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Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications.
The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions
Hepatic cytochromes P450: structural degrons and barcodes, posttranslational modifications and cellular adapters in the ERAD-endgame.
The endoplasmic reticulum (ER)-anchored hepatic cytochromes P450 (P450s) are enzymes that metabolize endo- and xenobiotics i.e. drugs, carcinogens, toxins, natural and chemical products. These agents modulate liver P450 content through increased synthesis or reduction via inactivation and/or proteolytic degradation, resulting in clinically significant drug-drug interactions. P450 proteolytic degradation occurs via ER-associated degradation (ERAD) involving either of two distinct routes: Ubiquitin (Ub)-dependent 26S proteasomal degradation (ERAD/UPD) or autophagic lysosomal degradation (ERAD/ALD). CYP3A4, the major human liver/intestinal P450, and the fast-turnover CYP2E1 species are degraded via ERAD/UPD entailing multisite protein phosphorylation and subsequent ubiquitination by gp78 and CHIP E3 Ub-ligases. We are gaining insight into the nature of the structural determinants involved in CYP3A4 and CYP2E1 molecular recognition in ERAD/UPD [i.e. K48-linked polyUb chains and linear and/or "conformational" phosphodegrons consisting either of consecutive sequences on surface loops and/or disordered regions, or structurally-assembled surface clusters of negatively charged acidic (Asp/Glu) and phosphorylated (Ser/Thr) residues, within or vicinal to which, Lys-residues are targeted for ubiquitination]. Structural inspection of select human liver P450s reveals that such linear or conformational phosphodegrons may indeed be a common P450-ERAD/UPD feature. By contrast, although many P450s such as the slow-turnover CYP2E1 species and rat liver CYP2B1 and CYP2C11 are degraded via ERAD/ALD, little is known about the mechanism of their ALD-targeting. On the basis of our current knowledge of ALD-substrate targeting, we propose a tripartite conjunction of K63-linked Ub-chains, P450 structural "LIR" motifs and selective cellular "cargo receptors" as plausible P450-ALD determinants
Onstage and off: The shifting relevance of gender in womenâs prisons
uncorrected proofEven though international research on menâs prisons is no longer oblivious to gender, approaches to womenâs prisons have tended to be more gender-bound as a whole. Besides having informed a specific reflexive agenda of representation, the angle of gender has presided to most research issues as an analytical overall parti pris: from the gendered nature of prison regimes to the gendered character of prison cultures, socialities and âpains of imprisonmentâ. This more âgendercentricâ agenda is however becoming more diversified for theoretical and empirical reasons alike. These involve a recognition of the diversity of women prisonersâ experiences and identities, and an attention to a wider variety of aspects of carceral life. Drawing on field approaches to the Portuguese carceral world spanning three decades, I propose to take this debate further by focusing on contextual shifts in the actual saliency of gender as a category of identity and social life in womenâs prisons.(undefined)(undefined)info:eu-repo/semantics/publishedVersio
Clinical outcome of protein-energy malnourished patients in a Brazilian university hospital
Nutritional risk in hospitalized patients: impact of nutritional status on serum prealbumin
Design and development of a prototype electrotherapy device
This article describes a complete prototype system that can be used in electrotherapy treatments, that is, in medical treatments involving electric currents. The system is composed of two main blocks: the master and the slave. The Master block, whose main component is a CPU, controls the user interface. The Slave block, which is composed of a microcontroller and a wave generator, produces the appropriated voltages and currents compatible with the desired treatment. The whole system is powered by a 12 V power supply and the output signal voltage ranges between -100 V and 100 V. Despite the prototype being able of performing all the electrotherapy treatments in the low-medium frequency ranges, it was tested in aesthetic mesotherapy, namely in anticellulite, located anticellulite, antistretch, and antiflaccidity. In these treatments, the output signal is composed of an overlap of two frequencies: the first one is selected in the range of 1.2 kHz - 1.8 kHz and the second in the range of 0.07 Hz - 2 Hz. The system was tested in a clinical environment with real patients. It showed good results both in effectiveness of treatments and in terms of pain suffered by the patients.(undefined
Prevalence and determinants of sunbed use in thirty European countries : data from the Euromelanoma skin cancer prevention campaign
Management of Montados and Dehesas for High Nature Value: an interdisciplinary pathway
Fabrication and characterization of Eri silk fibers-based sponges for biomedical application
Cocoon-derived semi-domesticated Eri silk fibers still lack exploitation for tissue engineering applications due to their poor solubility using conventional methods. The present work explores the ability to process cocoon fibers of non-mulberry Eri silk (Samia/Philosamia ricini) into sponges through a green approach using ionic liquid (IL) Ăą 1-buthyl-imidazolium acetate as a solvent. The formation of ĂÂČ-sheet structures during Eri silk/IL gelation was acquired by exposing the Eri silk/IL gels to a saturated atmosphere composed of two different solvents: (i) isopropanol/ethanol (physical stabilization) and (ii) genipin, a natural crosslinker, dissolved in ethanol (chemical crosslinking). The sponges were then obtained by freeze-drying. This approach promotes the formation of both stable and ordered non-crosslinked Eri silk fibroin matrices. Moreover, genipin-crosslinked silk fibroin sponges presenting high height recovery capacity after compression, high swelling degree and suitable mechanical properties for tissue engineering applications were produced. The incorporation of a model drug Ăą ibuprofen Ăą and the corresponding release study from the loaded sponges demonstrated the potential of using these matrices as effective drug delivery systems. The assessment of the biological performance of ATDC5 chondrocyte-like cells in contact with the developed sponges showed the promotion of cell adhesion and proliferation, as well as extracellular matrix production within two weeks of culture. SpongesĂą intrinsic properties and biological findings open up their potential use for biomedical applications.The authors SSS, DSC, MBO, NMO acknowledge financial support
from Portuguese Foundation for Science and Technology â
FCT (Grants SFRH/BPD/45307/2008, SFRH/BPD/85790/2012,
SFRH/BD/71396/2010 and SFRH/BD/73172/2010, respectively),
ââFundo Social Europeuâ â FSE, and ââPrograma Diferencial de Potencial
Humano POPHâ. This work is also financially supported by the European Union Seventh Framework Programme (FP7/2007-2013)
under grant agreement n REGPOT-CT2012-316331-POLARIS and
from Fundação para a CiĂȘncia e Tecnologia (FCT) through the project
ENIGMA â PTDC/EQU-EPR/121491/2010. The laboratory work
of SCK is supported by Department of Biotechnology and Indian
Council of Medical Research, Govt of India. SCK and RLR acknowledge
their short visits either Institutes. SCK is also grateful to 3BÂŽ s
Research Group- Biomaterials, Biodegradables and Biomimetics,
University of Minho, Portugal for providing facilities during his
short visit
Observation of associated near-side and away-side long-range correlations in âsNN=5.02ââTeV proton-lead collisions with the ATLAS detector
Two-particle correlations in relative azimuthal angle (ÎÏ) and pseudorapidity (Îη) are measured in âsNN=5.02ââTeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1ââÎŒb-1 of data as a function of transverse momentum (pT) and the transverse energy (ÎŁETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Îη|<5) ânear-sideâ (ÎÏâŒ0) correlation that grows rapidly with increasing ÎŁETPb. A long-range âaway-sideâ (ÎÏâŒÏ) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ÎŁETPb, is found to match the near-side correlation in magnitude, shape (in Îη and ÎÏ) and ÎŁETPb dependence. The resultant ÎÏ correlation is approximately symmetric about Ï/2, and is consistent with a dominant cosâĄ2ÎÏ modulation for all ÎŁETPb ranges and particle pT
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