Redox Proteomics of the Inflammatory Secretome Identifies a Common Set of Redoxins and Other Glutathionylated Proteins Released in Inflammation, Influenza Virus Infection and Oxidative Stress
Protein cysteines can form transient disulfides with glutathione (GSH), resulting in the production of glutathionylated proteins, and this process is regarded as a mechanism by which the redox state of the cell can regulate protein function. Most studies on redox regulation of immunity have focused on intracellular proteins. In this study we have used redox proteomics to identify those proteins released in glutathionylated form by macrophages stimulated with lipopolysaccharide (LPS) after pre-loading the cells with biotinylated GSH. Of the several proteins identified in the redox secretome, we have selected a number for validation. Proteomic analysis indicated that LPS stimulated the releas…
Cisplatin-induced peripheral neuropathy: neuroprotection by erythropoietin without affecting tumour growth
This study examined the dose-dependent efficacy of erythropoietin (EPO) for preventing and/or treating cisplatin (CDDP) induced peripheral neurotoxicity (CINP), and its influence on tumour treatment and growth. Rats received eight intraperitoneal (ip) injections of 2 mg/kg CDDP twice weekly. EPO co-administered (50 or 10 microg/kg ip, three times/week) had a dose-dependent effect, partially preventing CINP, but 0.5 microg/kg ip was not effective. The neuroprotective effect lasted at least 5 weeks after the last dose of EPO and CDDP. In addition, EPO (50 microg/kg ip three times/week) after the last injection of CDDP still induced a significant recovery of CINP. In a separate experiment in r…
Is erythropoietin a worthy candidate for traumatic brain injury or are we heading the wrong way? [version 1; referees: 2 approved]
Traumatic brain injury (TBI) is a leading cause of death and disability in the modern society. Although primary prevention is the only strategy that can counteract the primary brain damage, numerous preclinical studies have been accumulated in order to find therapeutic strategies against the secondary damage. In this scenario erythropoietin (EPO) has been shown to be a promising candidate as neuroprotective agent. A recent clinical trial, however, has shown that EPO has not an overall effect on outcomes following TBI thus renewing old concerns. However, the results of a prespecified sensitivity analysis indicate that the effect of EPO on mortality remains still unclear. In the light of the…
Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor {kappa}B.
Cells of the monocyte-macrophage lineage play a central role in the orchestration and resolution of inflammation. Plasticity is a hallmark of mononuclear phagocytes, and in response to environmental signals these cells undergo different forms of polarized activation, the extremes of which are called classic or M1 and alternative or M2. NF-kappaB is a key regulator of inflammation and resolution, and its activation is subject to multiple levels of regulation, including inhibitory, which finely tune macrophage functions. Here we identify the p50 subunit of NF-kappaB as a key regulator of M2-driven inflammatory reactions in vitro and in vivo. p50 NF-kappaB inhibits NF-kappaB-driven, M1-polariz…
Derivatives of Erythropoietin That Are Tissue Protective But Not Erythropoietic
Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype–selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyeli…
Response to I. Batinic-Haberle et al.
Letter to the editor.-- et al.
Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor
The cytokine erythropoietin (Epo) is tissue-protective in preclinical models of ischemic, traumatic, toxic, and inflammatory injuries. We have recently characterized Epo derivatives that do not bind to the Epo receptor (EpoR) yet are tissue-protective. For example, carbamylated Epo (CEpo) does not stimulate erythropoiesis, yet it prevents tissue injury in a wide variety ofin vivoandin vitromodels. These observations suggest that another receptor is responsible for the tissue-protective actions of Epo. Notably, prior investigation suggests that EpoR physically interacts with the common β receptor (βcR), the signal-transducing subunit shared by the granulocyte-macrophage colony stimulating fa…
Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach
Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This netw…
Corrigendum to “European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)” [Redox Biol. 13 (2017) 94–162]
The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics b…
Is erythropoietin a worthy candidate for traumatic brain injury or are we heading the wrong way?
Traumatic brain injury (TBI) is a leading cause of death and disability in the modern society. Although primary prevention is the only strategy that can counteract the primary brain damage, numerous preclinical studies have been accumulated in order to find therapeutic strategies against the secondary damage. In this scenario erythropoietin (EPO) has been shown to be a promising candidate as neuroprotective agent. A recent clinical trial, however, has shown that EPO has not an overall effect on outcomes following TBI thus renewing old concerns. However, the results of a prespecified sensitivity analysis indicate that the effect of EPO on mortality remains still unclear. In the light of the…
Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κB
Cells of the monocyte-macrophage lineage play a central role in the orchestration and resolution of inflammation. Plasticity is a hallmark of mononuclear phagocytes, and in response to environmental signals these cells undergo different forms of polarized activation, the extremes of which are called classic or M1 and alternative or M2. NF-kappaB is a key regulator of inflammation and resolution, and its activation is subject to multiple levels of regulation, including inhibitory, which finely tune macrophage functions. Here we identify the p50 subunit of NF-kappaB as a key regulator of M2-driven inflammatory reactions in vitro and in vivo. p50 NF-kappaB inhibits NF-kappaB-driven, M1-polariz…
European contribution to the study of ROS : A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)
WOS: 000410470000009