TY  - JOUR
AB  - Despite advances in multimodal therapy approaches such as resection, chemotherapy and radiotherapy, the overall survival of patients with grade 4 glioblastoma (GBM) remains extremely poor (average survival time <2 years). Altered lipid metabolism, which increases fatty acid synthesis and thereby contributes to radioresistance in GBM, is a hallmark of cancer. Therefore, we explored the radiosensitizing effect of the clinically approved, lipid-lowering drug fenofibrate (FF) in different GBM cell lines (U87, LN18). Interestingly, FF (50 μM) significantly radiosensitizes U87 cells by inducing DNA double-strand breaks through oxidative stress and impairing mitochondrial membrane integrity, but radioprotects LN18 cells by reducing the production of reactive oxygen species (ROS) and stabilizing the mitochondrial membrane potential. A comparative protein and lipid analysis revealed striking differences in the two GBM cell lines: LN18 cells exhibited a significantly higher membrane expression density of the fatty acid (FA) cluster protein transporter CD36 than U87 cells, a higher expression of glycerol-3-phosphate acyltransferase 4 (GPAT4) which supports the production of large lipid droplets (LDs), and a lower expression of diacylglycerol O-acyltransferase 1 (DGAT1) which regulates the formation of small LDs. Consequently, large LDs are predominantly found in LN18 cells, whereas small LDs are found in U87 cells. After a combined treatment of FF and irradiation, the number of large LDs significantly increased in radioresistant LN18 cells, whereas the number of small LDs decreased in radiosensitive U87 cells. The radioprotective effect of FF in LN18 cells could be associated with the presence of large LDs, which act as a sink for the lipophilic drug FF. To prevent uptake of FF by large LDs and to ameliorate its function as a radiosensitizer, FF was encapsulated in biomimetic cell membrane extracellular lipid vesicles (CmEVs) which alter the intracellular trafficking of the drug. In contrast to the free drug, CmEV-encapsulated FF was predominantly enriched in the lysosomal compartment, causing necrosis by impairing lysosomal membrane integrity. Since the stability of plasma and lysosomal membranes is maintained by the presence of the stress-inducible heat shock protein 70 (Hsp70) which has a strong affinity to tumor-specific glycosphingolipids, necrosis occurs predominantly in LN18 cells having a lower membrane Hsp70 expression density than U87 cells. In summary, our findings indicate that the lipid metabolism of tumor cells can affect the radiosensitizing capacity of FF when encountered either as a free drug or as a drug loaded in biomimetic lipid vesicles.
AU  - Alkotub, Ab.
AU  - Bauer, L.*
AU  - Bashiri Dezfouli, A.*
AU  - Hachani, K.*
AU  - Ntziachristos, V.
AU  - Multhoff, G.*
AU  - Kafshgari, M.H.*
C1  - 72753
C2  - 56726
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Radiosensitizing capacity of fenofibrate in glioblastoma cells depends on lipid metabolism.
JO  - Redox Biol.
VL  - 79
PB  - Elsevier
PY  - 2025
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Metabolic pathways fuel tumor progression and resistance to stress conditions including chemotherapeutic drugs, such as DNA damage response (DDR) inhibitors. Yet, significant gaps persist in how metabolic pathways confer resistance to DDR inhibition in cancer cells. Here, we employed a metabolism-focused CRISPR knockout screen and identified genetic vulnerabilities to DDR inhibitors. We unveiled Peroxiredoxin 1 (PRDX1) as a synthetic lethality partner with Ataxia Telangiectasia Mutated (ATM) kinase. Tumor cells depleted of PRDX1 displayed heightened sensitivity to ATM inhibition in vitro and in mice in a manner dependent on p53 status. Mechanistically, we discovered that the ribosomal protein RPL32 undergoes redox modification on active cysteine residues 91 and 96 upon ATM inhibition, promoting p53 stability and altered cell fitness. Our findings reveal a new pathway whereby RPL32 senses stress and induces p53 activation impairing tumor cell survival.
AU  - Li, H.*
AU  - Furusawa, T.*
AU  - Cavero, R.*
AU  - Xiao, Y.*
AU  - Chari, R.*
AU  - Wu, X.*
AU  - Sun, D.*
AU  - Hartmann, O.
AU  - Dhall, A.*
AU  - Holewinski, R.*
AU  - Andresson, T.*
AU  - Karim, B.*
AU  - Villamor-Payà, M.*
AU  - Gallardo, D.*
AU  - Day, C.P.*
AU  - Pal, L.R.*
AU  - Nair, N.U.*
AU  - Ruppin, E.*
AU  - Aladjem, M.I.*
AU  - Pommier, Y.*
AU  - Diefenbacher, M.
AU  - Lim, J.M.*
AU  - Levine, R.L.*
AU  - Stracker, T.H.*
AU  - Weyemi, U.*
C1  - 73176
C2  - 56946
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition.
JO  - Redox Biol.
VL  - 80
PB  - Elsevier
PY  - 2025
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Plants and animals/humans have evolved sophisticated innate immune systems to cope with microbial attack. Innate immunity implies the presence of membrane-located and intracellular receptors to recognize compounds released by damage or by invading pathogens. After detection the receptor molecules initiate intracellular defense signaling, resulting in cell death and/or production of defense molecules. Interestingly, the defense response includes also memory mechanisms, which allow the organisms to better cope with future microbial attacks. Redox mechanisms play an important role in defense signaling. In this review article, we compare the innate immune memory of animals/humans and plants and describe how reversible nitric oxide- and reactive oxygen species-dependent protein modifications enable the activation of defense signaling proteins and transcription factors and regulate the activity of chromatin modifying enzymes to establish innate immune memory. We hope to encourage efforts to characterize further molecular redox mechanisms of the innate immune memory, which might enable the development of new immunotherapies.
AU  - Lindermayr, C.
AU  - Yildirim, A.Ö.
C1  - 74849
C2  - 57603
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Redox-signaling in innate immune memory: Similar mechanisms in animals/humans and plants.
JO  - Redox Biol.
