Selective activation of oxidized PTP1B by the thioredoxin system modulates PDGF-ß receptor tyrosine kinase signaling

The inhibitory reversible oxidation of protein tyrosine phosphatases (PTPs) is an important regulatory mechanism in growth factor signaling. Studies on PTP oxidation have focused on pathways that increase or decrease reactive oxygen species levels and thereby affect PTP oxidation. The processes involved in reactivation of oxidized PTPs remain largely unknown. Here the role of the thioredoxin (Trx) system in reactivation of oxidized PTPs was analyzed using a combination of in vitro and cell-based assays. Cells lacking the major Trx reductase TrxR1 (Txnrd1-/-) displayed increased oxidation of PTP1B, whereas SHP2 oxidation was unchanged. Furthermore, in vivo-oxidized PTP1B was reduced by exogenously added Trx system components, whereas SHP2 oxidation remained unchanged. Trx1 reduced oxidized PTP1B in vitro but failed to reactivate oxidized SHP2. Interestingly, the alternative TrxR1 substrate TRP14 also reactivated oxidized PTP1B, but not SHP2. Txnrd1-depleted cells displayed increased phosphorylation of PDGF-ß receptor, and an enhanced mitogenic response, after PDGF-BB stimulation. The TrxR inhibitor auranofin also increased PDGF-ß receptor phosphorylation. This effect was not observed in cells specifically lacking PTP1B. Together these results demonstrate that the Trx system, including both Trx1 and TRP14, impacts differentially on the oxidation of individual PTPs, with a preference of PTP1B over SHP2 activation. The studies demonstrate a previously unrecognized pathway for selective redox-regulated control of receptor tyrosine kinase signaling

Clinical relevance of biomarkers of oxidative stress

SIGNIFICANCE Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. CRITICAL ISSUES The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. FUTURE DIRECTIONS Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 00, 000-000

Queen Elizabeth’s Leadership Abroad: The Netherlands in the 1570s

In 1576, after Edmund Grindal, archbishop of Canterbury, presumed to lecture Queen Elizabeth on the importance of preaching and on her duty to listen to such lectures, his influence diminished precipitously, and leadership of the established English church fell to Bishop Aylmer. Grindal’s friends on the queen’s Privy Council, “forward” Calvinists (or ultra-Protestants), were powerless to save him from the consequences of his indiscretion, which damaged the ultras’ other initiatives’ chances of success. This paper concerns one of those initiatives. From the late 1560s, they urged their queen “actively” to intervene in the Dutch wars. They collaborated with Calvinists on the Continent who befriended Prince William of Orange and who hoped to help him hold together a coalition of religiously reformed and Roman Catholic insurgents in the seventeen provinces of the Low Countries. The English ultra-Protestants would have their government send money, munitions, and men in arms to the Netherlands, to tip the balance against viceroys sent by King Philip II of Spain. Grindal’s setback undermined the English Calvinists’ efforts to form an Anglo-Dutch alliance which, they assumed, would boost the prospects for an international Protestant league. Yet Elizabeth did assist the Dutch as they wrestled with decisions forced on them by developments in the Netherlands during the 1570s, and she did so more consistently and more cleverly than many historians of Tudor diplomacy have thought. Two competing assessments determine the way questions are formulated in the study of the queen’s and regime’s Dutch diplomacy. The general consensus is that she was indecisive and inconsistent. Paul Hammer characterizes Elizabeth’s responses to the crises in the Low Countries as a “zigzag of different” (“even contradictory”) maneuvers. Wallace McCaffrey and R. B. Wernham agree that England’s “hesitations and gyrations” do not pass as coherent, creditable policy. Charles Wilson scolds Elizabeth for being timid and tepid--incapable of enthusiasm for “a great cause.” But David J.B. Trim’s striking counterthrust depicts the queen’s overtures to Netherlanders as part of her courageous – and “confessionally driven” – foreign policy; Trim replaces “hesitation” and “zigzag” with a coherent “Protestant programme of action prioritized by the Elizabethan government” with the aim of improving prospects for “Calvinist internationalism.” What follows is an alternative to all these characterizations, one that, as noted, finds evidence for greater consistency and coherence in Elizabeth’s leadership and less confessional “drive.” That she would have been uneasy around religious extremists ought not to astonish us; her father’s, step-brother’s, and step-sister’s reigns as well as the start of her own were disturbed by zealous subjects, who were bent on shoring up or dismantling the realm’s religious settlements

