Browsing by Subject "oxidative stress"

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  • Neumann, Hartmut P.; Young, William F.; Krauss, Tobias; Bayley, Jean-Pierre; Schiavi, Francesca; Opocher, Giuseppe; Boedeker, Carsten C.; Tirosh, Amit; Castinetti, Frederic; Ruf, Juri; Beltsevich, Dmitry; Walz, Martin; Groeben, Harald-Thomas; von Dobschuetz, Ernst; Gimm, Oliver; Wohllk, Nelson; Pfeifer, Marija; Lourenco, Delmar M.; Peczkowska, Mariola; Patocs, Attila; Ngeow, Joanne; Makay, Ozer; Shah, Nalini S.; Tischler, Arthur; Leijon, Helena; Pennelli, Gianmaria; Villar Gomez de las Heras, Karina; Links, Thera P.; Bausch, Birke; Eng, Charis (2018)
    Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.
  • Melicher, Pavol; Dvorak, Petr; Krasylenko, Yuliya; Shapiguzov, Alexey; Kangasjärvi, Jaakko; Samaj, Jozef; Takac, Tomas (2022)
    Iron superoxide dismutase 1 (FSD1) was recently characterized as a plastidial, cytoplasmic, and nuclear enzyme with osmoprotective and antioxidant functions. However, the current knowledge on its role in oxidative stress tolerance is ambiguous. Here, we characterized the role of FSD1 in response to methyl viologen (MV)-induced oxidative stress in Arabidopsis thaliana. In accordance with the known regulation of FSD1 expression, abundance, and activity, the findings demonstrated that the antioxidant function of FSD1 depends on the availability of Cu2+ in growth media. Arabidopsis fsdl mutants showed lower capacity to decompose superoxide at low Cu2+ concentrations in the medium. Prolonged exposure to MV led to reduced ascorbate levels and higher protein carbonylation in fsdl mutants and transgenic plants lacking a plastid FSD1 pool as compared to the wild type. MV induced a rapid increase in FSD1 activity, followed by a decrease after 4 h long exposure. Genetic disruption of FSD1 negatively affected the hydrogen peroxide-decomposing ascorbate peroxidase in fsdl mutants. Chloroplastic localization of FSD1 is crucial to maintain redox homeostasis. Proteomic analysis showed that the sensitivity of fsd1 mutants to MV coincided with decreased abundances of ferredoxin and photosystem II light-harvesting complex proteins. These mutants have higher levels of chloroplastic proteases indicating an altered protein turnover in chloroplasts. Moreover, FSD1 disruption affects the abundance of proteins involved in the defense response. Collectively, the study provides evidence for the conditional antioxidative function of FSD1 and its possible role in signaling.
  • Leppilahti, Jussi; Majuri, Marja-Leena; Sorsa, Timo; Hirvonen, Ari; Piirilä, Päivi (2019)
    Introduction: Di-isocyanates TDI (toluene di-isocyanate), MDI (diphenylmethane di-isocyanate), and HDI (hexamethylene di-isocyanate) are the most common chemicals causing occupational asthma. Di-isocyanate inhalation has been reported to induce oxidative stress via reactive oxygen and nitrogen species leading to tissue injury. Glutathione transferases (GSTs) and N-acetyltransferases (NATs) are detoxifying enzymes whose general function is to inactivate electrophilic substances. The most important genes regulating these enzymes, i.e., GSTM1, GSTP1, GSTT1, NAT1, and NAT2 have polymorphic variants resulting in enhanced or lowered enzyme activities. Since inability to detoxify harmful oxidants can lead to inflammatory processes involving activation of bronchoconstrictive mechanisms, we studied whether the altered GST and NAT genotypes were associated with bronchial hyperreactivity (BHR) in patients with di-isocyanate exposure related occupational asthma, irrespective of cessation of di-isocyanate exposure, and adequacy of asthma treatment.Methods: Polymerase chain reaction (PCR) based methods were used to analyze nine common polymorphisms in GSTM1, GSTM3, GSTP1, GSTT1, NAT1, and NAT2 genes in 108 patients with diagnosed occupational di-isocyanate-induced asthma. The genotype data were compared with spirometric lung function and BHR status at diagnosis and in the follow-up examination on average 11 years (range 1–22 years) after the asthma diagnosis. Serum IgE and IL13 levels were also assessed in the follow-up phase.Results: An association between BHR and GSTP1 slow activity (Val105/Val105) genotype was demonstrated in the subjects at the follow-up phase but not at the diagnosis phase. Moreover, the patients with the GSTP1 slow activity genotype exhibited characteristics of Th-2 type immune response more often compared to those with the unaltered GSTP1 gene. Interestingly, all 10 patients with the GSTP1 slow activity genotype had both the GSTM3 slow activity genotype and the unaltered GSTT1 gene.Discussion: The results suggest associations of the low activity variants of the GSTP1 gene with BHR. The fact that these associations came up only at the follow-up phase when the subjects were not any more exposed to di-isocyanates, and used asthma medication, suggest that medication and environmental factors influence the presentation of these associations. However, due to the exploratory character of the study and relatively small study size, the findings remain to be confirmed in future studies with larger sample sizes.