VL  - 84
PB  - Elsevier
PY  - 2025
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - The physiological functions of supersulfides, inorganic and organic sulfides with sulfur catenation, have been extensively studied. Their synthesis is mainly mediated by mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulfide synthase. This study aimed to investigate the role of supersulfides in joint homeostasis and bone regeneration. Using Cars2AINK/+ mutant mice, in which the KIIK motif of CARS2 essential for supersulfide production was replaced with AINK, we evaluated the role of supersulfides in fracture healing and cartilage homeostasis during osteoarthritis (OA). Tibial fracture surgery was performed on the wild-type (Cars2+/+) and Cars2AINK/+ mice littermates. Bulk RNA-seq analysis for the osteochondral regeneration in the fracture model showed increased inflammatory markers and reduced osteogenic factors, indicative of impaired bone regeneration, in Cars2AINK/+ mice. Destabilization of the medial meniscus (DMM) surgery was performed to produce the mouse OA model. Histological analyses with Osteoarthritis Research Society International and synovitis scores revealed accelerated OA progression in Cars2AINK/+ mice compared with that in Cars2+/+ mice. To assess the effects of supersulfides on OA progression, glutathione trisulfide (GSSSG) or saline was periodically injected into the mouse knee joints after the DMM surgery. Thus, supersulfides derived from CARS2 and GSSSG exogenously administered significantly inhibited inflammation and lipid peroxidation of the joint cartilage, possibly through suppression of ferroptosis, during OA development. This study represents a significant advancement in understanding anti-inflammatory and anti-oxidant functions of supersulfides in skeletal tissues and may have a clinical relevance for the bone healing and OA therapeutics.
AU  - Maemura, M.*
AU  - Morita, M.*
AU  - Ogata, S.*
AU  - Miyamoto, Y.*
AU  - Ida, T.*
AU  - Shibusaka, K.*
AU  - Negishi, S.*
AU  - Hosonuma, M.*
AU  - Saito, T.*
AU  - Yoshitake, J.*
AU  - Takata, T.*
AU  - Matsunaga, T.*
AU  - Mishima, E.
AU  - Barayeu, U.*
AU  - Akaike, T.*
AU  - Yano, F.*
C1  - 73443
C2  - 57065
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Supersulfides contribute to joint homeostasis and bone regeneration.
JO  - Redox Biol.
VL  - 81
PB  - Elsevier
PY  - 2025
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells' susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis.
AU  - Berndt, C.*
AU  - Alborzinia, H.*
AU  - Amen, V.S.*
AU  - Ayton, S.*
AU  - Barayeu, U.*
AU  - Bartelt, A.
AU  - Bayir, H.*
AU  - Bebber, C.M.*
AU  - Birsoy, K.*
AU  - Böttcher, J.P.*
AU  - Brabletz, S.*
AU  - Brabletz, T.*
AU  - Brown, A.R.*
AU  - Brüne, B.*
AU  - Bulli, G.*
AU  - Bruneau, A.*
AU  - Chen, Q.*
AU  - DeNicola, G.M.*
AU  - Dick, T.P.*
AU  - Distéfano, A.*
AU  - Dixon, S.J.*
AU  - Engler, J.B.*
AU  - Esser-von Bieren, J.*
AU  - Fedorova, M.*
AU  - Friedmann Angeli, J.P.*
AU  - Friese, M.A.*
AU  - Fuhrmann, D.C.*
AU  - García-Sáez, A.J.*
AU  - Garbowicz, K.*
AU  - Götz, M.
AU  - Gu, W.*
AU  - Hammerich, L.*
AU  - Hassannia, B.*
AU  - Jiang, X.*
AU  - Jeridi, A.
AU  - Kang, Y.P.*
AU  - Kagan, V.E.*
AU  - Konrad, D.B.*
AU  - Kotschi, S.*
AU  - Lei, P.*
AU  - Le Tertre, M.*
AU  - Lev, S.*
AU  - Liang, D.*
AU  - Linkermann, A.*
AU  - Lohr, C.*
AU  - Lorenz, S.
AU  - Luedde, T.*
AU  - Methner, A.*
AU  - Michalke, B.
AU  - Milton, A.V.*
AU  - Min, J.*
AU  - Mishima, E.
AU  - Müller, S.*
AU  - Motohashi, H.*
AU  - Muckenthaler, M.U.*
AU  - Murakami, S.*
AU  - Olzmann, J.A.*
AU  - Pagnussat, G.C.*
AU  - Pan, Z.*
AU  - Papagiannakopoulos, T.*
AU  - Pedrera Puentes, L.*
AU  - Pratt, D.A.*
AU  - Proneth, B.
AU  - Ramsauer, L.*
AU  - Rodriguez, R.*
AU  - Saito, Y.*
AU  - Schmidt, F.*
AU  - Schmitt, C.*
AU  - Schulze, A.*
AU  - Schwab, A.*
AU  - Schwantes, A.*
AU  - Soula, M.*
AU  - Spitzlberger, B.
AU  - Stockwell, B.R.*
AU  - Thewes, L.*
AU  - Thorn-Seshold, O.*
AU  - Toyokuni, S.*
AU  - Tonnus, W.*
AU  - Trumpp, A.*
AU  - Vandenabeele, P.*
AU  - Vanden Berghe, T.*
AU  - Venkataramani, V.*
AU  - Vogel, F.C.E.*
AU  - von Karstedt, S.*
AU  - Wang, F.*
AU  - Westermann, F.*
AU  - Wientjens, C.*
AU  - Wilhelm, C.*
AU  - Wölk, M.*
AU  - Wu, K.*
AU  - Yang, X.*
AU  - Yu, F.*
AU  - Zou, Y.*
AU  - Conrad, M.
C1  - 70906
C2  - 55804
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Ferroptosis in health and disease.
JO  - Redox Biol.
VL  - 75
PB  - Elsevier
PY  - 2024
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Higher eukaryotes' life is impossible without copper redox activity and, literally, every breath we take biochemically demonstrates this. However, this dependence comes at a considerable price to ensure target-oriented copper action. Thereto its uptake, distribution but also excretion are executed by specialized proteins with high affinity for the transition metal. Consequently, malfunction of copper enzymes/transporters, as is the case in hereditary Wilson disease that affects the intracellular copper transporter ATP7B, comes with serious cellular damage. One hallmark of this disease is the progressive copper accumulation, primarily in liver but also brain that becomes deadly if left untreated. Such excess copper toxicity may also result from accidental ingestion or attempted suicide. Recent research has shed new light into the cell-toxic mechanisms and primarily affected intracellular targets and processes of such excess copper that may even be exploited with respect to cancer therapy. Moreover, new therapies are currently under development to fight against deadly toxic copper.
AU  - Sailer, J.*
AU  - Nagel, J.*
AU  - Akdogan, B.
AU  - Jauch, A.T.*
AU  - Engler, J.B.*
AU  - Knolle, P.A.*
AU  - Zischka, H.
C1  - 71054
C2  - 55898
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Deadly excess copper.
JO  - Redox Biol.