Adipose tissue concentrations of non-persistent environmental phenols and local redox balance in adults from Southern Spain

The aim was to evaluate the associations of environmental phenol and paraben concentrations with the oxidative microenvironment in adipose tissue. This study was conducted in a subsample (n=144) of the GraMo cohort (Southern Spain). Concentrations of 9 phenols and 7 parabens, and levels of oxidative stress biomarkers were quantified in adipose tissue. Associations were estimated using multivariable linear regression analyses adjusted for potential confounders. Benzophenone-3 (BP-3) concentration was borderline associated with enhanced glutathione peroxidase (GPx) activity [exp(β)=1.20, p=0.060] and decreased levels of reduced glutathione (GSH) [exp(β)=0.55, p=0.070]. Concentrations of bisphenol A (BPA) and methylparaben (MeP) were associated to lower glutathione reductase (GRd) activity [exp(β)=0.83, exp(β)=0.72, respectively], and BPA was borderline associated to increased levels of oxidized glutathione (GSSG) [exp(β)=1.73, p-value=0.062]. MeP was inversely associated to both hemeoxygenase-1 (HO-1) and superoxide dismustase (SOD) activity, as well as to the levels of thiobarbituric acid reactive substances (TBARS) [0.75 < exp(β) < 0.79]. Our results suggest that some specific non-persistent pollutants may be associated with a disruption of the activity of relevant antioxidant enzymes, in addition to the depletion of the glutathione stock. They might act as a tissue-specific source of free radicals, contributing to the oxidative microenvironment in the adipose tissue.This research was supported in part by research grants from the European Union Commission (H2020-EJP-HBM4EU and SOE1/P1/F0082), Biomedical Research Networking Center-CIBER de Epidemiología y Salud Pública (CIBERESP), from the Institute of Health Carlos III, supported by European Regional Development Fund/FEDER (FIS-PI13/02406, FISPI14/ 00067, FIS-PI16/01820, FIS-PI16/01812, FIS-PI16/01858 and FIS-PI17/01743), and from the Consejería de Salud, Junta de Andalucía (PS-0506-2016). Funding for the equipment used was provided by Velux Fonden, Augustinus Fonden and Svend Andersen Fonden. The authors thank Kirsten og Freddy Johansens Fond and the International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC, Rigshospitalet, Copenhagen University) for economic support. Dr. Juan Pedro Arrebola is under contract within Ramón y Cajal Program (Ministerio de Economía, Industria y Competitividad de España, RYC-2016-20155)

Anglo-Dutch translations of medical and scientific texts

In the seventeenth century the use of vernacular languages became more and more accepted in scientific publications and communications, and began to supplement the traditional language in this field, namely: Latin. The increase in the number of languages used in science and medicine was accompanied by a heightened need for translators. The close relationship between England and the Low Countries in the seventeenth century has led to a focus in the existing research on political and religious issues, and this has been reflected in the study of translations between English and Dutch. Yet one also finds in the fields of medicine and science an exchange of ideas through translation. The language skills of both Dutch and English men and women were often not sufficient to understand each other's language, which means that translations were vital. By considering the examples of how Thomas Browne's Religio medici was translated into Dutch, and how letters by Antoni van Leeuwenhoek and a publication by Jan Baptista van Helmont were translated into English, this essay examines the exchange of scientific and medical ideas across the Channel.Part of this article was written during a visiting fellowship in the Summer of 2016 at the Max Planck Institute for the History of Science in Berlin, and I would like to thank the MPIWG and the Global Knowledge Society Project for hosting me, as well as the Making Visible Project (Arts and Humanities Research Council, grant number AH/M001928/1) for providing me with support and the time to write

DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity

A História da Alimentação: balizas historiográficas

Os M. pretenderam traçar um quadro da História da Alimentação, não como um novo ramo epistemológico da disciplina, mas como um campo em desenvolvimento de práticas e atividades especializadas, incluindo pesquisa, formação, publicações, associações, encontros acadêmicos, etc. Um breve relato das condições em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biológica, a econômica, a social, a cultural e a filosófica!, assim como da identificação das contribuições mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histórica, foi ela organizada segundo critérios morfológicos. A seguir, alguns tópicos importantes mereceram tratamento à parte: a fome, o alimento e o domínio religioso, as descobertas européias e a difusão mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rápido balanço crítico da historiografia brasileira sobre o tema