Browsing by Subject "hypoxia"

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  • Barmaki, Samineh; Obermaier, Daniela; Kankuri, Esko; Vuola, Jyrki; Franssila, Sami; jokinen, Ville (2020)
    A hypoxic (low oxygen level) microenvironment and nitric oxide paracrine signaling play important roles in the control of both biological and pathological cell responses. In this study, we present a microfluidic chip architecture for nitric oxide delivery under a hypoxic microenvironment in human embryonic kidney cells (HEK-293). The chip utilizes two separate, but interdigitated microfluidic channels. The hypoxic microenvironment was created by sodium sulfite as the oxygen scavenger in one of the channels. The nitric oxide microenvironment was created by sodium nitroprusside as the light-activated nitric oxide donor in the other channel. The solutions are separated from the cell culture by a 30 µm thick gas-permeable, but liquid-impermeable polydimethylsiloxane membrane. We show that the architecture is preliminarily feasible to define the gaseous microenvironment of a cell culture in the 100 µm and 1 mm length scales.
  • Ala-Kurikka, Tommi; Pospelov, Alexey; Summanen, Milla; Alafuzoff, Aleksander; Kurki, Samu; Voipio, Juha; Kaila, Kai (2021)
    Objective Birth asphyxia (BA) is often associated with seizures that may exacerbate the ensuing hypoxic-ischemic encephalopathy. In rodent models of BA, exposure to hypoxia is used to evoke seizures, that commence already during the insult. This is in stark contrast to clinical BA, in which seizures are typically seen upon recovery. Here, we introduce a term-equivalent rat model of BA, in which seizures are triggered after exposure to asphyxia. Methods Postnatal day 11-12 male rat pups were exposed to steady asphyxia (15 min; air containing 5% O-2 + 20% CO2) or to intermittent asphyxia (30 min; three 5 + 5-min cycles of 9% and 5% O-2 at 20% CO2). Cortical activity and electrographic seizures were recorded in freely behaving animals. Simultaneous electrode measurements of intracortical pH, Po-2, and local field potentials (LFPs) were made under urethane anesthesia. Results Both protocols decreased blood pH to Significance The rate of brain pH recovery has a strong influence on post-asphyxia seizure propensity. The recurring hypoxic episodes during intermittent asphyxia promote neuronal excitability, which leads to seizures only after the suppressing effect of the hypercapnic acidosis is relieved. The present rodent model of BA is to our best knowledge the first one in which, consistent with clinical BA, behavioral and electrographic seizures are triggered after and not during the BA-mimicking insult.
  • Lalowski, Maciej M.; Björk, Susann; Finckenberg, Piet; Soliymani, Rabah; Tarkia, Miikka; Calza, Giulio; Blokhina, Daria; Tulokas, Sari; Kankainen, Matti; Lakkisto, Päivi; Baumann, Marc; Kankuri, Esko; Mervaala, Eero (2018)
    The heart of a newborn mouse has an exceptional capacity to regenerate from myocardial injury that is lost within the first week of its life. In order to elucidate the molecular mechanisms taking place in the mouse heart during this critical period we applied an untargeted combinatory multiomics approach using large-scale mass spectrometry-based quantitative proteomics, metabolomics and mRNA sequencing on hearts from 1-day-old and 7-day-old mice. As a result, we quantified 1.937 proteins (366 differentially expressed), 612 metabolites (263 differentially regulated) and revealed 2.586 differentially expressed gene loci (2.175 annotated genes). The analyses pinpointed the fructose-induced glycolysis-pathway to be markedly active in 1-day-old neonatal mice. Integrated analysis of the data convincingly demonstrated cardiac metabolic reprogramming from glycolysis to oxidative phosphorylation in 7-days old mice, with increases of key enzymes and metabolites in fatty acid transport (acylcarnitines) and beta-oxidation. An upsurge in the formation of reactive oxygen species and an increase in oxidative stress markers, e.g., lipid peroxidation, altered sphingolipid and plasmalogen metabolism were also evident in 7-days mice. In vitro maintenance of physiological fetal hypoxic conditions retained the proliferative capacity of cardiomyocytes isolated from newborn mice hearts. In summary, we provide here a holistic, multiomics view toward early postnatal changes associated with loss of a tissue regenerative capacity in the neonatal mouse heart. These results may provide insight into mechanisms of human cardiac diseases associated with tissue regenerative incapacity at the molecular level, and offer a prospect to discovery of novel therapeutic targets.