VL  - 75
PB  - Elsevier
PY  - 2024
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Cobalt (Co) and Nickel (Ni) are used nowadays in various industrial applications like lithium-ion batteries, raising concerns about their environmental release and public health threats. Both metals are potentially carcinogenic and may cause neurological and cardiovascular dysfunctions, though underlying toxicity mechanisms have to be further elucidated. This study employs untargeted transcriptomics to analyze downstream cellular effects of individual and combined Co and Ni toxicity in human liver carcinoma cells (HepG2). The results reveal a synergistic effect of Co and Ni, leading to significantly higher number of differentially expressed genes (DEGs) compared to individual exposure. There was a clear enrichment of Nrf2 regulated genes linked to pathways such as glycolysis, iron and glutathione metabolism, and sphingolipid metabolism, confirmed by targeted analysis. Co and Ni exposure alone and combined caused nuclear Nrf2 translocation, while only combined exposure significantly affects iron and glutathione metabolism, evidenced by upregulation of HMOX-1 and iron storage protein FTL. Both metals impact sphingolipid metabolism, increasing dihydroceramide levels and decreasing ceramides, sphingosine and lactosylceramides, along with diacylglycerol accumulation. By combining transcriptomics and analytical methods, this study provides valuable insights into molecular mechanisms of Co and Ni toxicity, paving the way for further understanding of metal stress.
AU  - Thiel, A.*
AU  - Drews, F.*
AU  - Pirritano, M.*
AU  - Schumacher, F.*
AU  - Michaelis, V.*
AU  - Schwarz, M.*
AU  - Franzenburg, S.*
AU  - Schwerdtle, T.*
AU  - Michalke, B.
AU  - Kipp, A.P.*
AU  - Kleuser, B.*
AU  - Simon, M.*
AU  - Bornhorst, J.*
C1  - 71381
C2  - 56085
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Transcriptomics pave the way into mechanisms of cobalt and nickel toxicity: Nrf2-mediated cellular responses in liver carcinoma cells.
JO  - Redox Biol.
VL  - 75
PB  - Elsevier
PY  - 2024
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - COVID-19 infections are accompanied by adverse changes in inflammatory pathways that are also partly influenced by increased oxidative stress and might result in elevated DNA damage. The aim of this case-control study was to examine whether COVID-19 patients show differences in oxidative stress-related markers, unconjugated bilirubin (UCB), an inflammation panel and DNA damage compared to healthy, age-and sex-matched controls. The Comet assay with and without the treatment of formamidopyrimidine DNA glycosylase (FPG) and H2O2 challenge was used to detect DNA damage in whole blood. qPCR was applied for gene expression, UCB was analyzed via HPLC, targeted proteomics were applied using Olink® inflammation panel and various oxidative stress as well as clinical biochemistry markers were analyzed in plasma. Hospitalized COVID-19 patients (n = 48) demonstrated higher serum levels of 55 inflammatory proteins (p < 0.001), including hs-C-reactive protein levels (p < 0.05), compared to healthy controls (n = 48). Interestingly, significantly increased age-related DNA damage (%-DNA in tail) after formamidopyrimidine DNA glycosylase (FPG) treatment was measured in younger (n = 24, average age 55.7 years; p < 0.05) but not in older COVID-19 patients (n = 24, average age 83.5 years; p > 0.05). Although various oxidative stress markers were not altered (e.g., FRAP, malondialdehyde, p > 0.05), a significant increased ratio of oxidized to reduced glutathione was detected in COVID-19 patients compared to healthy controls (p < 0.05). UCB levels were significantly lower in individuals with COVID-19, especially in younger COVID-19 patients (p < 0.05). These results suggest that COVID-19 infections exert effects on DNA damage related to age in hospitalized COVID-19 patients that might be driven by changes in inflammatory pathways but are not altered by oxidative stress parameters.
AU  - Draxler, A.*
AU  - Blaschke, A.*
AU  - Binar, J.*
AU  - Weber, M.*
AU  - Haslacher, M.*
AU  - Bartak, V.*
AU  - Bragagna, L.*
AU  - Mare, G.*
AU  - Maqboul, L.*
AU  - Klapp, R.*
AU  - Herzog, T.*
AU  - Széll, M.*
AU  - Petrera, A.
AU  - Laky, B.*
AU  - Wagner, K.H.*
AU  - Thell, R.*
C1  - 68177
C2  - 54861
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Age-related influence on DNA damage, proteomic inflammatory markers and oxidative stress in hospitalized COVID-19 patients compared to healthy controls.
JO  - Redox Biol.
VL  - 67
PB  - Elsevier
PY  - 2023
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Objective: Enhancing energy turnover via uncoupled mitochondrial respiration in adipose tissue has great potential to improve human obesity and other metabolic complications. However, the amount of human brown adipose tissue and its uncoupling protein 1 (UCP1) is low in obese patients. Recently, a class of endogenous molecules, N-acyl amino acids (NAAs), was identified as mitochondrial uncouplers in murine adipocytes, presumably acting via the adenine nucleotide translocator (ANT). Given the translational potential, we investigated the bioenergetic effects of NAAs in human adipocytes, characterizing beneficial and adverse effects, dose ranges, amino acid derivatives and underlying mechanisms. Method: NAAs with neutral (phenylalanine, leucine, isoleucine) and polar (lysine) residues were synthetized and assessed in intact and permeabilized human adipocytes using plate-based respirometry. The Seahorse technology was applied to measure bioenergetic parameters, dose-dependency, interference with UCP1 and adenine nucleotide translocase (ANT) activity, as well as differences to the established chemical uncouplers niclosamide ethanolamine (NEN) and 2,4-dinitrophenol (DNP). Result: NAAs with neutral amino acid residues potently induce uncoupled respiration in human adipocytes in a dose-dependent manner, even in the presence of the UCP1-inhibitor guanosine diphosphate (GDP) and the ANT-inhibitor carboxyatractylate (CAT). However, neutral NAAs significantly reduce maximal oxidation rates, mitochondrial ATP-production, coupling efficiency and reduce adipocyte viability at concentrations above 25 μM. The in vitro therapeutic index (using induced proton leak and viability as determinants) of NAAs is lower than that of NEN and DNP. Conclusion: NAAs are potent mitochondrial uncouplers in human adipocytes, independent of UCP1 and ANT. However, previously unnoticed adverse effects harm adipocyte functionality, reduce the therapeutic index of NAAs in vitro and therefore question their suitability as anti-obesity agents without further chemical modifications.
AU  - Herrnhold, M.*
AU  - Hamp, I.
AU  - Plettenburg, O.
AU  - Jastroch, M.*
AU  - Keuper, M.*
C1  - 68313
C2  - 54723
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Adverse bioenergetic effects of N-acyl amino acids in human adipocytes overshadow beneficial mitochondrial uncoupling.
