensis cultivation and compared with conventional synthetic medium. Cultivation was carried out in four different concentrations of industrial process water (25, 50, 75, and 100%). The biomass was then harvested by microfiltration, and centrifugation followed by freeze drying. Variations in biomass composition were studied, in order to investigate effects of industrial process water on A. platensis over 30 days of cultivation. Applied harvesting techniques were evaluated for their effect on physiochemical properties of the biomass. Arthrospira platensis was able to grow in all tested wastewater concentrations except 100%, however, increase of wastewater concentration in medium resulted in a decreased growth rate. Partial substitution of synthetic Zarrouk medium with 25% of wastewater showed no adverse effect on chemical composition of the biomass including high protein content (45–58% dry weight) and favorable fatty acid composition (42–45% PUFAs of total fatty acids). Evaluation by optical microscopy showed that microfiltration caused cell rupture at the moderate level while centrifugation had more severe effect on A. platensis. Effect of centrifugal forces and shear stress on A. platensis cells was confirmed by detecting lower lipid content in samples after applying both microfiltration and centrifugation due to cell content leakage