  • Chandola, C.; Casteleijn, M.G.; Chandola, U.M.; Gopalan, L.N.; Urtti, A.; Neerathilingam, M. (2019)
    Age related macular degeneration (AMD) is a progressive, neurodegenerative disorder that leads to the severe loss of central vision in elderlies. The health of retinal pigment epithelial (RPE) cells is critical for the onset of AMD. Chronic oxidative stress along with loss of lysosomal activity is a major cause for RPE cell death during AMD. Hence, development of a molecule for targeted lysosomal delivery of therapeutic protein/drugs in RPE cells is important to prevent RPE cell death during AMD. Using human RPE cell line (ARPE-19 cells) as a study model, we confirmed that hydrogen peroxide (H2O2) induced oxidative stress results in CD44 cell surface receptor overexpression in RPE cells; hence, an important target for specific delivery to RPE cells during oxidative stress. We also demonstrate that the known nucleic acid CD44 aptamer - conjugated with a fluorescent probe (FITC) - is delivered into the lysosomes of CD44 expressing ARPE-19 cells. Hence, as a proof of concept, we demonstrate that CD44 aptamer may be used for lysosomal delivery of cargo to RPE cells under oxidative stress, similar to AMD condition. Since oxidative stress may induce wet and dry AMD, both, along with proliferative vitreoretinopathy, CD44 aptamer may be applicable as a carrier for targeted lysosomal delivery of therapeutic cargoes in ocular diseases showing oxidative stress in RPE cells. © 2019
  • Kemppinen, Jasmin (Helsingin yliopisto, 2020)
    Reactive oxygen species (ROS) are one of the prominent groups of signal compounds that are produced in stress conditions such as excess light. Nuclear protein RADICAL-INDUCED CELL DEAT (RCD1) is sensitive to ROS and controls the expression of organelle components, e.g. mitochondrial alternative oxidases (AOX), thus balancing the redox-status of a plant cell. Plants have fast responses to fluctuating light conditions that happen even before gene expression: i.e. readjusting the capability to receive light energy between the two photosystems by state transitions and increasing the capacity to remove excess energy by non-photochemical quenching (NPQ). Various small auxiliary proteins function in these fast acclimation events. However, many of them are identified on gene level only. The goal of this master’s thesis is to describe the role of a hypothetical protein, PPD8 in Arabidopsis thaliana. We evaluate how PPD8 is associated with RCD1 and a chloroplast thiol-regulator enzyme NTRC. We created double (rcd1 ppd8) and triple mutant plant lines (rcd1 ppd8 ntrc) by crossing single knockout lines ppd8, rcd1 and ntrc. Photosynthetic performance, NPQ and sensitivity to ROS were observed in each line by using two different chlorophyll fluorescence measurement methods: pulse-amplitude-modulation (PAM) and novel OJIP imaging fluorometry. The leaves were exposed to methyl viologen (MV), which accelerates the chloroplastic ROS production in light, and also to hypoxic conditions in order to study how the effect of MV is altered in low concentrations of oxygen. Additionally, we examined the amount of photosynthetic proteins and stoichiometry of photosystems in ppd8, rcd1 and rcd1 ppd8 by immunological methods. Finally, PPD8 gene with attached hemagglutinin encoding tags was generated by cloning and reintroduced back to the ppd8 knockout lines. Plants lacking RCD1 are very tolerant against MV and ROS, but when rcd1 was crossed with ppd8 the resistance was suppressed. Both rcd1 ppd8 and ppd8 exhibited elevated chlorophyll fluorescence and NPQ values. The removal of PPD8 gene had an impact on the abundance and the stoichiometry of photosynthetic proteins reducing the plants’ performance. When RCD1, PPD8 and NTRC were simultaneously absent the plants had major defects: their NPQ and fluorescence values were drastically increased. Furthermore, several results hinted towards possible issues in the function of ATP synthase in ppd8 background plants. It is also known that NTRC regulates ATP synthase: taken together, the results suggest that PPD8 is necessary for a fully operative ATP synthase and photosynthetic machinery. By reintroducing PPD8 to knockout line ppd8, the phenotype could be reverted back to wild type -like, thus confirming the significance of the PPD8 gene product in plant.