JO  - Redox Biol.
VL  - 66
PB  - Elsevier
PY  - 2023
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.
AU  - Gonzalez-Franquesa, A.*
AU  - Gama-Perez, P.*
AU  - Kulis, M.*
AU  - Szczepanowska, K.*
AU  - Dahdah, N.*
AU  - Moreno-Gomez, S.*
AU  - Latorre-Pellicer, A.*
AU  - Fernández-Ruiz, R.*
AU  - Aguilar-Mogas, A.*
AU  - Hoffmann, A.
AU  - Monelli, E.*
AU  - Samino, S.*
AU  - Miró-Blanch, J.*
AU  - Oemer, G.*
AU  - Duran, X.*
AU  - Sanchez-Rebordelo, E.*
AU  - Schneeberger, M.*
AU  - Obach, M.*
AU  - Montane, J.*
AU  - Castellano, G.*
AU  - Chapaprieta, V.*
AU  - Sun, W.*
AU  - Navarro, L.*
AU  - Prieto, I.*
AU  - Castaño, C.*
AU  - Novials, A.*
AU  - Gomis, R.*
AU  - Monsalve, M.*
AU  - Claret, M.*
AU  - Graupera, M.*
AU  - Soria, G.*
AU  - Wolfrum, C.*
AU  - Vendrell, J.*
AU  - Fernández-Veledo, S.*
AU  - Enríquez, J.A.*
AU  - Carracedo, A.*
AU  - Perales, J.C.*
AU  - Nogueiras, R.*
AU  - Herrero, L.*
AU  - Trifunovic, A.*
AU  - Keller, M.A.*
AU  - Yanes, O.*
AU  - Sales-Pardo, M.*
AU  - Guimerà, R.*
AU  - Blüher, M.
AU  - Martín-Subero, J.I.*
AU  - Garcia-Roves, P.M.*
C1  - 65674
C2  - 52884
TI  - Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue.
JO  - Redox Biol.
VL  - 54
PY  - 2022
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Mice with constitutive disruption of the Selenop gene have been key to delineate the importance of selenoproteins in neurobiology. However, the phenotype of this mouse model is exquisitely dependent on selenium supply and timing of selenium supplementation. Combining biochemical, histological, and behavioral methods, we tested the hypothesis that parvalbumin-expressing interneurons in the primary somatosensory cortex and hippocampus depend on dietary selenium availability in Selenop-/- mice. Selenop-deficient mice kept on adequate selenium diet (0.15 mg/kg, i.e. the recommended dietary allowance, RDA) developed ataxia, tremor, and hyperexcitability between the age of 4-5 weeks. Video-electroencephalography demonstrated epileptic seizures in Selenop-/- mice fed the RDA diet, while Selenop± heterozygous mice behaved normally. Both neurological phenotypes, hyperexcitability/seizures and ataxia/dystonia were successfully prevented by selenium supplementation from birth or transgenic expression of human SELENOP under a hepatocyte-specific promoter. Selenium supplementation with 10 μM selenite in the drinking water on top of the RDA diet increased the activity of glutathione peroxidase in the brains of Selenop-/- mice to control levels. The effects of selenium supplementation on the neurological phenotypes were dose- and time-dependent. Selenium supplementation after weaning was apparently too late to prevent ataxia/dystonia, while selenium withdrawal from rescued Selenop-/- mice eventually resulted in ataxia. We conclude that SELENOP expression is essential for preserving interneuron survival under limiting Se supply, while SELENOP appears dispensable under sufficiently high Se status.
AU  - Schweizer, U.*
AU  - Wirth, E.K.*
AU  - Klopstock, T.*
AU  - Hölter, S.M.
AU  - Becker, L.
AU  - Moskovitz, J.*
AU  - Grune, T.*
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Köhrle, J.*
AU  - Schomburg, L.*
C1  - 66366
C2  - 52787
TI  - Seizures, ataxia and parvalbumin-expressing interneurons respond to selenium supply in Selenop-deficient mice.
JO  - Redox Biol.
VL  - 57
PY  - 2022
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Selenoproteins are a small family of proteins containing the trace element selenium in form of the rare amino acid selenocysteine (Sec), which is decoded by the UGA codon. In humans, a number of pathogenic variants in genes encoding distinct selenoproteins or selenoprotein biosynthesis factors have been identified. Pathogenic variants in selenocysteine synthase (SEPSECS), which catalyzes the last step in Sec-tRNA[Ser]Sec biosynthesis, were reported in children suffering from progressive cerebello-cerebral atrophy. To understand the pathomechanism associated with SEPSECS deficiency, we generated a novel mouse model recapitulating the respective human pathogenic p.Y334C variant in the murine Sepsecs gene (SepsecsY334C). Unlike in patients, pups homozygous for the p.Y334C variant died perinatally with signs of cardio-respiratory failure. Perinatal death is reminiscent of the Sedaghatian spondylometaphyseal dysplasia disorder in humans, which is caused by pathogenic variants in the gene encoding the selenoprotein and key ferroptosis regulator glutathione peroxidase 4 (GPX4). Protein expression levels of distinct selenoproteins in SepsecsY334C/Y334C mice were found to be generally reduced in brain and isolated cortical neurons, while transcriptomics analysis uncovered an upregulation of NRF2-regulated genes. Crossbreeding of SepsecsY334C/Y334C mice with mice harboring a targeted mutation of the catalytically active Sec to Cys in GPX4 rescued perinatal death of SepsecsY334C/Y334C mice, showing that the cardio-respiratory defects of SepsecsY334C/Y334C mice were caused by the lack of GPX4. Like in SepsecsY334C/Y334C mice, selenoprotein expression levels remained low and NRF2-regulated genes remained highly expressed in these compound mutant mice, indicating that selenium-independent GPX4, along with a sustained antioxidant response are sufficient to compensate for dysfunctional Sec-tRNA[Ser]Sec biosynthesis. Our findings imply that children with pathogenic variants in SEPSECS or GPX4 may even benefit from treatments that incompletely compensate for impaired GPX4 activity.
AU  - Fradejas-Villar, N.*
AU  - Zhao, W.*
AU  - Reuter, U.*
AU  - Doengi, M.*
AU  - Ingold, I.
AU  - Bohleber, S.*
AU  - Conrad, M.
AU  - Schweizer, U.*
C1  - 63529
C2  - 51439
TI  - Missense mutation in selenocysteine synthase causes cardio-respiratory failure and perinatal death in mice which can be compensated by selenium-independent GPX4.
JO  - Redox Biol.
