Browsing by Subject "oxidative stress"

Sort by: Order: Results:

Now showing items 1-20 of 24
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • Hemilä, H; Kaprio, J; Albanes, D; Virtamo, J (2006)
    It has been proposed that moderate exercise may enhance the immune system. We evaluated whether physical activity at work or at leisure is associated with the risk of pneumonia, and whether the antioxidants vitamin E and beta-carotene affect pneumonia risk in physically active people. A cohort of 16 804 male smokers aged 50 - 69 years and working at study entry was drawn from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, which examined the effect of vitamin E, 50 mg/day, and beta-carotene, 20 mg/day, on lung and other cancers. Physical activity at work, and the type of leisure-time exercise, were recorded at study entry. We retrieved the first occurrence of hospital-treated pneumonia during a 3-year follow-up from the National Hospital Discharge Register (133 cases). Physical activity at work and at leisure had no association with the risk of pneumonia. In participants with physically loading jobs, neither vitamin E nor beta-carotene affected the risk of pneumonia. In participants carrying out moderate or heavy exercise at leisure, beta-carotene had no effect, but vitamin E reduced the risk of pneumonia by 50% (95% CI: 16-70%). Previously, exercise has been shown to affect diverse laboratory measures of the immune system which are, however, only surrogate markers for the resistance to infections. The lack of association between physical activity and the risk of pneumonia observed in our study emphasizes the problem of drawing conclusions from surrogate end points. The finding that vitamin E reduced the risk of pneumonia in persons carrying out leisure-time exercise warrants further study.
  • Sipari, Nina; Lihavainen, Jenna; Shapiguzov, Alexey; Kangasjärvi, Jaakko; Keinänen, Markku (2020)
    Rcd1 (radical-induced cell death1) is an Arabidopsis thaliana mutant, which exhibits high tolerance to paraquat [methyl viologen (MV)], herbicide that interrupts photosynthetic electron transport chain causing the formation of superoxide and inhibiting NADPH production in the chloroplast. To understand the biochemical mechanisms of MV resistance and the role of RCD1 in oxidative stress responses, we performed metabolite profiling of wild type (Col-0) and rcd1 plants in light, after MV exposure and after prolonged darkness. The function of RCD1 has been extensively studied at transcriptomic and biochemical level, but comprehensive metabolite profiling of rcd1 mutant has not been conducted until now. The mutant plants exhibited very different metabolic features from the wild type under light conditions implying enhanced glycolytic activity, altered nitrogen and nucleotide metabolism. In light conditions, superoxide production was elevated in rcd1, but no metabolic markers of oxidative stress were detected. Elevated senescence-associated metabolite marker levels in rcd1 at early developmental stage were in line with its early-senescing phenotype and possible mitochondrial dysfunction. After MV exposure, a marked decline in the levels of glycolytic and TCA cycle intermediates in Col-0 suggested severe plastidic oxidative stress and inhibition of photosynthesis and respiration, whereas in rcd1 the results indicated sustained photosynthesis and respiration and induction of energy salvaging pathways. The accumulation of oxidative stress markers in both plant lines indicated that MV-resistance in rcd1 derived from the altered regulation of cellular metabolism and not from the restricted delivery of MV into the cells or chloroplasts. Considering the evidence from metabolomic, transcriptomic and biochemical studies, we propose that RCD1 has a negative effect on reductive metabolism and rerouting of the energy production pathways. Thus, the altered, highly active reductive metabolism, energy salvaging pathways and redox transfer between cellular compartments in rcd1 could be sufficient to avoid the negative effects of MV-induced toxicity.
  • Rugemalira, Emilie; Roine, Irmeli; Kuligowski, Julia; Sanchez-Illana, Angel; David Pineiro-Ramos, Jose; Andersson, Sture; Peltola, Heikki; Leite Cruzeiro, Manuel; Pelkonen, Tuula; Vento, Maximo (2019)
    The immunological response in bacterial meningitis (BM) causes the formation of reactive oxygen and nitrogen species (ROS, RNS) and activates myeloperoxidase (MPO), an inflammatory enzyme. Thus, structural oxidative and nitrosative damage to proteins and DNA occurs. We aimed to asses these events in the cerebrospinal fluid (CSF) of pediatric BM patients. Phenylalanine (Phe), para-tyrosine (p-Tyr), nucleoside 2'-deoxiguanosine (2dG), and biomarkers of ROS/RNS-induced protein and DNA oxidation: ortho-tyrosine (o-Tyr), 3-chlorotyrosine (3Cl-Tyr), 3-nitrotyrosine (3NO(2)-Tyr) and 8-oxo-2'-deoxyguanosine (8OHdG), concentrations were measured by liquid chromatography coupled to tandem mass spectrometry in the initial CSF of 79 children with BM and 10 without BM. All biomarkers, normalized with their corresponding precursors, showed higher median concentrations (p <0.0001) in BM compared with controls, except 8OHdG/2dG. The ratios o-Tyr/Phe, 3Cl-Tyr/p-Tyr and 3NO(2)-Tyr/p-Tyr were 570, 20 and 4.5 times as high, respectively. A significantly higher 3Cl-Tyr/p-Tyr ratio was found in BM caused by Streptococcus pneumoniae, than by Haemophilus influenzae type b, or Neisseria meningitidis (p = 0.002 for both). In conclusion, biomarkers indicating oxidative damage to proteins distinguished BM patients from non-BM, most clearly the o-Tyr/Phe ratio. The high 3Cl-Tyr/p-Tyr ratio in pneumococcal meningitis suggests robust inflammation because 3Cl-Tyr is a marker of MPO activation and, indirectly, of inflammation.