  • Dietrich, Stefan; Elorinne, Anna-Liisa; Bergau, Nick; Abraham, Klaus; Grune, Tilman; Laakso, Juha; Weber, Daniela; Weikert, Cornelia; Monien, Bernhard H. (2022)
    When the amount of reactive oxygen species produced by human metabolism cannot be balanced by antioxidants, this phenomenon is commonly referred to as oxidative stress. It is hypothesised that diets with high amounts of plant food products may have a beneficial impact on oxidative stress status. However, few studies have examined whether a vegan diet is associated with lower oxidative stress compared to an omnivorous diet. The present cross-sectional study aimed to compare the levels of five oxidative stress biomarkers in vegans and omnivores. Data of 36 vegans and 36 omnivores from Germany and of 21 vegans and 18 omnivores from Finland were analysed. HPLC coupled with mass spectrometry or fluorescence detection and ELISA methods were used to measure the oxidative stress biomarkers malondialdehyde (MDA), protein carbonyls and 3-nitrotyrosine in plasma and 8-hydroxy-2 '-deoxyguanosine (8-OHdG) and 8-iso-prostaglandin F2 alpha (8-iso-PGF2 alpha) in 24 h urine. Analyses of variance and covariance, considering potential confounders, were used. Vegans and omnivores showed no differences in MDA and protein carbonyl concentrations. In Finnish but not in German vegans, the concentrations of 3-nitrotyrosine were lower compared to those in omnivores (p = 0.047). In Germany, vegans showed lower excretion levels of 8-iso-PGF2 alpha than omnivores (p = 0.002) and with a trend also of 8-OHdG (p = 0.05). The sensitivity analysis suggests lower 8-iso-PGF2 alpha excretion levels in women compared to men, independently of the dietary group. The present study contributes to expanding our knowledge of the relationship between diet and oxidative stress and showed that 3-nitrotyrosine, 8-OHdG and 8-iso-PGF2 alpha tended to be lower in vegans. Furthermore, studies are recommended to validate the present findings.
  • von Weissenberg, Ella; Jansson, Anna; Vuori, Kristiina A.; Engström-Öst, Jonna (2022)
    The marine ecosystems are under severe climate change-induced stress globally. The Baltic Sea is especially vulnerable to ongoing changes, such as warming. The aim of this study was to measure eco-physiological responses of a key copepod species to elevated temperature in an experiment, and by collecting field samples in the western Gulf of Finland. The potential trade-off between reproductive output and oxidative balance in copepods during thermal stress was studied by incubating female Acartia sp. for reproduction rate and oxidative stress measurements in ambient and elevated temperatures. Our field observations show that the glutathione cycle had a clear response in increasing stress and possibly had an important role in preventing oxidative damage: Lipid peroxidation and ratio of reduced and oxidized glutathione were negatively correlated throughout the study. Moreover, glutathione-s-transferase activated in late July when the sea water temperature was exceptionally high and Acartia sp. experienced high oxidative stress. The combined effect of a heatwave, increased cyanobacteria, and decreased dinoflagellate abundance may have caused larger variability in reproductive output in the field. An increase of 7 degrees C had a negative effect on egg production rate in the experiment. However, the effect on reproduction was relatively small, implying that Acartia sp. can tolerate warming at least within the temperature range of 9-16 degrees C. However, our data from the experiment suggest a link between reproductive success and oxidative stress during warming, shown as a significant combined effect of temperature and catalase on egg production rate.