VL  - 48
PY  - 2021
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Ischemic cerebral stroke is one of the leading causes of death and disability in humans. However, molecular processes underlying the development of this pathology remain poorly understood. There are major gaps in our understanding of metabolic changes that occur in the brain tissue during the early stages of ischemia and reperfusion. In particular, it is generally accepted that both ischemia (I) and reperfusion (R) generate reactive oxygen species (ROS) that cause oxidative stress which is one of the main drivers of the pathology, although ROS generation during I/R was never demonstrated in vivo due to the lack of suitable methods. In the present study, we record for the first time the dynamics of intracellular pH and H2O2 during I/R in cultured neurons and during experimental stroke in rats using the latest generation of genetically encoded biosensors SypHer3s and HyPer7. We detect a buildup of powerful acidosis in the brain tissue that overlaps with the ischemic core from the first seconds of pathogenesis. At the same time, no significant H2O2 generation was found in the acute phase of ischemia/reperfusion. HyPer7 oxidation in the brain was detected only 24 h later. Comparison of in vivo experiments with studies on cultured neurons under I/R demonstrates that the dynamics of metabolic processes in these models significantly differ, suggesting that a cell culture is a poor predictor of metabolic events in vivo.
AU  - Kelmanson, I.V.*
AU  - Shokhina, A.G.*
AU  - Kotova, D.A.*
AU  - Pochechuev, M.S.*
AU  - Ivanova, A.D.*
AU  - Kostyuk, A.I.*
AU  - Panova, A.S.*
AU  - Borodinova, A.A.*
AU  - Solotenkov, M.A.*
AU  - Stepanov, E.A.*
AU  - Raevskii, R.I.*
AU  - Moshchenko, A.A.*
AU  - Pak, V.V.*
AU  - Ermakova, Y.G.*
AU  - van Belle, G.J.C.*
AU  - Tarabykin, V.*
AU  - Balaban, P.M.*
AU  - Fedotov, I.V.*
AU  - Fedotov, A.B.*
AU  - Conrad, M.
AU  - Bogeski, I.*
AU  - Katschinski, D.M.*
AU  - Doeppner, T.R.*
AU  - Bähr, M.*
AU  - Zheltikov, A.M.*
AU  - Bilan, D.S.*
AU  - Belousov, V.V.*
C1  - 63520
C2  - 51350
TI  - In vivo dynamics of acidosis and oxidative stress in the acute phase of an ischemic stroke in a rodent model.
JO  - Redox Biol.
VL  - 48
PY  - 2021
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Ferroptosis is primarily triggered by a failure of the glutathione (GSH)-glutathione peroxidase 4 (GPX4) reductive system and associated overwhelming lipid peroxidation, in which enzymes regulating polyunsaturated fatty acid (PUFA) metabolism, and in particular acyl-CoA synthetase long chain family member 4 (ACSL4), are central. Here, we found that exogenous oxygen radicals generated by photodynamic therapy (PDT) can directly peroxidize PUFAs and initiate lipid autoxidation, coinciding with cellular GSH depletion. Different from canonical ferroptosis induced by RSL3 or erastin, PDT-initiated lipid peroxidation and ferroptotis-like cell death is independent of lipoxygenase (ALOXs) and ACSL4. Especially, this form of cell death modality can be triggered in malignant cells insensitive to or acquired resistance to canonical ferroptosis inducers. We also observed a distinct iron metabolism pathway in this PDT-triggered cell death modality, in which cytosolic labile iron is decreased probably due to its relocation to mitochondria. Inhibition of the mitochondrial Ca2+ and Fe2+ uniporter (MCU) effectively prevented PDT-triggered lipid peroxidation and subsequent cell death. Therefore, we tentatively term this distinct ferroptosis-like cell death as liperoptosis. Moreover, using the clinically approved photosensitizer Verteporfin, PDT inhibited tumor growth through inducing prevailing ferroptosis-like cell death in a mouse xenograft model. With its site-specific advantages, these findings highlight the value of using PDT to trigger lipid peroxidation and ferroptosis-like cell death in vivo, and will benefit exploring the exact molecular mechanism of immunological effects of PDT in cancer treatment.
AU  - Shui, S.*
AU  - Zhao, Z.*
AU  - Wang, H.*
AU  - Conrad, M.
AU  - Liu, G.*
C1  - 62408
C2  - 50845
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Non-enzymatic lipid peroxidation initiated by photodynamic therapy drives a distinct ferroptosis-like cell death pathway.
JO  - Redox Biol.
VL  - 45
PB  - Elsevier
PY  - 2021
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Ferroptosis is a form of regulated cell necrosis, as a consequence of Fe(II)-dependent lipid peroxidation. Although ferroptosis has been linked to cancer cell death, neurodegeneration and reperfusion injury, physiological roles of ferroptosis have not been elucidated to date mostly due to the lack of appropriate methodologies. Here, we show that 4-hydroxy-2-nonenal (HNE)-modified proteins detected by a HNEJ-1 mouse monoclonal antibody is a robust immunohistochemical technology to locate ferroptosis in tissues in combination with morphological nuclear information, based on various models of ferroptosis, including erastin-induced cysteine-deprivation, conditional Gpx4 knockout and Fe(II)-dependent renal tubular injury, as well as other types of regulated cell death. Specificity of HNEJ-1 with ferroptosis was endorsed by non-selective identification of HNE-modified proteins in an Fe(II)-dependent renal tubular injury model. We further comprehensively searched for signs of ferroptosis in different developmental stages of Fischer-344 rats from E9.5-2.5 years of age. We observed that there was a significant age-dependent increase in ferroptosis in the kidney, spleen, liver, ovary, uterus, cerebellum and bone marrow, which was accompanied by iron accumulation. Not only phagocytic cells but also parenchymal cells were affected. Epidermal ferroptosis in ageing SAMP8 mice was significantly promoted by high-fat or carbohydrate-restricted diets. During embryogenesis of Fischer-344 rats, we found ferroptosis in nucleated erythrocytes at E13.5, which disappeared in enucleated erythrocytes at E18.5. Administration of a ferroptosis inhibitor, liproxstatin-1, significantly delayed erythrocyte enucleation. Therefore, our results demonstrate for the first time the involvement of ferroptosis in physiological processes, such as embryonic erythropoiesis and aging, suggesting the evolutionally acquired mechanism and the inevitable side effects, respectively.
AU  - Zheng, H.*
AU  - Jiang, L.*
AU  - Tsuduki, T.*
AU  - Conrad, M.
AU  - Toyokuni, S.*
C1  - 63412
C2  - 51425
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Embryonal erythropoiesis and aging exploit ferroptosis.
JO  - Redox Biol.
