Oxidative stress-related diseases underlie many if not all of the major leading causes of death in United States and the Western World. Thus, enormous interest from both academia and pharmaceutical ...industry has been placed on the development of agents which attenuate oxidative stress. With that in mind, great efforts have been placed in the development of inhibitors of NADPH oxidase (Nox), the major enzymatic source of reactive oxygen species and oxidative stress in many cells and tissue. The regulation of a catalytically active Nox enzyme involves numerous protein-protein interactions which, in turn, afford numerous targets for inhibition of its activity. In this review, we will provide an updated overview of the available Nox inhibitors, both peptidic and small molecules, and discuss the body of data related to their possible mechanisms of action and specificity towards each of the various isoforms of Nox. Indeed, there have been some very notable successes. However, despite great commitment by many in the field, the need for efficacious and well-characterized, isoform-specific Nox inhibitors, essential for the treatment of major diseases as well as for delineating the contribution of a given Nox in physiological redox signalling, continues to grow.
The last three decades have witnessed the emergence of a new species of capitalism. In spite of marked differences between its national varieties, a common characteristic of this species can be found ...in the global monopolisation of knowledge. This monopolisation involves hierarchical relations among firms and between capital and labour, because the capital of some firms includes the exclusive ownership of much of the knowledge used in production. Since the 1994 Trade-Related Aspects of Intellectual Property Rights agreements, the growing commoditisation of knowledge has extended the role of closed science and closed markets at the expense of open science and open markets. The intrinsic long-term dynamics of this species of capitalism is increasingly characterised by financialisation, inequality and stagnation. In order to exit from the current crisis, we must change many features of intellectual monopoly capitalism and rely on an eclectic approach that draws insights from liberal, Keynesian and Marxian traditions.
Vascular hyperproliferative disorders are characterized by excessive smooth muscle cell (SMC) proliferation leading to vessel remodeling and occlusion. In pulmonary arterial hypertension (PAH), SMC ...phenotype switching from a terminally differentiated contractile to synthetic state is gaining traction as our understanding of the disease progression improves. While maintenance of SMC contractile phenotype is reportedly orchestrated by a MEF2C-myocardin (MYOCD) interplay, little is known regarding molecular control at this nexus. Moreover, the burgeoning interest in microRNAs (miRs) provides the basis for exploring their modulation of MEF2C-MYOCD signaling, and in turn, a pro-proliferative, synthetic SMC phenotype. We hypothesized that suppression of SMC contractile phenotype in pulmonary hypertension is mediated by miR-214 via repression of the MEF2C-MYOCD-leiomodin1 (LMOD1) signaling axis.
In SMCs isolated from a PAH patient cohort and commercially obtained hPASMCs exposed to hypoxia, miR-214 expression was monitored by qRT-PCR. miR-214 was upregulated in PAH- vs. control subject hPASMCs as well as in commercially obtained hPASMCs exposed to hypoxia. These increases in miR-214 were paralleled by MEF2C, MYOCD and SMC contractile protein downregulation. Of these, LMOD1 and MEF2C were directly targeted by the miR. Mir-214 overexpression mimicked the PAH profile, downregulating MEF2C and LMOD1. AntagomiR-214 abrogated hypoxia-induced suppression of the contractile phenotype and its attendant proliferation. Anti-miR-214 also restored PAH-PASMCs to a contractile phenotype seen during vascular homeostasis.
Our findings illustrate a key role for miR-214 in modulation of MEF2C-MYOCD-LMOD1 signaling and suggest that an antagonist of miR-214 could mitigate SMC phenotype changes and proliferation in vascular hyperproliferative disorders including PAH.
Precision medicine in oncology requires not only identification of cancer-associated mutations but also effective drugs for each cancer genotype, which is still a largely unsolved problem. One ...approach for the latter challenge has been large-scale testing of small molecules in genetically characterized cell lines. We hypothesized that compounds with high cell-line-selective lethality exhibited consistent results across such pharmacogenomic studies. We analyzed the compound sensitivity data of 6,259 lethal compounds from the NCI-60 project. A total of 2,565 cell-line-selective lethal compounds were identified and grouped into 18 clusters based on their median growth inhibitory GI50 profiles across the 60 cell lines, which were shown to represent distinct mechanisms of action. Further transcriptome analysis revealed a biomarker, NADPH abundance, for predicting sensitivity to ferroptosis-inducing compounds, which we experimentally validated. In summary, incorporating cell-line-selectivity filters improves the predictive power of pharmacogenomic analyses and enables discovery of biomarkers that predict the sensitivity of cells to specific cell death inducers.
