Browsing by Subject "Hypoxia"

Sort by: Order: Results:

Now showing items 1-20 of 22
  • Barmaki, Samineh; Jokinen, Ville; Obermaier, Daniela; Blokhina, Daria; Korhonen, Matti; Ras, Robin H. A.; Vuola, Jyrki; Franssila, Sami; Kankuri, Esko (2018)
    Physiological oxygen levels within the tissue microenvironment are usually lower than 14%, in stem cell niches these levels can be as low as 0-1%. In cell cultures, such low oxygen levels are usually mimicked by altering the global culture environment either by O-2 removal (vacuum or oxygen absorption) or by N-2 supplementation for O-2 replacement. To generate a targeted cellular hypoxic microenvironment under ambient atmospheric conditions, we characterised the ability of the dissolved oxygen-depleting sodium sulfite to generate an in-liquid oxygen sink. We utilised a microfluidic design to place the cultured cells in the vertical oxygen gradient and to physically separate the cells from the liquid. We demonstrate generation of a chemical in-liquid oxygen sink that modifies the surrounding O-2 concentrations. O-2 level control in the sink-generated hypoxia gradient is achievable by varying the thickness of the polydimethylsiloxane membrane. We show that intracellular hypoxia and hypoxia response element-dependent signalling is instigated in cells exposed to the microfluidic in-liquid O-2 sink-generated hypoxia gradient. Moreover, we show that microfluidic flow controls site-specific microenvironmental kinetics of the chemical O-2 sink reaction, which enables generation of intermittent hypoxia/re-oxygenation cycles. The microfluidic O-2 sink chip targets hypoxia to the cell culture microenvironment exposed to the microfluidic channel architecture solely by depleting O-2 while other sites in the same culture well remain unaffected. Thus, responses of both hypoxic and bystander cells can be characterised. Moreover, control of microfluidic flow enables generation of intermittent hypoxia or hypoxia/re-oxygenation cycles. (C) 2018 Published by Elsevier Ltd on behalf of Acta Materialia Inc.
  • Laursen, Jens Christian; Sondergaard-Heinrich, Niels; de Melo, Joana Mendes Lopes; Haddock, Bryan; Rasmussen, Ida Kirstine Bull; Safavimanesh, Farzaneh; Hansen, Christian Stevns; Storling, Joachim; Larsson, Henrik Bo Wiberg; Groop, Per-Henrik; Frimodt-Moller, Marie; Andersen, Ulrik Bjorn; Rossing, Peter (2021)
    Background: Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria. Methods: A randomised, double-blind, placebo-controlled, crossover trial with a single 50 mg dose of the SGLT2 inhibitor dapagliflozin and placebo in random order, separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal R-2* (a low value corresponds to a high tissue oxygenation), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline, three- and six hours from tablet ingestion. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation, peripheral blood mononuclear cell mitochondrial oxygen consumption rate, and biomarkers of inflammation were evaluated at baseline and 12 h from medication. The study is registered in the EU Clinical Trials Register (EudraCT 2019-004,557-92), on ClinicalTrials.gov (NCT04193566), and is completed. Findings: Between February 3, 2020 and October 23, 2020, 31 individuals were screened, and 19 eligible individuals were randomised. Three dropped out before receiving any of the interventions and one dropped out after receiving only placebo. We included 15 individuals (33% female) in the per-protocol analysis with a mean age of 58 (SD 14) years, median urinary albumin creatinine ratio of 46 [IQR 21-58] mg/g and an eGFR of 73 (32) ml/min/1.73m(2). The mean changes in renal cortical R-2* from baseline to six hours were for dapagliflozin -1.1 (SD 0.7) s(-1) and for placebo +1.3 (0.7) s(-1), resulting in a difference between interventions of -2.3 s(-1) [95% CI -4.0 to -0.6]; p = 0.012. No between-intervention differences were found in any other MRI outcomes, physiological parameters or exploratory outcomes. There were no adverse events. Interpretation: A single dose of 50 mg dapagliflozin acutely improved renal cortical R-2* without changing renal perfusion or blood flow. This suggests improved renal cortical oxygenation due to a reduced tubular transport workload in the proximal tubules. Such improved oxygenation may in part explain the long-term beneficial renal effects seen with SGLT2 inhibitors, but it remains to be determined whether the observed effects can be achieved with lower doses, with chronic treatment and if they occur in type 2 diabetes as well. (C) 2021 The Author(s). Published by Elsevier Ltd.