VL  - 48
PB  - Elsevier
PY  - 2021
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - The tumor suppressor p16(INK4A) induces cell cycle arrest and senescence in response to oncogenic transformation and is therefore frequently lost in cancer. p16(INK4A) is also known to accumulate under conditions of oxidative stress. Thus, we hypothesized it could potentially be regulated by reversible oxidation of cysteines (redox signaling). Here we report that oxidation of the single cysteine in p16(INK4A) in human cells occurs under relatively mild oxidizing conditions and leads to disulfide-dependent dimerization. p16(INK4A) is an all a-helical protein, but we find that upon cysteine-dependent dimerization, p16(INK4A) undergoes a dramatic structural rearrangement and forms aggregates that have the typical features of amyloid fibrils, including binding of diagnostic dyes, presence of cross-beta sheet structure, and typical dimensions found in electron microscopy. p16(INK4A) amyloid formation abolishes its function as a Cyclin Dependent Kinase 4/6 inhibitor. Collectively, these observations mechanistically link the cellular redox state to the inactivation of p16(INK4A) through the formation of amyloid fibrils.
AU  - Göbl, C.
AU  - Morris, V.K.
AU  - van Dam, L.*
AU  - Visscher, M.*
AU  - Polderman, P.E.*
AU  - Hartlmüller, C.
AU  - de Ruiter, H.*
AU  - Hora, M.
AU  - Liesinger, L.*
AU  - Birner-Gruenberger, R.*
AU  - Vos, H.R.*
AU  - Reif, B.
AU  - Madl, T.*
AU  - Dansen, T.B.*
C1  - 56933
C2  - 47437
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16(INK4A).
JO  - Redox Biol.
VL  - 28
PB  - Elsevier
PY  - 2020
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Increased methylglyoxal (MG) formation is associated with diabetes and its complications. In zebrafish, knockout of the main MG detoxifying system Glyoxalase 1, led to limited MG elevation but significantly elevated aldehyde dehydrogenases (ALDH) activity and aldh3a1 expression, suggesting the compensatory role of Aldh3a1 in diabetes. To evaluate the function of Aldh3a1 in glucose homeostasis and diabetes, aldh3a1(-/-) zebrafish mutants were generated using CRISPR-Cas9. Vasculature and pancreas morphology were analysed by zebrafish transgenic reporter lines. Corresponding reactive carbonyl species (RCS), glucose, transcriptome and metabolomics screenings were performed and ALDH activity was measured for further verification. Aldh3a1(-/-) zebrafish larvae displayed retinal vasodilatory alterations, impaired glucose homeostasis, which can be aggravated via pdx1 silencing induced hyperglycaemia. Unexpectedly, MG was not altered, but 4-hydroxynonenal (4-HNE), another prominent lipid peroxidation RCS exhibited high affinity with Aldh3a1, was increased in aldh3a1 mutants. 4-HNE was responsible for the retinal phenotype via pancreas disruption induced hyperglycaemia and can be rescued via L-Carnosine treatment. Furthermore, in type 2 diabetic patients, serum 4-HNE was increased and correlated with disease progression. Thus, our data suggest impaired 4-HNE detoxification and elevated 4-HNE concentration as biomarkers but also the possible inducers for diabetes, from genetic susceptibility to the pathological progression.
AU  - Lou, B.*
AU  - Boger, M.*
AU  - Bennewitz, K.*
AU  - Sticht, C.*
AU  - Kopf, S.*
AU  - Morgenstern, J.
AU  - Fleming, T.*
AU  - Hell, R.*
AU  - Yuan, Z.*
AU  - Nawroth, P.P.
AU  - Kroll, J.*
C1  - 61126
C2  - 49770
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Elevated 4-hydroxynonenal induces hyperglycaemia via Aldh3a1 loss in zebrafish and associates with diabetes progression in humans.
JO  - Redox Biol.
VL  - 37
PB  - Elsevier
PY  - 2020
SN  - 2213-2317
ER  - 

TY  - JOUR
AU  - Egea, J.*
AU  - Fabregat, I.*
AU  - Frapart, Y.M.*
AU  - Ghezzi, P.*
AU  - Görlach, A.*
AU  - Kietzmann, T.*
AU  - Kubaichuk, K.*
AU  - Knaus, U.G.*
AU  - Lopez, M.G.*
AU  - Olaso-Gonzalez, G.*
AU  - Petry, A.*
AU  - Schulz, R.*
AU  - Vina, J.*
AU  - Winyard, P.*
AU  - Abbas, K.*
AU  - Ademowo, O.S.*
AU  - Afonso, C.B.*
AU  - Andreadou, I.*
AU  - Antelmann, H.*
AU  - Antunes, F.*
AU  - Aslan, M.*
AU  - Bachschmid, M.M.*
AU  - Barbosa, R.M.*
AU  - Belousov, V.*
AU  - Berndt, C.*
AU  - Bernlohr, D.*
AU  - Bertrán, E.*
AU  - Bindoli, A.*
AU  - Bottari, S.P.*
AU  - Brito, P.M.*
AU  - Carrara, G.*
AU  - Casas, A.I.*
AU  - Chatzi, A.*
AU  - Chondrogianni, N.*
AU  - Conrad, M.
AU  - Cooke, M.S.
AU  - Costa, J.G.*
AU  - Cuadrado, A.*
AU  - My-Chan Dang, P.*
AU  - De Smet, B.*
AU  - Debelec-Butuner, B.*
AU  - Dias, I.H.K.*
AU  - Dunn, J.D.*
AU  - Edson, A.J.*
AU  - El Assar, M.*
AU  - El-Benna, J.*
AU  - Ferdinandy, P.*
AU  - Fernandes, A.S.*
AU  - Fladmark, K.E.*
AU  - Förstermann, U.*
AU  - Giniatullin, R.*
AU  - Giricz, Z.*
AU  - Görbe, A.*
AU  - Griffiths, H.*
AU  - Hampl, V.*
AU  - Hanf, A.*
AU  - Herget, J.*
AU  - Hernansanz-Agustín, P.*
AU  - Hillion, M.*
AU  - Huang, J.*
AU  - Ilikay, S.*
AU  - Jansen-Dürr, P.*
AU  - Jaquet, V.*
AU  - Joles, J.A.*
AU  - Kalyanaraman, B.*
AU  - Kaminskyy, D.*
AU  - Karbaschi, M.*
AU  - Kleanthous, M.*
AU  - Klotz, L.O.*
AU  - Korac, B.*
AU  - Korkmaz, K.S.*
AU  - Koziel, R.*
AU  - Kračun, D.*
AU  - Krause, K.H.*
AU  - Křen, V.*
AU  - Krieg, T.*
AU  - Laranjinha, J.*
AU  - Lazou, A.*
AU  - Li, H.*
AU  - Martínez-Ruiz, A.*
AU  - Matsui, R.*
AU  - McBean, G.J.*
AU  - Meredith, S.P.*
AU  - Messens, J.*
AU  - Miguel, V.*
AU  - Mikhed, Y.*
AU  - Milisav, I.*
AU  - Milković, L.*
AU  - Miranda-Vizuete, A.*
AU  - Mojović, M.*
AU  - Monsalve, M.*
AU  - Mouthuy, P.A.*
AU  - Mulvey, J.*
AU  - Münzel, T.*
AU  - Muzykantov, V.*
AU  - Nguyen, I.T.N.*
AU  - Oelze, M.*
AU  - Oliveira, N.G.*
AU  - Palmeira, C.M.*
AU  - Papaevgeniou, N.*
C1  - 52261
C2  - 43845
CY  - Amsterdam
SP  - 694-696
TI  - European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS) (vol 13, pg 94, 2017).