  • Shapiguzov, Alexey; Nikkanen, Lauri; Fitzpatrick, Duncan; Vainonen, Julia P.; Gossens, Richard; Alseekh, Saleh; Aarabi, Fayezeh; Tiwari, Arjun; Blokhina, Olga; Panzarova, Klara; Benedikty, Zuzana; Tyystjärvi, Esa; Fernie, Alisdair R.; Trtilek, Martin; Aro, Eva-Mari; Rintamäki, Eevi; Kangasjarvi, Jaakko (2020)
    The Arabidopsis mutant rcd1 is tolerant to methyl viologen (MV). MV enhances the Mehler reaction, i.e. electron transfer from Photosystem I (PSI) to O-2, generating reactive oxygen species (ROS) in the chloroplast. To study the MV tolerance of rcd1, we first addressed chloroplast thiol redox enzymes potentially implicated in ROS scavenging. NADPH-thioredoxin oxidoreductase type C (NTRC) was more reduced in rcd1. NTRC contributed to the photosynthetic and metabolic phenotypes of rcd1, but did not determine its MV tolerance. We next tested rcd1 for alterations in the Mehler reaction. In rcd1, but not in the wild type, the PSI-to-MV electron transfer was abolished by hypoxic atmosphere. A characteristic feature of rcd1 is constitutive expression of mitochondrial dysfunction stimulon (MDS) genes that affect mitochondrial respiration. Similarly to rcd1, in other MDS-overexpressing plants hypoxia also inhibited the PSI-to-MV electron transfer. One possible explanation is that the MDS gene products may affect the Mehler reaction by altering the availability of O-2. In green tissues, this putative effect is masked by photosynthetic O-2 evolution. However, O-2 evolution was rapidly suppressed in MV-treated plants. Transcriptomic meta-analysis indicated that MDS gene expression is linked to hypoxic response not only under MV, but also in standard growth conditions. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.
  • Endzelins, Edgars; Abols, Arturs; Buss, Arturs; Zandberga, Elina; Palviainen, Mari Johanna; Siljander, Pia Riitta-Maria; Line, Aija (2018)
    Background/Aim: Tumor-secreted extracellular vesicles (EVs) play an important role as mediators of intercellular communication. Hypoxia is a common feature of solid tumors frequently associated with an aggressive clinical behavior. This study aimed to gain a deeper understanding into the functions of EVs in intercellular communication between primary and metastatic cancer cells under hypoxic conditions. Materials and Methods: EVs were isolated from two isogenic colorectal cancer (CRC) cell lines SW480 and SW620 cultured under normoxic and hypoxic conditions. Their uptake and effects in SW480 and SW620 cells were studied using EV uptake, proliferation, spheroid-formation, wound healing and invasion assays. Results: Our data showed that hypoxia enhanced the release of EVs from CRC cells in a Hypoxia Induced Factor (HIF)-1-dependent manner. Hypoxic EVs were taken up by CRC cells more efficiently than normoxic EVs. Hypoxic EVs stimulated motility, invasiveness and sternness of primary tumour-derived SW480 cells, whereas they had a little effect on metastasis-derived SW620 cells. Conclusion: Hypoxic colorectal cancer-derived EVs confer aggressiveness and invasiveness to hypoxia-naive cancer cells.