  • Raykhel, Irina; Moafi, Fazeh; Myllymaki, Satu M.; Greciano, Patricia G.; Matlin, Karl S.; Moyano, Jose V.; Manninen, Aki; Myllyharju, Johanna (2018)
    Hypoxia and loss of cell polarity are common features of malignant carcinomas. Hypoxia-inducible factor 1 (HIF1) is the major regulator of cellular hypoxia response and mediates the activation of similar to 300 genes. Increased HIF1 signaling is known to be associated with epithelial-mesenchymal transformation. Here, we report that hypoxia disrupts polarized epithelial morphogenesis of MDCK cells in a HIF1 alpha-dependent manner by modulating the transforming growth factor-beta (TGF beta) signaling pathway. Analysis of potential HIF1 targets in the TGF beta pathway identified the bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), a transmembrane glycoprotein related to the type I receptors of the TGF beta family, whose expression was essentially lost in HIF1-depleted cells. Similar to what was observed in HIF1-deficient cells, BAMBI-depleted cells failed to efficiently activate TGF beta signaling and retained epithelial polarity during hypoxia. Taken together, we show that hypoxic conditions promote TGF beta signaling in a HIF1-dependent manner and BAMBI is identified in this pathway as a novel HIF1-regulated gene that contributes to hypoxia-induced loss of epithelial polarity.
  • Saarela, Taija; Rissanen, Antti J.; Ojala, Anne; Pumpanen, Jukka; Aalto, Sanni L.; Tiirola, Marja; Vesala, Timo; Jantti, Helena (2020)
    Freshwater ecosystems represent a significant natural source of methane (CH4). CH4 produced through anaerobic decomposition of organic matter (OM) in lake sediment and water column can be either oxidized to carbon dioxide (CO2) by methanotrophic microbes or emitted to the atmosphere. While the role of CH4 oxidation as a CH4 sink is widely accepted, neither the magnitude nor the drivers behind CH4 oxidation are well constrained. In this study, we aimed to gain more specific insight into CH4 oxidation in the water column of a seasonally stratified, typical boreal lake, particularly under hypoxic conditions. We used (CH4)-C-13 incubations to determine the active CH4 oxidation sites and the potential CH4 oxidation rates in the water column, and we measured environmental variables that could explain CH4 oxidation in the water column. During hypolimnetic hypoxia, 91% of available CH4 was oxidized in the active CH4 oxidation zone, where the potential CH4 oxidation rates gradually increased from the oxycline to the hypolimnion. Our results showed that in warm springs, which become more frequent, early thermal stratification with cold well-oxygenated hypolimnion delays the period of hypolimnetic hypoxia and limits CH4 production. Thus, the delayed development of hypolimnetic hypoxia may partially counteract the expected increase in the lacustrine CH4 emissions caused by the increasing organic carbon load from forested catchments.
  • Gammal, Johanna; Norkko, Joanna; Pilditch, Conrad A.; Norkko, Alf (2017)
    Coastal ecosystems are important because of the vital ecosystem functions and services they provide, but many are threatened by eutrophication and hypoxia. This results in loss of biodiversity and subsequent changes in ecosystem functioning. Consequently, the need for empirical field studies regarding biodiversity-ecosystem functioning in coastal areas has been emphasized. The present field study quantified the links between benthic macrofaunal communities (abundance, biomass, and species richness), sediment oxygen consumption, and solute fluxes (NO3- + NO2-, NH4+, PO43-, SiO4, Fe, Mn) along a 7.5-km natural gradient of seasonal hypoxia in the coastal northern Baltic Sea. Sampling was done in late August 2010 in the middle archipelago zone of the Hanko peninsula, Finland. As predicted, the macrofaunal communities were decimated with increasing hypoxia, and the nutrient transformation processes were changed at the sediment-water interface, with notably higher effluxes of phosphate and ammonium from the sediment. Solute fluxes varied even during normoxia, which implies a high context-dependency, and could be explained by even small variations in environmental variables such as organic matter and C/N ratios. Importantly, the low diversity benthic macrofaunal communities, which were dominated by Macoma balthica and the invasive Marenzelleria spp., had a large influence on the solute fluxes, especially under normoxia, but also under hypoxia.