  • Niemelä, Markus; Niemelä, Onni; Bloigu, Risto; Bloigu, Aini; Kangastupa, Päivikki; Juvonen, Tatu (2020)
    Purpose: While extreme physical exertion is known to induce changes in the status of inflammation comparisons of the responses for various mediators of inflammation after acute bouts of high-intensity exercise have been limited. Subjects and Methods: We examined the responses in serum levels of novel inflammatory proteins, calprotectin, suPAR, CD163, and pro- and anti-inflammatory cytokines in 12 physically active volunteers (10 men, 2 women, mean age 37 +/- 14 years) before and after completing various types of extreme physical exertion (marathon run, half-marathon run or 24-h cross-country skiing). For comparisons, the levels of the biomarkers were also measured at rest in 30 healthy controls (25 men, 5 women, mean age 42 +/- 12 years) with low or sedentary activity. Results: Extreme physical exertion induced significant increases in serum calprotectin (p <0.0005), suPAR (p <0.01), CD163 (p <0.05), IL-6 (p <0.0005), IL-8 (p <0.01) and IL-10 (p <0.0005) (pre- vs 3h-post-exercise). These responses were found to normalize within 48 hours. While the increases in blood leukocytes were of similar magnitude following the different types of exercise, markedly more pronounced responses occurred in serum TNF-alpha (p <0.01), IL-8 (p <0.01) and CD163 (p <0.05) in those with more intense activity. In 3-h post-exercise samples significant correlations were observed between serum calprotectin and IL-6 (r(s) = 0.720, p <0.01), IL-10 (r(s) = 0.615, p <0.05), TNF-alpha (r(s) = 0.594, p <0.05), suPAR (r(s) = 0.587, p <0.05) and blood leukocytes (r(s) = 0.762, p <0.01). Conclusion: The present results suggest distinct exercise-intensity dependent changes in mediators of inflammation (including calprotectin, suPAR and CD163) following extreme physical exertion. Our findings indicate that there is a major reversible impact of high-intensity physical exertion on the status of inflammation.
  • Siekkinen, Jenni (Helsingfors universitet, 2015)
    Parkinson's disease is a progressive neurodegenerative movement disorder which is characterized by the death of dopaminergic neurons in the substantia nigra. In addition, other neuropathological features of the disease are intracytoplasmic protein inclusions as well as oxidative and ER stress. Currently there is no cure for Parkinson's disease so there is a need for novel therapies which could stop the disease progression. Because neurotrophic factors can promote the survival of neurons they might be beneficial for the treatment of Parkinson's disease. Cerebral dopamine neurotrophic factor (CDNF) has proven to be neuroprotective and neurorestorative in rodent models of Parkinson's disease. However, the development of new therapies requires relevant disease models. The defects of the current models of Parkinson's disease increases the need for better and more descriptive disease models. The literature review of this thesis presents an overview of ER stress and oxidative stress. Their role in Parkinson's disease 6-OHDA, MPTP, α-synuclein and rotenone models is also reviewed. The experimental part consists of three studies. The aim of the first study was to establish a preformed α-synuclein fibril mouse model of Parkinson's disease. The development of the lesion was studied by testing the motoric skills with balance beam, rotarod, wire hanger and cylinder test. In addition, TH and α-synuclein immunostainings from striatum and substantia nigra sections was performed. In the second study the effect of CDNF on mice behaviour and TH- and α-synuclein-immunoreactivity in the α-synuclein fibril mouse model was examined. The same motoric behaviour tests as in the first study were used. The purpose of the third experimental part was to investigate the effect of CDNF and GDNF on ER stress proteins in 6-OHDA rat model of Parkinson's disease. The levels of ER stress markers GRP78 and phosphorylated eIF2α were analyzed by Western Blot. The results of the studies were promising. In further studies the effect of α-synuclein fibrils on mouse behaviour and TH- and α-synuclein-immunoreactivity could be studied for longer time. The effect of CDNF on α-synuclein aggregation could also be studied further. The expression levels of other ER stress markers could be investigated so it would clarify the effect of CDNF and GDNF on ER stress.