  • Lim, Soo; Taskinen, Marja-Riitta; Boren, Jan (2019)
    Nonalcoholic fatty liver disease (NAFLD) is a chronic condition characterized by fat accumulation combined with low-grade inflammation in the liver. A large body of clinical and experimental data shows that increased flux of free fatty acids from increased visceral adipose tissue and de novo lipogenesis can lead to NAFLD and insulin resistance. Thus, individuals with obesity, insulin resistance, and dyslipidaemia are at the greatest risk of developing NAFLD. Conversely, NAFLD is a phenotype of cardiometabolic syndrome. Notably, researchers have discovered a close association between NAFLD and impaired glucose metabolism and focused on the role of NAFLD in the development of type 2 diabetes. Moreover, recent studies provide substantial evidence for an association between NAFLD and atherosclerosis and cardiometabolic disorders. Even if NAFLD can progress into severe liver disorders including nonalcoholic steatohepatitis (NASH) and cirrhosis, the majority of subjects with NAFLD die from cardiovascular disease eventually. In this review, we propose a potential pathological link between NAFLD/NASH and cardiometabolic syndrome. The potential factors that can play a pivotal role in this link, such as inflammation, insulin resistance, alteration in lipid metabolism, oxidative stress, genetic predisposition, and gut microbiota are discussed.
  • Polianskyte-Prause, Zydrune; Tolvanen, Tuomas A.; Lindfors, Sonja; Kon, Kanta; Hautala, Laura C.; Wang, Hong; Wada, Tsutomu; Tsuneki, Hiroshi; Sasaoka, Toshiyasu; Lehtonen, Sanna (2022)
    Ebselen, a multifunctional organoselenium compound, has been recognized as a potential treatment for diabetes-related disorders. However, the underlying mechanisms whereby ebselen regulates metabolic pathways remain elusive. We discovered that ebselen inhibits lipid phosphatase SHIP2 (Src homology 2 domain-containing inositol-5-phosphatase 2), an emerging drug target to ameliorate insulin resistance in diabetes. We found that ebselen directly binds to and inhibits the catalytic activity of the recombinant SHIP2 phosphatase domain and SHIP2 in cultured cells, the skeletal muscle and liver of the diabetic db/db mice, and the liver of the SHIP2 overexpressing (SHIP2-Tg) mice. Ebselen increased insulin-induced Akt phosphorylation in cultured myotubes, enhanced insulin sensitivity and protected liver tissue from lipid peroxidation and inflammation in the db/db mice, and improved glucose tolerance more efficiently than metformin in the SHIP2-Tg mice. SHIP2 overexpression abrogated the ability of ebselen to induce glucose uptake and reduce ROS production in myotubes and blunted the effect of ebselen to inhibit SHIP2 in the skeletal muscle of the SHIP2-Tg mice. Our data reveal ebselen as a potent SHIP2 inhibitor and demonstrate that the ability of ebselen to ameliorate insulin resistance and act as an antioxidant is at least in part mediated by the reduction of SHIP2 activity.