  • HOT-ICU Investigators; Schjorring, Olav L.; Perner, Anders; Wetterslev, Jorn; Lange, Theis; Keus, Frederik; Laake, Jon H.; Okkonen, Marjatta; Siegemund, Martin; Morgan, Matthew; Thormar, Katrin M.; Rasmussen, Bodil S. (2019)
    Background Acutely ill adults with hypoxaemic respiratory failure are at risk of life-threatening hypoxia, and thus oxygen is often administered liberally. Excessive oxygen use may, however, increase the number of serious adverse events, including death. Establishing the optimal oxygenation level is important as existing evidence is of low quality. We hypothesise that targeting an arterial partial pressure of oxygen (PaO2) of 8 kPa is superior to targeting a PaO2 of 12 kPa in adult intensive care unit (ICU) patients with acute hypoxaemic respiratory failure. Methods The Handling Oxygenation Targets in the ICU (HOT-ICU) trial is an outcome assessment blinded, multicentre, randomised, parallel-group trial targeting PaO2 in acutely ill adults with hypoxaemic respiratory failure within 12 hours after ICU admission. Patients are randomised 1:1 to one of the two PaO2 targets throughout ICU stay until a maximum of 90 days. The primary outcome is 90-day mortality. Secondary outcomes are serious adverse events in the ICU, days alive without organ support and days alive out of hospital in the 90-day period; mortality, health-related quality-of-life at 1-year follow-up as well as 1-year cognitive and pulmonary function in a subgroup; and an overall health economic analysis. To detect or reject a 20% relative risk reduction, we aim to include 2928 patients. An interim analysis is planned after 90-day follow-up of 1464 patients. Conclusion The HOT-ICU trial will test the hypothesis that a lower oxygenation target reduces 90-day mortality compared with a higher oxygenation target in adult ICU patients with acute hypoxaemic respiratory failure.
  • Salminen, Sarianna; Tammelin, Mira; Jilbert, Tom; Fukumoto, Yu; Saarni, Saija (Kluwer Academic, 2021)
    Journal of Paleolimnology 2021
    The influence of lake restoration efforts on lake bottom-water conditions and varve preservation is not well known. We studied varved sediments deposited during the last 80 years along a water-depth transect in the Enonsaari Deep, a deep-water area of the southernmost Enonselkä Basin, Lake Vesijärvi, southern Finland. For the last few decades, the Enonselkä Basin has been subject to ongoing restoration efforts. Varve, elemental, and diatom analyses were undertaken to explore how these actions and other human activities affected varve preservation in the Enonsaari Deep. In contrast to most varved Finnish lakes, whose water columns have a natural tendency to stratify, and possess varve records that span thousands of years, varve formation and preservation in Lake Vesijärvi was triggered by relatively recent anthropogenic stressors. The multi-core varve analysis revealed that sediment in the Enonsaari Deep was initially non-varved, but became fully varved in the late 1930s, a time of increasing anthropogenic influence on the lake. The largest spatial extent of varves occurred in the 1970s, which was followed by a period of less distinguishable varves, which coincided with diversion of sewage from the lake. Varve preservation weakened during subsequent decades and was terminated completely by lake aeration in the 2010s. Despite improvements in water quality, hypolimnetic oxygen depletion and varve preservation persisted beyond the reduction in sewage loading, initial aeration, and biomanipulation. These restoration efforts, however, along with other human actions such as harbor construction and dredging, did influence varve characteristics. Varves were also influenced by diatom responses to anthropogenic forcing, because diatoms form a substantial part of the varve structure. Of all the restoration efforts, a second episode of aeration seems to have had the single most dramatic impact on profundal conditions in the basin, resulting in replacement of a sediment accumulation zone by a transport or erosional zone in the Enonsaari Deep. We conclude that human activities in a lake and its catchment can alter lake hypolimnetic conditions, leading to shifts in lake bottom dynamics and changes in varve preservation.
  • Miikkulainen, Petra; Högel, Heidi; Seyednasrollah, Fatemeh; Rantanen, Krista; Elo, Laura L.; Jaakkola, Panu M. (2019)
    Most clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL), resulting in the accumulation of hypoxia-inducible factor -subunits (HIF-) and their downstream targets. HIF-2 expression is particularly high in ccRCC and is associated with increased ccRCC growth and aggressiveness. In the canonical HIF signaling pathway, HIF-prolyl hydroxylase 3 (PHD3) suppresses HIF-2 protein by post-translational hydroxylation under sufficient oxygen availability. Here, using immunoblotting and immunofluorescence staining, qRT-PCR, and siRNA-mediated gene silencing, we show that unlike in the canonical pathway, PHD3 silencing in ccRCC cells leads to down-regulation of HIF-2 protein and mRNA. Depletion of other PHD family members had no effect on HIF-2 expression, and PHD3 knockdown in non-RCC cells resulted in the expected increase in HIF-2 protein expression. Accordingly, PHD3 knockdown decreased HIF-2 target gene expression in ccRCC cells and expression was restored upon forced HIF-2 expression. The effect of PHD3 depletion was pinpointed to HIF2A mRNA stability. In line with these in vitro results, a strong positive correlation of PHD3 and HIF2A mRNA expression in ccRCC tumors was detected. Our results suggest that in contrast to the known negative regulation of HIF-2 in most cell types, high PHD3 expression in ccRCC cells maintains elevated HIF-2 expression and that of its target genes, which may enhance kidney cancer aggressiveness.