JO  - Redox Biol.
VL  - 14
PB  - Elsevier Science Bv
PY  - 2018
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - NADPH oxidases are important sources of reactive oxygen species (ROS). Several Nox homologues are present together in the vascular system but whether they exhibit crosstalk at the activity level is unknown. To address this, vessel function of knockout mice for the cytosolic Nox organizer proteins p47phox, NoxO1 and a p47phox-NoxO1-double knockout were studied under normal condition and during streptozotocin-induced diabetes.
      
      	RESULTS:
      
      	In the mouse aorta, mRNA expression for NoxO1 was predominant in smooth muscle and endothelial cells, whereas p47phox was markedly expressed in adventitial cells comprising leukocytes and tissue resident macrophages. Knockout of either NoxO1 or p47phox resulted in lower basal blood pressure. Deletion of any of the two subunits also prevented diabetes-induced vascular dysfunction. mRNA expression analysis by MACE (Massive Analysis of cDNA ends) identified substantial gene expression differences between the mouse lines and in response to diabetes. Deletion of p47phox induced inflammatory activation with increased markers of myeloid cells and cytokine and chemokine induction. In contrast, deletion of NoxO1 resulted in an attenuated interferon gamma signature and reduced expression of genes related to antigen presentation. This aspect was also reflected by a reduced number of circulating lymphocytes in NoxO1-/- mice.
      
      	INNOVATION AND CONCLUSION:
      
      	ROS production stimulated by NoxO1 and p47phox limit endothelium-dependent relaxation and maintain blood pressure in mice. However, NoxO1 and p47phox cannot substitute each other despite their similar effect on vascular function. Deletion of NoxO1 induced an anti-inflammatory phenotype, whereas p47phox deletion rather elicited a hyper-inflammatory response.
AU  - Rezende, F.*
AU  - Moll, F.*
AU  - Walter, M.*
AU  - Helfinger, V.*
AU  - Hahner, F.*
AU  - Janetzko, P.*
AU  - Ringel, C.*
AU  - Weigert, A.*
AU  - Fleming, I.*
AU  - Weissmann, N.*
AU  - Kuenne, C.*
AU  - Looso, M.*
AU  - Rieger, M.A.*
AU  - Nawroth, P.P.
AU  - Fleming, T.
AU  - Brandes, R.P.*
AU  - Schröder, K.*
C1  - 52450
C2  - 44141
CY  - Po Box 211, 1000 Ae Amsterdam, Netherlands
SP  - 12-21
TI  - The NADPH organizers NoxO1 and p47phox are both mediators of diabetes-induced vascular dysfunction in mice.
JO  - Redox Biol.
VL  - 15
PB  - Elsevier Science Bv
PY  - 2018
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - 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 briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.
AU  - Egea, J.*
AU  - Fabregat, I.*
AU  - Frapart, Y.M.*
AU  - Ghezzi, P.*
AU  - Görlach, A.*
AU  - Kietzmann, T.*
AU  - Kubaichuk, K.*
AU  - Knaus, U.G.*
AU  - Lopez, M.G.*
AU  - Olaso-Gonzalez, G.*
AU  - Petry, A.*
AU  - Schulz, R.*
AU  - Vina, J.*
AU  - Winyard, P.*
AU  - Abbas, K.*
AU  - Ademowo, O.S.*
AU  - Afonso, C.B.*
AU  - Andreadou, I.*
AU  - Antelmann, H.*
AU  - Antunes, F.*
AU  - Aslan, M.*
AU  - Bachschmid, M.M.*
AU  - Barbosa, R.M.*
AU  - Belousov, V.*
AU  - Berndt, C.*
AU  - Bernlohr, D.*
AU  - Bertrán, E.*
AU  - Bindoli, A.*
AU  - Bottari, S.P.*
AU  - Brito, P.M.*
AU  - Carrara, G.*
AU  - Casas, A.I.*
AU  - Chatzi, A.*
AU  - Chondrogianni, N.*
AU  - Conrad, M.