  • Kujawska, Malgorzata; Domanskyi, Andrii; Kreiner, Grzegorz (2021)
  • Pflugmacher, Stephan; Huttunen, Johanna; van Wollf, Marya-Anne; Penttinen, Olli-Pekka; Kim, Yongjun; Kim, Sanghun; Mitrovic, Simon; Esterhuizen, Maranda (2020)
    Microplastics (MPs) of varying sizes are widespread pollutants in our environment. The general opinion is that the smaller the size, the more dangerous the MPs are due to enhanced uptake possibilities. It would be of considerable ecological significance to understand the response of biota to microplastic contamination both physically and physiologically. Here, we report on an area choice experiment (avoidance test) using Enchytraeus crypticus, in which we mixed different amounts of high-density polyethylene microplastic particles into the soil. In all experimental scenarios, more Enchytraeids moved to the unspiked sections or chose a lower MP-concentration. Worms in contact with MP exhibited an enhanced oxidative stress status, measured as the induced activity of the antioxidative enzymes catalase and glutathione S-transferase. As plastic polymers per se are nontoxic, the exposure time employed was too short for chemicals to leach from the microplastic, and as the microplastic particles used in these experiments were too large (4 mm) to be consumed by the Enchytraeids, the likely cause for the avoidance and oxidative stress could be linked to altered soil properties.
  • Bhattarai, Niina; Korhonen, Eveliina; Mysore, Yashavanthi; Kaarniranta, Kai; Kauppinen, Anu (2021)
    Age-related macular degeneration (AMD) is a retinal disease leading to impaired vision. Cigarette smoke increases the risk for developing AMD by causing increased reactive oxygen species (ROS) production and damage in the retinal pigment epithelium (RPE). We have previously shown that the cigarette tar component hydroquinone causes oxidative stress in human RPE cells. In the present study, we investigated the propensity of hydroquinone to induce the secretion of interleukin (IL)-1 beta and IL-18. The activation of these cytokines is usually regulated by the Nucleotide-binding domain, Leucine-rich repeat, and Pyrin domain 3 (NLRP3) inflammasome. ARPE-19 cells were exposed to hydroquinone, and cell viability was monitored using the lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide salt (MTT) assays. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the levels of proinflammatory cytokines IL-1 beta and IL-18 as well as NLRP3, caspase-1, and poly (ADP-ribose) polymerase (PARP). Hydroquinone did not change IL-1 beta release but significantly increased the secretion of IL-18. Cytoplasmic NLRP3 levels increased after the hydroquinone treatment of IL-1 alpha-primed RPE cells, but IL-18 was equally released from primed and nonprimed cells. Hydroquinone reduced the intracellular levels of PARP, which were restored by treatment with the ROS scavenger N-acetyl-cysteine (NAC). NAC concurrently reduced the NLRP3 levels but had no effect on IL-18 release. In contrast, the NADPH oxidase inhibitor ammonium pyrrolidinedithiocarbamate (APDC) reduced the release of IL-18 but had no effect on the NLRP3 levels. Collectively, hydroquinone caused DNA damage seen as reduced intracellular PARP levels and induced NLRP3-independent IL-18 secretion in human RPE cells.
  • Konovalova, Julia; Gerasymchuk, Dmytro; Parkkinen, Ilmari; Chmielarz, Piotr; Domanskyi, Andrii (2019)
    MicroRNAs are post-transcriptional regulators of gene expression, crucial for neuronal differentiation, survival, and activity. Age-related dysregulation of microRNA biogenesis increases neuronal vulnerability to cellular stress and may contribute to the development and progression of neurodegenerative diseases. All major neurodegenerative disorders are also associated with oxidative stress, which is widely recognized as a potential target for protective therapies. Albeit often considered separately, microRNA networks and oxidative stress are inextricably entwined in neurodegenerative processes. Oxidative stress affects expression levels of multiple microRNAs and, conversely, microRNAs regulate many genes involved in an oxidative stress response. Both oxidative stress and microRNA regulatory networks also influence other processes linked to neurodegeneration, such as mitochondrial dysfunction, deregulation of proteostasis, and increased neuroinflammation, which ultimately lead to neuronal death. Modulating the levels of a relatively small number of microRNAs may therefore alleviate pathological oxidative damage and have neuroprotective activity. Here, we review the role of individual microRNAs in oxidative stress and related pathways in four neurodegenerative conditions: Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) disease, and amyotrophic lateral sclerosis (ALS). We also discuss the problems associated with the use of oversimplified cellular models and highlight perspectives of studying microRNA regulation and oxidative stress in human stem cell-derived neurons.