  • Klemetti, Miira M.; Teramo, Kari; Kautiainen, Hannu; Wasenius, Niko; Eriksson, Johan G.; Laine, Merja K. (2021)
    Objective To investigate associations between exposure to fetal hypoxia and indicators of metabolic health in young adult offspring of women with type 1 diabetes (OT1D). Methods 156 OT1D born between 7/1995 and 12/2000 at Helsinki University Hospital, Finland, were invited for follow-up between 3/2019 and 11/2019. A control group of 442 adults born from non-diabetic pregnancies, matched for date and place of birth, was obtained from the Finnish Medical Birth Register. In total, 58 OT1D and 86 controls agreed to participate. All OT1D had amniotic fluid (AF) sampled for erythropoietin (EPO) measurement within two days before delivery in order to diagnose fetal hypoxia. In total, 29 OTID had an AF EPO concentration = 14.0 mU/ml, defined as fetal hypoxia, and were categorized into the high EPO (H-EPO) group. At the age of 18-23 years, participants underwent a 2-h 75g oral glucose tolerance test (OGTT) in addition to height, weight, waist circumference, body composition, blood pressure, HbA(1c), cholesterol, triglyceride, high-sensitivity CRP and leisure-time physical activity measurements. Results Two OT1D were diagnosed with diabetes and excluded from further analyses. At young adult age, OT1D in the H-EPO group had a higher BMI than those in the L-EPO group. In addition, among female participants, waist circumference and body fat percentage were highest in the H-EPO group. In the OGTTs, the mean (SD) 2-h post-load plasma glucose (mmol/L) was higher in the H-EPO [6.50 (2.11)] than in the L-EPO [5.21 (1.10)] or control [5.67 (1.48)] offspring (p=0.009). AF EPO concentrations correlated positively with 2-h post-load plasma glucose [r=0.35 (95% CI: 0.07 to 0.62)] and serum insulin [r=0.44 (95% CI: 0.14 to 0.69)] concentrations, even after adjusting for maternal BMI, birth weight z-score, gestational age at birth and adult BMI. Control, L-EPO and H-EPO groups did not differ with regards to other assessed parameters. Conclusions High AF EPO concentrations in late pregnancy, indicating fetal hypoxia, are associated with increased adiposity and elevated post-load glucose and insulin concentrations in young adult OT1D.
  • Andersen, Jesper H.; Carstensen, Jacob; Conley, Daniel J.; Dromph, Karsten; Fleming-Lehtinen, Vivi; Gustafsson, Bo G.; Josefson, Alf B.; Norkko, Alf; Villnäs, Anna; Murray, Ciaran (2017)
    Much of the Baltic Sea is currently classified as 'affected by eutrophication'. The causes for this are twofold. First, current levels of nutrient inputs (nitrogen and phosphorus) from human activities exceed the natural processing capacity with an accumulation of nutrients in the Baltic Sea over the last 50-100 years. Secondly, the Baltic Sea is naturally susceptible to nutrient enrichment due to a combination of long retention times and stratification restricting ventilation of deep waters. Here, based on a unique data set collated from research activities and long-term monitoring programs, we report on the temporal and spatial trends of eutrophication status for the open Baltic Sea over a 112-year period using the HELCOM Eutrophication Assessment Tool (HEAT 3.0). Further, we analyse variation in the confidence of the eutrophication status assessment based on a systematic quantitative approach using coefficients of variation in the observations. The classifications in our assessment indicate that the first signs of eutrophication emerged in the mid-1950s and the central parts of the Baltic Sea changed from being unaffected by eutrophication to being affected. We document improvements in eutrophication status that are direct consequences of long-term efforts to reduce the inputs of nutrients. The reductions in both nitrogen and phosphorus loads have led to large-scale alleviation of eutrophication and to a healthier Baltic Sea. Reduced confidence in our assessment is seen more recently due to reductions in the scope of monitoring programs. Our study sets a baseline for implementation of the ecosystem-based management strategies and policies currently in place including the EU Marine Strategy Framework Directives and the HELCOM Baltic Sea Action Plan.