AU  - Cooke, M.S.*
AU  - Costa, J.G.*
AU  - Cuadrado, A.*
AU  - My-Chan Dang, P.*
AU  - De Smet, B.*
AU  - Debelec-Butuner, B.*
AU  - Dias, I.H.K.*
AU  - Dunn, J.D.*
AU  - Edson, A.J.*
AU  - El Assar, M.*
AU  - El-Benna, J.*
AU  - Ferdinandy, P.*
AU  - Fernandes, A.S.*
AU  - Fladmark, K.E.*
AU  - Förstermann, U.*
AU  - Giniatullin, R.*
AU  - Giricz, Z.*
AU  - Görbe, A.*
AU  - Griffiths, H.*
AU  - Hampl, V.*
AU  - Hanf, A.*
AU  - Herget, J.*
AU  - Hernansanz-Agustín, P.*
AU  - Hillion, M.*
AU  - Huang, J.*
AU  - Ilikay, S.*
AU  - Jansen-Dürr, P.*
AU  - Jaquet, V.*
AU  - Joles, J.A.*
AU  - Kalyanaraman, B.*
AU  - Kaminskyy, D.*
AU  - Karbaschi, M.*
AU  - Kleanthous, M.*
AU  - Klotz, L.O.*
AU  - Korac, B.*
AU  - Korkmaz, K.S.*
AU  - Koziel, R.*
AU  - Kračun, D.*
AU  - Krause, K.H.*
AU  - Křen, V.*
AU  - Krieg, T.*
AU  - Laranjinha, J.*
AU  - Lazou, A.*
AU  - Li, H.*
AU  - Martínez-Ruiz, A.*
AU  - Matsui, R.*
AU  - McBean, G.J.*
AU  - Meredith, S.P.*
AU  - Messens, J.*
AU  - Miguel, V.*
AU  - Mikhed, Y.*
AU  - Milisav, I.*
AU  - Milković, L.*
AU  - Miranda-Vizuete, A.*
AU  - Mojović, M.*
AU  - Monsalve, M.*
AU  - Mouthuy, P.A.*
AU  - Mulvey, J.*
AU  - Münzel, T.*
AU  - Muzykantov, V.*
AU  - Nguyen, I.T.N.*
AU  - Oelze, M.*
AU  - Oliveira, N.G.*
AU  - Palmeira, C.M.*
AU  - Papaevgeniou, N.*
AU  - Pavićević, A.*
AU  - Pedre, B.*
AU  - Peyrot, F.*
AU  - Phylactides, M.*
AU  - Pircalabioru, G.G.*
AU  - Pitt, A.R.*
AU  - Poulsen, H.E.*
AU  - Prieto, I.*
AU  - Rigobello, M.P.*
AU  - Robledinos-Antón, N.*
AU  - Rodríguez-Mañas, L.*
AU  - Rolo, A.P.*
AU  - Rousset, F.*
AU  - Ruskovska, T.*
AU  - Saraiva, N.*
AU  - Sasson, S.*
AU  - Schröder, K.*
AU  - Semen, K.*
AU  - Seredenina, T.*
AU  - Shakirzyanova, A.*
AU  - Smith, G.L.*
AU  - Soldati, T.*
AU  - Sousa, B.C.*
AU  - Spickett, C.M.*
AU  - Stancic, A.*
AU  - Stasia, M.J.*
AU  - Steinbrenner, H.*
AU  - Stepanić, V.*
AU  - Steven, S.*
AU  - Tokatlidis, K.*
AU  - Tuncay, E.*
AU  - Turan, B.*
AU  - Ursini, F.*
AU  - Vacek, J.*
AU  - Vajnerova, O.*
AU  - Valentová, K.*
AU  - van Breusegem, F.*
AU  - Varisli, L.*
AU  - Veal, E.A.*
AU  - Yalçın, A.S.*
AU  - Yelisyeyeva, O.*
AU  - Žarković, N.*
AU  - Zatloukalová, M.*
AU  - Zielonka, J.*
AU  - Touyz, R.M.*
AU  - Papapetropoulos, A.*
AU  - Grune, T.*
AU  - Lamas, S.*
AU  - Schmidt, H.H.H.W.*
AU  - Di Lisa, F.*
AU  - Daiber, A.*
C1  - 51235
C2  - 43097
CY  - Amsterdam
SP  - 94-162
TI  - European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS).
JO  - Redox Biol.
VL  - 13
PB  - Elsevier Science Bv
PY  - 2017
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - Energy production is inevitably linked to the generation of toxic metabolites, such as reactive oxygen and carbonyl species, known as major contributors to ageing and degenerative diseases. It remains unclear how cells can adapt to elevated energy flux accompanied by accumulating harmful by-products without taking any damage. Therefore, effects of a sudden rise in glucose concentrations were studied in yeast cells. This revealed a feedback mechanism initiated by the reactive dicarbonyl methylglyoxal, which is formed non-enzymatically during glycolysis. Low levels of methylglyoxal activate a multi-layered defence response against toxic metabolites composed of prevention, detoxification and damage remission. The latter is mediated by the protein quality control system and requires inducible Hsp70 and Btn2, the aggregase that sequesters misfolded proteins. This glycohormetic mechanism enables cells to pre-adapt to rising energy flux and directly links metabolic to proteotoxic stress. Further data suggest the existence of a similar response in endothelial cells.
AU  - Zemva, J.*
AU  - Fink, C.A.*
AU  - Fleming, T.H.*
AU  - Schmidt, L.*
AU  - Loft, A.
AU  - Herzig, S.
AU  - Knieß, R.A.*
AU  - Mayer, M.*
AU  - Bukau, B.*
AU  - Nawroth, P.P.
AU  - Tyedmers, J.*
C1  - 51739
C2  - 43457
CY  - Amsterdam
SP  - 674-686
TI  - Hormesis enables cells to handle accumulating toxic metabolites during increased energy flux.
JO  - Redox Biol.
VL  - 13
PB  - Elsevier Science Bv
PY  - 2017
SN  - 2213-2317
ER  - 

TY  - JOUR
AB  - The selenoenzyme glutathione peroxidase 4 (Gpx4) is an essential mammalian glutathione peroxidase, which protects cells against detrimental lipid peroxidation and governs a novel form of regulated necrotic cell death, called ferroptosis. To study the relevance of Gpx4 and of another vitally important selenoprotein, cytosolic thioredoxin reductase (Txnrd1), for liver function, mice with conditional deletion of Gpx4 in hepatocytes were studied, along with those lacking Txnrd1 and selenocysteine (Sec) tRNA (Trsp) in hepatocytes. Unlike Txnrd1- and Trsp-deficient mice, Gpx4(-/-) mice died shortly after birth and presented extensive hepatocyte degeneration. Similar to Txnrd1-deficient livers, Gpx4(-/-) livers manifested upregulation of nuclear factor (erythroid-derived)-like 2 (Nrf2) response genes. Remarkably, Gpx4(-/-) pups born from mothers fed a vitamin E-enriched diet survived, yet this protection was reversible as subsequent vitamin E deprivation caused death of Gpx4-deficient mice ~4 weeks thereafter. Abrogation of selenoprotein expression in Gpx4(-/-) mice did not result in viable mice, indicating that the combined deficiency aggravated the loss of Gpx4 in liver. By contrast, combined Trsp/Txnrd1-deficient mice were born, but had significantly shorter lifespans than either single knockout, suggesting that Txnrd1 plays an important role in supporting liver function of mice lacking Trsp. In sum our study demonstrates that the ferroptosis regulator Gpx4 is critical for hepatocyte survival and proper liver function, and that vitamin E can compensate for its loss by protecting cells against deleterious lipid peroxidation.
AU  - Carlson, B.A.*
AU  - Tobe, R.*
AU  - Yefremova, E.
AU  - Tsuji, P.A.*
AU  - Hoffmann, V.J.*
AU  - Schweizer, U.*
AU  - Gladyshev, V.N.*
AU  - Hatfield, D.L.*
AU  - Conrad, M.
C1  - 48744
C2  - 41304
CY  - Amsterdam
SP  - 22-31
TI  - Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration.
JO  - Redox Biol.
VL  - 9
PB  - Elsevier Science Bv
PY  - 2016
SN  - 2213-2317
ER  -