  • Jokinen, Sami A.; Koho, Karoliina; Virtasalo, Joonas J.; Jilbert, Tom (2020)
    Molybdenum (Mo) and uranium (U) contents in sedimentary archives are often used to reconstruct past changes in seafloor oxygenation. However, their sequestration processes are as yet poorly constrained in low-salinity coastal waters, which often suffer from anthropogenic eutrophication but only mild oxygen depletion. Due to the consequent lack of robust long-term paleo-redox reconstructions in such settings often characterized by a shallow front of dissolved sulfide accumulation within the sediment pore waters, inadequate understanding of the long-term drivers behind oxygen loss impedes cost-effective mitigation of this environmental problem. Here, we investigate the mechanisms of Mo and U sequestration in an oxic, low-salinity coastal setting in the northern Baltic Sea where anthropogenic eutrophication over the 20th century has resulted in formation of a shallow sulfate-methane transition zone (SMTZ) in the sediment column of this brackish-water basin. Our results demonstrate remarkably similar patterns for authigenic Mo and U sequestration, whereby the depth and intensity of the SMTZ exerts a first-order control on their solid-phase uptake. Sequential extraction analysis suggests that a large part of the authigenic Mo pool is hosted by refractory Fe-S phases such as pyrite and nanoscale FeMoS4, implying that the Fe-sulfide pathway is the dominating process of authigenic Mo scavenging. However, we also observe a pool of extremely labile Mo deep within the SMTZ, which might record an intermediate phase in authigenic Mo sequestration and/or partial switch to the organic matter (OM) pathway at low dissolved Fe levels. Authigenic U resides in acid-extractable and refractory phases, likely reflecting uptake into poorly crystalline monomeric U(IV) and crystalline uraninite, respectively. Similarly to Mo, authigenic U uptake is active at two fronts within the SMTZ, paralleled by increases in dissolved sulfide levels, suggesting coupling between sulfide production and U reduction. Our results imply that both Mo and U could provide viable proxies for mild bottom water deoxygenation in these settings, through the indirect link between seafloor oxygen conditions and the depth of SMTZ. Of these, Mo appears to more robustly capture variations in seafloor oxygen levels due to the significantly higher share of the authigenic pool. However, temporal resolution of these proxies is limited by the vertical offset between seafloor and the zone of authigenic uptake, and the superimposed character of the signal at a given depth due to vertical migrations of the SMTZ. These results have important implications for the use of Mo and U as paleo-redox proxies in other low-salinity coastal settings exposed to eutrophication.
  • Norkko, Joanna; Pilditch, Conrad A.; Gammal, Johanna; Rosenberg, Rutger; Enemar, Arvid; Magnussond, Marina; Granberg, Maria E.; Lindgren, J. Fredrik; Agrenius, Stefan; Norkko, Alf (2019)
    Marine ecosystems world-wide are threatened by oxygen deficiency, with potential serious consequences for ecosystem functioning and the goods and services they provide. While the effects of hypoxia on benthic species diversity are well documented, the effects on ecosystem function have only rarely been assessed in real-world settings. To better understand the links between structural changes in macro- and meiofaunal communities, hypoxic stress and benthic ecosystem function (benthic nutrient fluxes, community metabolism), we sampled a total of 11 sites in Haystensfjord and Askerofjord (Swedish west coast) in late summer, coinciding with the largest extent and severity of seasonal hypoxia in the area. The sites spanned oxic to anoxic bottom water, and a corresponding gradient in faunal diversity. Intact sediment cores were incubated to measure fluxes of oxygen and nutrients (NO3-, NO2-, NH4+, PO43-, SiO4) across the sediment-water interface. Sediment profile imaging (SPI) footage was obtained from all sites to assess structural elements and the bioturbadon depth, and additional samples were collected to characterise sediment properties and macro- and meiofaunal community composition. Bottom-water O-2 concentration was the main driver of macrofauna communities, with highest abundance and biomass, as well as variability, at the sites with intermediate O-2 concentration. Meiofauna on the other hand was less sensitive to bottom-water O-2 concentration. Oxygen was the main driver of nutrient fluxes too, but macrofauna as well meiofauna were also significant predictors; DistLM analyses indicated that O-2 concentration, macrofaunal abundance or biomass, and meiofaunal abundance collectively explained 63%, 30% and 28% of the variation in sediment O-2 consumption, NH4+ flux and PO43+ flux, respectively. The study provides a step towards a more realistic understanding of the link between benthic fauna and ecosystem functioning, and the influence of disturbance on this relationship, which is important for management decisions aimed at protecting the dwindling biodiversity in the coastal zones around the world.