  • Kovakoski, Elina (Helsingin yliopisto, 2020)
    Microplastics are widely studied subject and have raised concern towards water security worldwide but the vector effect of microplastic has not yet fully understood. In this study the ability of microplastic to attach hydrophobic organic compounds is tested with a nonsteroidal anti-inflammatory drug diclofenac. The ability to attach hydrophobic organic compounds has been proved by microplastics but not with diclofenac. Diclofenac is also causing water security threats nearby wastewater treatment plants because it is biologically active and can cause stress to the aquatic organisms even in small quantities. The aim of this study is to see if microplastic has vector effect for the diclofenac. If microplastic retains diclofenac on its surface area it would decrease the stress factor effect of diclofenac towards the investigated macroalgae Aegagropila linnaei. The possible change of oxidative stress levels in A. linnaei is measured by peroxidase enzyme activity. The aim is to see if the enzyme activity raises or decreases when A. linnaei is exposed to microplastic with and without diclofenac. If the peroxidase enzyme activity decreases in macroalgae while exposing A. linnaei to both microplastic and diclofenac it would strengthen the vector effect hypothesis. As a result, the peroxidase enzyme activity seems to have a decreasing trend when the diclofenac concentrations increase. Diclofenac affected to peroxidase enzyme activity but microplastic does not show any signs of binding of diclofenac in this study, and therefore microplastic cannot act as a vector for diclofenac.
  • Scopetani, Costanza; Esterhuizen, Maranda; Cincinelli, Alessandra; Pflugmacher, Stephan (2020)
    Microplastics (MPs) are emerging pollutants, which are considered ubiquitous in aquatic ecosystems. The effects of MPs on aquatic biota are still poorly understood, and consequently, there is a need to understand the impacts that MPs may pose to organisms. In the present study, Tubifex tubifex, a freshwater oligochaete commonly used as a bioindicator of the aquatic environment, was exposed to fluorescent polyethylene microspheres (up to 10 µm in size) to test whether the oxidative stress status was affected. The mortality rate of T. tubifex, as well as the activities of the oxidative stress status biomarker enzymes glutathione reductase and peroxidase, were assessed. In terms of oxidative stress, no significant differences between the exposure organisms and the corresponding controls were detected. Even though the data suggest that polyethylene MPs and the selected concentrations did not pose a critical risk to T. tubifex, the previously reported tolerance of T. tubifex to environmental pollution should be taken into account and thus MPs as aquatic pollutants could still represent a threat to more sensitive oligochetes.
  • Gomez, Miguel; Leung, Whinkie; Dantuluri, Swathi; Pillai, Alexander; Gani, Zyan; Hwang, Sungmin; McMillan, Lana J.; Kiljunen, Saija; Savilahti, Harri; Maupin-Furlow, Julie A. (2018)
    Halophilic archaea thrive in hypersaline conditions associated with desiccation, ultraviolet (UV) irradiation and redox active compounds, and thus are naturally tolerant to a variety of stresses. Here, we identified mutations that promote enhanced tolerance of halophilic archaea to redox-active compounds using Haloferax volcanii as a model organism. The strains were isolated from a library of random transposon mutants for growth on high doses of sodium hypochlorite (NaOCl), an agent that forms hypochlorous acid (HOCl) and other redox acid compounds common to aqueous environments of high concentrations of chloride. The transposon insertion site in each of twenty isolated clones was mapped using the following: (i) inverse nested two-step PCR (INT-PCR) and (ii) semi-random two-step PCR (ST-PCR). Genes that were found to be disrupted in hypertolerant strains were associated with lysine deacetylation, proteasomes, transporters, polyamine biosynthesis, electron transfer, and other cellular processes. Further analysis revealed a Delta psmA1 (alpha 1) markerless deletion strain that produces only the alpha 2 and beta proteins of 20S proteasomes was hypertolerant to hypochlorite stress compared with wild type, which produces alpha 1, alpha 2, and beta proteins. The results of this study provide new insights into archaeal tolerance of redox active compounds such as hypochlorite.