  • Shah, Disheet; Virtanen, Laura; Prajapati, Chandra; Kiamehr, Mostafa; Gullmets, Josef; West, Gun; Kreutzer, Joose; Pekkanen-Mattila, Mari; Heliö, Tiina; Kallio, Pasi; Taimen, Pekka; Aalto-Setälä, Katriina (2019)
    Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure and heart transplantation. A portion of familial DCM is due to mutations in the LMNA gene encoding the nuclear lamina proteins lamin A and C and without adequate treatment these patients have a poor prognosis. To get better insights into pathobiology behind this disease, we focused on modeling LMNA-related DCM using human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM). Primary skin fibroblasts from DCM patients carrying the most prevalent Finnish founder mutation (p.S143P) in LMNA were reprogrammed into hiPSCs and further differentiated into cardiomyocytes (CMs). The cellular structure, functionality as well as gene and protein expression were assessed in detail. While mutant hiPSC-CMs presented virtually normal sarcomere structure under normoxia, dramatic sarcomere damage and an increased sensitivity to cellular stress was observed after hypoxia. A detailed electrophysiological evaluation revealed bradyarrhythmia and increased occurrence of arrhythmias in mutant hiPSC-CMs on beta -adrenergic stimulation. Mutant hiPSC-CMs also showed increased sensitivity to hypoxia on microelectrode array and altered Ca2+ dynamics. Taken together, p.S143P hiPSC-CM model mimics hallmarks of LMNA-related DCM and provides a useful tool to study the underlying cellular mechanisms of accelerated cardiac degeneration in this disease.
  • Brek-Laitinen, Grazyna; López Bellido, Jessica; Ojala, Anne (2012)
    The clearwater boreal Lake Vesijärvi experiences annual periods of hypolimnetic hypoxia with unknown consequences for the microbial food web. We quantified the abundance of heterotrophic bacteria, autotrophic picoplankton (APP), nanoflagellates (NF) and ciliates in Lake Vesijärvi throughout the water column and vegetation season and determined how these varied with changes in environmental conditions, including dissolved oxygen concentrations. The abundance and diversity of ciliates increased significantly throughout the water column with the development of thermal stratification and the onset of hypoxia leading to distinct ciliate communities in the oxic epilimnion and hypoxic hypolimnion. Bacterivorous taxa dominated in the hypoxic zone, while in the epilimnion, bacterivorous, algivorous and predatory taxa feeding on other protozoa were present. Seasonal changes in oxygen and temperature explained nearly 80% of variance in ciliate community composition. Changes in total ciliate numbers correlated with seasonal dynamics of bacteria, but not with the dynamics of NF. In the epilimnion, NF were abundant in early spring and their numbers were positively correlated to numbers of prostomatids and haptorids, but not to APP or bacteria. In the hypolimnion, a significant correlation was found between NF and bacteria, but not NF and ciliates. Significant positive correlations between ciliates and bacteria suggest that concentrations of food resources are important in determining the abundance of ciliates in the plankton. Moreover, we recorded close coupling between seasonal dynamics of bacteria and productivity of phytoplankton, including APP.