  • Carstensen, Jacob; Conley, Daniel J.; Almroth-Rosell, Elin; Asmala, Eero; Bonsdorff, Erik; Fleming-Lehtinen, Vivi; Gustafsson, Bo G.; Gustafsson, Camilla; Heiskanen, Anna-Stiina; Janas, Urzsula; Norkko, Alf; Slomp, Caroline; Villnäs, Anna; Voss, Maren; Zilius, Mindaugas (2020)
    The coastal zone of the Baltic Sea is diverse with strong regional differences in the physico-chemical setting. This diversity is also reflected in the importance of different biogeochemical processes altering nutrient and organic matter fluxes on the passage from land to sea. This review investigates the most important processes for removal of nutrients and organic matter, and the factors that regulate the efficiency of the coastal filter. Nitrogen removal through denitrification is high in lagoons receiving large inputs of nitrate and organic matter. Phosphorus burial is high in archipelagos with substantial sedimentation, but the stability of different burial forms varies across the Baltic Sea. Organic matter processes are tightly linked to the nitrogen and phosphorus cycles. Moreover, these processes are strongly modulated depending on composition of vegetation and fauna. Managing coastal ecosystems to improve the effectiveness of the coastal filter can reduce eutrophication in the open Baltic Sea.
  • Salminen, Sarianna; Tammelin, Mira; Jilbert, Tom; Fukumoto, Yu; Saarni, Saija (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 Enonselka Basin, Lake Vesijarvi, southern Finland. For the last few decades, the Enonselka 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 Vesijarvi 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.
  • Mattila, Hans K; Mäkinen, Mari; Lundell, Taina (BioMed Central, 2020)
    Abstract Background Fungal decomposition of wood is considered as a strictly aerobic process. However, recent findings on wood-decaying fungi to produce ethanol from various lignocelluloses under oxygen-depleted conditions lead us to question this. We designed gene expression study of the white rot fungus Phlebia radiata (isolate FBCC0043) by adopting comparative transcriptomics and functional genomics on solid lignocellulose substrates under varying cultivation atmospheric conditions. Results Switch to fermentative conditions was a major regulator for intracellular metabolism and extracellular enzymatic degradation of wood polysaccharides. Changes in the expression profiles of CAZy (carbohydrate-active enzyme) encoding genes upon oxygen depletion, lead into an alternative wood decomposition strategy. Surprisingly, we noticed higher cellulolytic activity under fermentative conditions in comparison to aerobic cultivation. In addition, our results manifest how oxygen depletion affects over 200 genes of fungal primary metabolism including several transcription factors. We present new functions for acetate generating phosphoketolase pathway and its potential regulator, Adr1 transcription factor, in carbon catabolism under oxygen depletion. Conclusions Physiologically resilient wood-decomposing Basidiomycota species P. radiata is capable of thriving under respirative and fermentative conditions utilizing only untreated lignocellulose as carbon source. Hypoxia-response mechanism in the fungus is, however, divergent from the regulation described for Ascomycota fermenting yeasts or animal-pathogenic species of Basidiomycota.