  • Oksanen, Minna; Hyötyläinen, Ida; Trontti, Kalevi; Rolova, Taisia; Wojciechowski, Sara; Koskuvi, Marja; Viitanen, Matti; Levonen, Anna-Liisa; Hovatta, Iiris; Roybon, Laurent; Lehtonen, Sarka; Kanninen, Katja M.; Hämäläinen, Riikka H.; Koistinaho, Jari (2020)
    Alzheimer's disease (AD) is a common dementia affecting a vast number of individuals and significantly impairing quality of life. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for AD. Astrocytes, the most common cell type of the central nervous system, have been shown to play a role in the major AD pathologies, including accumulation of amyloid plaques, neuroinflammation, and oxidative stress. Here, we show that inflammatory stimulation leads to metabolic activation of human astrocytes and reduces amyloid secretion. On the other hand, the activation of oxidative metabolism leads to increased reactive oxygen species production especially in AD astrocytes. While healthy astrocytes increase glutathione (GSH) release to protect the cells, Presenilin-1-mutated AD patient astrocytes do not. Thus, chronic inflammation is likely to induce oxidative damage in AD astrocytes. Activation of NRF2, the major regulator of cellular antioxidant defenses, encoded by the NFE2L2 gene, poses several beneficial effects on AD astrocytes. We report here that the activation of NRF2 pathway reduces amyloid secretion, normalizes cytokine release, and increases GSH secretion in AD astrocytes. NRF2 induction also activates the metabolism of astrocytes and increases the utilization of glycolysis. Taken together, targeting NRF2 in astrocytes could be a potent therapeutic strategy in AD.
  • Hintsala, Hanna-Riikka; Jokinen, Elina; Haapasaari, Kirsi-Maria; Moza, Monica; Ristimaki, Ari; Soini, Ylermi; Koivunen, Jussi; Karihtala, Peeter (2016)
    Background/Aim: Increased expression and prognostic significance of major redox regulator nuclear factor erythroid-2-related factor (Nrf2) is recognized in many cancers. Our aim was to investigate the role of oxidative stress markers in melanoma. Materials and Methods: We characterized the immunohistochemical expression of Nrf2, kelch-like ECH-associated protein 1 (Keap1), BRAF(V600E), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine in 36 nevi, 14 lentigo maligna and 71 malignant melanomas. We measured Nrf2 expression in melanoma cell lines and conducted cytotoxicity assays combining BRAF/NRAS ablation and H2O2 treatment. Results: Nuclear Nrf2 expression in melanoma correlated with deeper Breslow (p
  • Hernandez-Rios, Patricia; Pussinen, Pirkko J.; Vernal, Rolando; Hernandez, Marcela (2017)
    Oxidative stress is involved in the pathogenesis of a variety of inflammatory disorders. Apical periodontitis (AP) usually results in the formation of an osteolytic apical lesion (AL) caused by the immune response to endodontic infection. Reactive oxygen species (ROS) produced by phagocytic cells in response to bacterial challenge represent an important host defense mechanism, but disturbed redox balance results in tissue injury. This mini review focuses on the role of oxidative stress in the local and associated systemic events in chronic apical periodontitis. During endodontic infection, ligation of Toll-like receptors (TLRs) on phagocytes' surface triggers activation, phagocytosis, synthesis of ROS, activation of humoral and cellular responses, and production of inflammatory mediators, such as, cytokines and matrix metalloproteinases (MMPs). The increment in ROS perturbs the normal redox balance and shifts cells into a state of oxidative stress. ROS induce molecular damage and disturbed redox signaling, that result in the loss of bone homeostasis, increased pro-inflammatory mediators, and MMP overexpression and activation, leading to apical tissue breakdown. On the other hand, oxidative stress has been strongly involved in the pathogenesis of atherosclerosis, where a chronic inflammatory process develops in the arterial wall. Chronic AP is associated with an increased risk of cardiovascular diseases (CVD) and especially atherogenesis. The potential mechanisms linking these diseases are also discussed.
  • Hemilä, Harri; Virtamo, Jarmo; Albanes, Demetrius; Kaprio, Jaakko (2003)