The Keap1/Nrf2 pathway in health and disease:from the bench to the clinic

The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, with gene called NFE2L2) is a master regulator of the antioxidant response. In the last decade, interest has intensified in this research area as its importance in several physiological and pathological processes has become widely recognized; these include redox signalling and redox homoeostasis, drug metabolism and disposition, intermediary metabolism, cellular adaptation to stress, chemoprevention and chemoresistance, toxicity, inflammation, neurodegeneration, lipogenesis and aging. Regulation of Nrf2 is complex and although much attention has focussed on its repression by Kelch-like ECH-associated protein-1 (Keap1), recently it has become increasingly apparent that it is also controlled by cross-talk with other signalling pathways including the glycogen synthase kinase-3 (GSK-3) - β-transducin repeat-containing protein (β-TrCP) axis, ERAD (endoplasmic reticulum-associated degradation)-associated E3 ubiquitin-protein ligase (Hrd1, also called synoviolin), nuclear factor-kappa B (NF-κB), Notch and AMP kinase. Due to its beneficial role in several diseases, Nrf2 has become a major therapeutic target, with novel natural, synthetic and targeted small molecules currently under investigation to modulate the pathway and in clinical trials.</p

Exploring International Differences in Rates of Return to Education: Evidence from EU SILC. ESRI WP311, September 2009

This paper uses EU-SILC data from 2005 and 2006 to explore the hypothesis that international differences in rates of return to education reflect variations in the level of risk associated with educational investments. While there was some evidence to support this hypothesis with regards to returns to ISCED level 5 qualifications among males, the majority of the variation in international returns was related to distributional impacts. The results suggest that higher rates of return to more advanced qualifications relate to more dispersed distributions among poorly qualified workers which, in turn, raise the returns to credentials further up the educational spectrum

Explaining International Differences in Rates of Overeducation in Europe. ESRI WP365, December 2010

This paper examines the factors determining variations in international rates of overeducation. We find significant effects for a range of factors including labour market structural imbalances, risk, trade-union density and the structure of academic funding. The results suggest that international levels of overeducation are particularly sensitive to variations in higher education funding arrangements

Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction

The Nrf2/Keap1 interaction is a target in the development of new therapeutic agents, where inhibition of the interaction activates Nrf2 and leads to the generation of downstream anti-inflammatory effects. Peptides that mimic the β-turn in the Keap1 active site and are constrained by a disulfide bridge have high affinity for Keap1 but no intracellular activity. The introduction of a perfluoroalkyl- bridging group to constrain the peptides, coupled with glutamic acid to proline replacement leads to a new peptide with a Ki of 6.1 nM for the Nrf2/Keap1 binding interaction, although this does not translate into intracellular activity

Cardiovascular Mechanisms of Action of Anthocyanins May Be Associated with the Impact of Microbial Metabolites on Heme Oxygenase-1 in Vascular Smooth Muscle Cells

Anthocyanins are reported to have cardio-protective effects, although their mechanisms of action remain elusive. We aimed to explore the effects of microbial metabolites common to anthocyanins and other flavonoids on vascular smooth muscle heme oxygenase-1 (HO-1) expression. Thirteen phenolic metabolites identified by previous anthocyanin human feeding studies, as well as 28 unique mixtures of metabolites and their known precursor structures were explored for their activity on HO-1 protein expression in rat aortic smooth muscle cells (RASMCs). No phenolic metabolites were active when treated in isolation; however, five mixtures of phenolic metabolites significantly increased HO-1 protein expression (127.4-116.6%, p ≤ 0.03). The present study demonstrates that phenolic metabolites of anthocyanins differentially affect HO-1 activity, often having additive, synergistic or nullifying effects

Enfortumab Vedotin and Pembrolizumab as Monotherapies and Combination Treatment in Locally Advanced or Metastatic Urothelial Carcinoma : A Narrative Review

Funding Information: Supported by the National Cancer Institute of the National Institutes of Health under Award No. K12CA076917 (C.J.H.). Supported in part by National Cancer Institute Cancer Center Support grant No. P30 CA008748.Peer reviewedPublisher PD

Ruthenium carbamoyl complexes: coordination chemistry and CO release

Reaction of Ru(CO) 4Br 2 with a series of heterocyclic amines leads to a family of ruthenium carbamoyl complexes. These are analogous to the related ferracyclic systems reported by us as potential photoCORM systems (Chem. Commun., 2020, 56, 4300–4303). In contrast to the iron compounds, the ruthenium carbamoyls release CO only when irradiated in the UV, and show no activity as anti-inflammatory agents

Evolution of the HIV-1 nef gene in HLA-B*57 Positive Elite Suppressors

Elite controllers or suppressors (ES) are HIV-1 infected patients who maintain viral loads of < 50 copies/ml without antiretroviral therapy. CD8+ T cells are thought to play a key role in the control of viral replication and exert selective pressure on gag and nef in HLA-B*57 positive ES. We previously showed evolution in the gag gene of ES which surprisingly was mostly due to synonymous mutations rather than non-synonymous mutation in targeted CTL epitopes. This finding could be the result of structural constraints on Gag, and we therefore examined the less conserved nef gene. We found slow evolution of nef in plasma virus in some ES. This evolution is mostly due to synonymous mutations and occurs at a rate similar to that seen in the gag gene in the same patients. The results provide further evidence of ongoing viral replication in ES and suggest that the nef and gag genes in these patients respond similarly to selective pressure from the host

Peptide directed phthalocyanine-gold nanoparticles for selective photodynamic therapy of EGFR overexpressing cancers

Gold nanoparticles, covalently functionalised with the photosensitiser C11Pc and PEG, were actively targeted towards epidermal growth factor receptor overexpressing cancers using the peptide FITC-βAAEYLRK. Selective phototoxicity was observed at nanomolar concentrations with minimal dark toxicity