  • Bernardi, Luciano; Bianchi, Lucio (2016)
    Autonomic dysfunction is a frequent and relevant complication of diabetes mellitus, as it is associated with increased morbidity and mortality. In addition, it is today considered as predictive of the most severe diabetic complications, like nephropathy and retinopathy. The classical methods of screening are the cardiovascular reflex tests and were originally interpreted as evidence of nerve damage. A more modern approach, based on the integrated control of cardiovascular and respiratory function, reveals that these abnormalities are to a great extent functional, at least in the early stage of the disease, thus suggesting new potential interventions. Therefore, this review aims to go further investigating how the imbalance of the autonomic nervous system is altered and can be influenced in many chronic pathologies through a global view of cardio-respiratory and metabolic interactions and how the same mechanisms are applicable to diabetes.
  • Bianchi, L.; Porta, C.; Rinaldi, A.; Gazzaruso, C.; Fratino, P.; DeCata, P.; Protti, P.; Paltro, R.; Bernardi, L. (2017)
    Background: Cardiovascular (baroreflex) and respiratory (chemoreflex) control mechanisms were studied separately in diabetes, but their reciprocal interaction (well known for diseases like heart failure) had never been comprehensively assessed. We hypothesized that prevalent autonomic neuropathy would depress both reflexes, whereas prevalent autonomic imbalance through sympathetic activation would depress the baroreflex but enhance the chemoreflexes. Methods: In 46 type-1 diabetic subjects (7.0 +/- 0.9 year duration) and 103 age-matched controls we measured the baroreflex (average of 7 methods), and the chemoreflexes, (hypercapnic: ventilation/carbon dioxide slope during hyperoxic progressive hypercapnia; hypoxic: ventilation/oxygen saturation slope during normocapnic progressive hypoxia). Autonomic dysfunction was evaluated by cardiovascular reflex tests. Results: Resting oxygen saturation and baroreflex sensitivity were reduced in the diabetic group, whereas the hypercapnic chemoreflex was significantly increased in the entire diabetic group. Despite lower oxygen saturation the hypoxic chemoreflex showed a trend toward a depression in the diabetic group. Conclusion: Cardio-respiratory control imbalance is a common finding in early type 1 diabetes. A reduced sensitivity to hypoxia seems a primary factor leading to reflex sympathetic activation (enhanced hypercapnic chemoreflex and baroreflex depression), hence suggesting a functional origin of cardio-respiratory control imbalance in initial diabetes. (C) 2017 Elsevier B.V. All rights reserved.
  • Arponen, Heidi; Bachour, Adel; Bäck, Leif; Valta, Helena; Mäkitie, Antti; Waltimo-Siren, Janna; Mäkitie, Outi (2018)
    BackgroundPatients with Osteogenesis imperfecta (OI) suffer from increased bone fracture tendency generally caused by a mutation in genes coding for type I collagen. OI is also characterized by numerous co-morbidities, and recent data from questionnaire studies suggest that these may include increased risk for sleep apnea, a finding that lacks clinical evidence from cohort studies. In this cross-sectional study, 25 adults with OI underwent clinical otorhinolaryngology examination as well as overnight polysomnography to address the question. The participants were aged between 19 and 77years, and ten of them had mild clinical OI phenotype, seven had a moderately severe phenotype, and eight had a severe phenotype.ResultsWe found obstructive sleep apnea (apnea hypopnea index 5/h) in as many as 52% of the OI patients in the cohort. Unexpectedly, however, no correlation was present between sleep apnea and daytime sleepiness, experienced bodily pain, severity of OI, Mallampati score, or neck circumference.ConclusionsSeeing that the usual predictors showed no association with occurrence of sleep apnea, we conclude that obstructive sleep apnea may easily be left as an undetected disorder in individuals with OI. Recurrent nocturnal hypoxia due to episodes of apneas can even affect bone metabolism, thereby further aggravating bone fragility in patients with OI.