Display omitted
•Cell-line-selective lethal compounds are consistent across pharmacogenomic studies•Compounds with distinct sensitivity profiles indicate distinct mechanisms of action•The GI50 profiles of ferroptosis inducers are cell-line selective and unique•Basal NADP(H) level correlates with sensitivity to ferroptosis inducers
Large-scale compound profiling across cancer cell lines has been of interest, but discrepancies between different projects have been suggested. The methodology of Shimada et al. allows for consistent analyses of such data and identifies robust biomarkers for drug sensitivity, including NADPH as a biomarker for ferroptosis-inducing compounds.
Interferon regulatory factor 7 (IRF7) was originally identified in the context of Epstein-Barr virus (EBV) infection, and has since emerged as the crucial regulator of type I interferons (IFNs) ...against pathogenic infections, which activate IRF7 by triggering signaling cascades from pathogen recognition receptors (PRRs) that recognize pathogenic nucleic acids. Moreover, IRF7 is a multifunctional transcription factor, underscored by the fact that it is associated with EBV latency, in which IRF7 is induced as well as activated by the EBV principal oncoprotein latent membrane protein-1 (LMP1). Aberrant production of type I IFNs is associated with many types of diseases such as cancers and autoimmune disorders. Thus, tight regulation of IRF7 expression and activity is imperative in dictating appropriate type I IFN production for normal IFN-mediated physiological functions. Posttranslational modifications have important roles in regulation of IRF7 activity, exemplified by phosphorylation, which is indicative of its activation. Furthermore, mounting evidence has shed light on the importance of regulatory ubiquitination in activation of IRF7. Albeit these exciting findings have been made in the past decade since its discovery, many questions related to IRF7 remain to be addressed.
"In Italy to Argentina: Travel Writing and Emigrant Colonialism, Tullio Pagano examines Italian emigration to Argentina and the Rio de la Plata region through the writings of Italian economists, ...poets, anthropologists, and political activists from the 1860s to the beginning of World War I. He shows that Italians played an important role in the so-called conquest of the desert, which led to Argentina's economic expansion and the suppression and killing of the remaining indigenous population. Many of the texts he discusses have hardly been studied before: from Paolo Mantegazza's real and imaginary travel narratives at the time of Italian unification to Gina Lombroso's descriptions of Brazil, Uruguay, and Argentina in early 1900s. Pagano questions the apparent opposition between diaspora and empire and argues that there was a continuity between the "peaceful conquest" through spontaneous emigration envisioned by Italian liberal intellectuals at the turn of the century and the military colonialism of Italian Nationalists and Fascists. He shows that racist assumptions about Native American and "creole" cultures were present in the work of progressive authors like Edmondo de Amicis, whose writings became enormously popular in Argentina, and anarchist militants and legal scholars like Pietro Gori, who founded the first revolutionary unions in Buenos Aires while remaining dangerously attached to Cesare Lombroso's theories of atavism and primitivism. The "growl" of Italian emigrants about to land in Argentina, found in Dino Campana's poem Buenos Aires (1907), echoes throughout Pagano's book, and encourages the reader to explore the apparent oxymoron of "emigration colonialism" and the role of literature and public media in the formation of our social imaginary."--
Present technologies for wastewater treatment do not sufficiently address the increasing pollution situation of receiving water bodies, especially with the growing use of personal care products and ...pharmaceuticals (PPCP) in the private household and health sector. The relevance of addressing this problem of organic pollutants was taken into account by the Directive 2013/39/EU that introduced (i) the quality evaluation of aquatic compartments, (ii) the
polluter pays
principle, (iii) the need for innovative and affordable wastewater treatment technologies, and (iv) the identification of pollution causes including a list of principal compounds to be monitored. In addition, a watch list of 10 other substances was recently defined by Decision 2015/495 on March 20, 2015. This list contains, among several recalcitrant chemicals, the painkiller diclofenac and the hormones 17β-estradiol and 17α-ethinylestradiol. Although some modern approaches for their removal exist, such as advanced oxidation processes (AOPs), retrofitting most wastewater treatment plants with AOPs will not be acceptable as consistent investment at reasonable operational cost. Additionally, by-product and transformation product formation has to be considered. The same is true for membrane-based technologies (nanofiltration, reversed osmosis) despite of the incredible progress that has been made during recent years, because these systems lead to higher operation costs (mainly due to higher energy consumption) so that the majority of communities will not easily accept them. Advanced technologies in wastewater treatment like membrane bioreactors (MBR) that integrate biological degradation of organic matter with membrane filtration have proven a more complete elimination of emerging pollutants in a rather cost- and labor-intensive technology. Still, most of the presently applied methods are incapable of removing critical compounds completely. In this opinion paper, the state of the art of European WWTPs is reflected, and capacities of single methods are described. Furthermore, the need for analytical standards, risk assessment, and economic planning is stressed. The survey results in the conclusion that combinations of different conventional and advanced technologies including biological and plant-based strategies seem to be most promising to solve the burning problem of polluting our environment with hazardous emerging xenobiotics.