  • Dia, Nay (Helsingfors universitet, 2016)
    The interactions between sediment chemistry and bacterial communities are multidirectional and complex. A hypoxia-driven decrease in dissolved oxygen (O2) leads to changes in sediment chemistry, bacterial community and ultimately alters their interactions. The sediment components very sensitive to changes in O2 are iron (Fe) and manganese (Mn) oxides. When O2 content decreases, they will be reduced by bacteria in order to obtain energy. This study was carried out with sediment samples collected from sites of different oxygen status in the Gulf of Finland. The focus was to unravel the interactions between sediment chemistry and bacterial communities by means of chemical extractions distinguishing between Fe and Mn pools of different solubility and, thus, bioavailability. For this purpose, a two-step chemical extraction was carried out in order to selectively quantify the easily reducible and more crystalline fractions of Fe and Mn oxides. The chemistry of phosphorus (P) is intrinsically linked to Fe and aluminum (Al) oxides but not to Mn oxides which are not able to retain P. Unlike Fe and Mn, Al is not a redox-sensitive element but its oxides are of importance in controlling the release of P from sediments by resorption of P. The extracts were analyzed for Fe, Mn, Al and P. Furthermore, a next generation high-input method was used to extract the DNA from the sediments. The results of the chemical extractions and taxonomical classification of the bacteria were statistically analyzed. Subsequently, the interactions between the easily-reducible fractions of Fe and Mn oxides and bacterial communities were established using correlations (correlation coefficient ≥ 0.7). The extractability of Fe and Mn increased in poorly-oxygenated and hypoxic conditions. Iron seemed to originate in the easily-reducible fraction, while Mn was in a less reactive form than Fe. As expected, the extractability of Al did not vary with changing oxygen status. In addition, the rather low extractability of P suggests a strong initial adsorption of P on Al oxides. In environment low in oxygen, P released from the Fe oxides was resorbed by Al oxides. We conclude that the major bacterial processes in the sediments are related to the reduction of sulfate and sulfur and decomposition of organic matter. The bacterial communities varied both vertically and horizontally. The vertical variation was mainly explained by the redox potential, while the horizontal variation was more complex and essentially related to easily-reducible Fe and total carbon and nitrogen in sediment. The correlations between the easily-reducible Fe and Mn and the bacterial communities revealed taxa that reduce Fe and/or Mn, some that oxidize metals, and others that could benefit from organic rich environments created by Fe, Mn and S-reducing bacteria. The correlations indicate causative relationships and indirect associations, which can provide leads for future research.
  • Khatun, Masuma; Arffman, Riikka K.; Lavogina, Darja; Kangasniemi, Marika; Laru, Johanna; Ahtikoski, Anne; Lehtonen, Siri; Paulson, Mariana; Hirschberg, Angelica Linden; Salumets, Andres; Andersson, Leif C.; Piltonen, Terhi T. (2020)
    Stanniocalcin-1 (STC-1) is a pro-survival factor that protects tissues against stressors, such as hypoxia and inflammation. STC-1 is co-expressed with the endometrial receptivity markers, and recently endometrial STC-1 was reported to be dysregulated in endometriosis, a condition linked with endometrial progesterone resistance and inflammation. These features are also common in the endometrium in women with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women. Given that women with PCOS present with subfertility, pregnancy complications, and increased risk for endometrial cancer, we investigated endometrial STC-1 expression in affected women. Endometrial biopsy samples were obtained from women with PCOS and controls, including samples from overweight/obese women with PCOS before and after a 3-month lifestyle intervention. A total of 98 PCOS and 85 control samples were used in immunohistochemistry, reverse-transcription polymerase chain reaction, or in vitro cell culture. STC-1 expression was analyzed at different cycle phases and in endometrial stromal cells (eSCs) after steroid hormone exposure. The eSCs were also challenged with 8-bromo-cAMP and hypoxia for STC-1 expression. The findings indicate that STC-1 expression is not steroid hormone mediated although secretory-phase STC-1 expression was blunted in PCOS. Lower expression seems to be related to attenuated STC-1 response to stressors in PCOS eSCs, shown as downregulation of protein kinase A activity. The 3-month lifestyle intervention did not restore STC-1 expression in PCOS endometrium. More studies are warranted to further elucidate the mechanisms behind the altered endometrial STC-1 expression and rescue mechanism in the PCOS endometrium. Summary sentence Endometrial expression of STC-1 in the secretory phase is blunted in women with PCOS, suggesting impaired protection against stress.