In Italy to Argentina: Travel Writing and Emigrant Colonialism, Tullio Pagano examines Italian emigration to Argentina and the Rio de la Plata region through the writings of Italian economists, ...poets, anthropologists, and political activists from the 1860s to the beginning of World War I. He shows that Italians played an important role in the so-called conquest of the desert, which led to Argentina's economic expansion and the suppression and killing of the remaining indigenous population. Many of the texts he discusses have hardly been studied before: from Paolo Mantegazza’s real and imaginary travel narratives at the time of Italian unification to Gina Lombroso’s descriptions of Brazil, Uruguay, and Argentina in early 1900s. Pagano questions the apparent opposition between diaspora and empire and argues that there was a continuity between the “peaceful conquest” though spontaneous emigration envisioned by Italian liberal intellectuals at the turn of the century and the military colonialism of Italian Nationalists and Fascists. He shows that racist assumptions about Native American and “creole” cultures were present in the work of progressive authors like Edmondo de Amicis, whose writings became enormously popular in Argentina, and anarchist militants and legal scholars like Pietro Gori, who founded the first revolutionary unions in Buenos Aires while remaining dangerously attached to Cesare Lombroso’s theories of atavism and primitivism. The “growl” of Italian emigrants about to land in Argentina, found in Dino Campana’s poem Buenos Aires (1907), echoes throughout Pagano’s book, and encourages the reader to explore the apparent oxymoron of “emigration colonialism” and the role of literature and public media in the formation of our social imaginary. Italy to Argentina shows meticulous bibliographic work and is attentive to both fundamental and marginal texts in a double task, on the one hand, of textual analysis, and on the other, of rescuing and recovering a corpus forgotten by critics even when it is highly significant. It is, then, a research work that addresses the Italian emigration to Argentina from an original point of view, linking texts that have not been studied or that have not been sufficiently analyzed.” —Fernanda Elisa Bravo Herrera, author of Huellas y recorridos de una utopía: La emigración italiana en la Argentina ""From Boccadasse to La Boca. Tullio Pagano complexifies the relationship between ‘diaspora’ and ‘colonialism’ in the context of Italian migration to South America. In six thematic chapters, Pagano explores the thought of authors on and off the canon. Such diverse voices lead the reader to a new approach to the study of emigrant colonialism and creole studies, towards a deeper, more realistic understanding of the ‘conquest of the desert’ that Italian emigrants wanted to perform in Argentina.""—Giuseppe Gazzola, Stony Brook University
Reactive oxygen species (ROS) and oxidative stress have long been linked to aging and diseases prominent in the elderly such as hypertension, atherosclerosis, diabetes and atrial fibrillation (AF). ...NADPH oxidases (Nox) are a major source of ROS in the vasculature and are key players in mediating redox signalling under physiological and pathophysiological conditions. In this review, we focus on the Nox-mediated ROS signalling pathways involved in the regulation of 'longevity genes' and recapitulate their role in age-associated vascular changes and in the development of age-related cardiovascular diseases (CVDs). This review is predicated on burgeoning knowledge that Nox-derived ROS propagate tightly regulated yet varied signalling pathways, which, at the cellular level, may lead to diminished repair, the aging process and predisposition to CVDs. In addition, we briefly describe emerging Nox therapies and their potential in improving the health of the elderly population.
PDF