  • Arponen, Heidi; Bachour, Adel; Bäck, Leif; Valta, Helena; Mäkitie, Antti; Waltimo-Sirén, Janna; Mäkitie, Outi (BioMed Central, 2018)
    Abstract Background Patients with Osteogenesis imperfecta (OI) suffer from increased bone fracture tendency generally caused by a mutation in genes coding for type I collagen. OI is also characterized by numerous co-morbidities, and recent data from questionnaire studies suggest that these may include increased risk for sleep apnea, a finding that lacks clinical evidence from cohort studies. In this cross-sectional study, 25 adults with OI underwent clinical otorhinolaryngology examination as well as overnight polysomnography to address the question. The participants were aged between 19 and 77 years, and ten of them had mild clinical OI phenotype, seven had a moderately severe phenotype, and eight had a severe phenotype. Results We found obstructive sleep apnea (apnea hypopnea index ≥5/h) in as many as 52% of the OI patients in the cohort. Unexpectedly, however, no correlation was present between sleep apnea and daytime sleepiness, experienced bodily pain, severity of OI, Mallampati score, or neck circumference. Conclusions Seeing that the usual predictors showed no association with occurrence of sleep apnea, we conclude that obstructive sleep apnea may easily be left as an undetected disorder in individuals with OI. Recurrent nocturnal hypoxia due to episodes of apneas can even affect bone metabolism, thereby further aggravating bone fragility in patients with OI.
  • Villnäs, Anna; Norkko, Alf; Lehtonen, Kari K. (2019)
    The frequency of seasonal and short-term hypoxia is increasing in coastal seas. How such repeated disturbances affect key species that have important roles for ecosystem processes and functions remains, however, unknown. By performing a field experiment we explored if the bivalve Macoma balthica can cope with short-term, recurring hypoxic stress, and investigated how hypoxia affects the condition of surviving bivalves. By combining data on different levels of biological organization, i.e., on physiology (biomarker response), behaviour and demography, we identified stress responses before the population declined. One pulse of hypoxic disturbance (3 days) resulted in behavioural alterations, as adult M. balthica extended their siphons, emerged towards the sediment surface and expressed decreased reburial rates. However, the demographic structure of the population remained unaltered. Several pulses of recurring hypoxic stress resulted in physiological response with changes in glutathione reductase and acetylcholinesterase enzyme activities. The recurring hypoxic disturbance was observed to affect juvenile bivalves before adults, while pro-longed hypoxia reduced the entire bivalve population. Our results clearly show that hypoxic stress changes the behaviour and physiology of M. balthica before demographic changes occur, which is likely to have severe implications for the contribution of this key species to ecosystem functioning. That a combination of measures at different levels of organization can detect disturbances at an early stage suggests that such an approach would be useful for assessing the effects of disturbances on marine ecosystems that are increasingly affected by anthropogenic change.
  • Aronen, Merja (2019)
  • Heliste, Juho; Jokilammi, Anne; Paatero, Ilkka; Chakroborty, Deepankar; Stark, Christoffer; Savunen, Timo; Laaksonen, Maria; Elenius, Klaus (BioMed Central, 2018)
    Abstract Background Receptor tyrosine kinases (RTK) are potential targets for the treatment of ischemic heart disease. The human RTK family consists of 55 members, most of which have not yet been characterized for expression or activity in the ischemic heart. Methods RTK gene expression was analyzed from human heart samples representing healthy tissue, acute myocardial infarction or ischemic cardiomyopathy. As an experimental model, pig heart with ischemia-reperfusion injury, caused by cardiopulmonary bypass, was used, from which phosphorylation status of RTKs was assessed with a phospho-RTK array. Expression and function of one RTK, ROR1, was further validated in pig tissue samples, and in HL-1 cardiomyocytes and H9c2 cardiomyoblasts, exposed to hypoxia and reoxygenation. ROR1 protein level was analyzed by Western blotting. Cell viability after ROR1 siRNA knockdown or activation with Wnt-5a ligand was assessed by MTT assays. Results In addition to previously characterized RTKs, a group of novel active and regulated RTKs was detected in the ischemic heart. ROR1 was the most significantly upregulated RTK in human ischemic cardiomyopathy. However, ROR1 phosphorylation was suppressed in the pig model of ischemia-reperfusion and ROR1 phosphorylation and expression were down-regulated in HL-1 cardiomyocytes subjected to short-term hypoxia in vitro. ROR1 expression in the pig heart was confirmed on protein and mRNA level. Functionally, ROR1 activity was associated with reduced viability of HL-1 cardiomyocytes in both normoxia and during hypoxia-reoxygenation. Conclusions Several novel RTKs were found to be regulated in expression or activity in ischemic heart. ROR1 was one of the most significantly regulated RTKs. The in vitro findings suggest a role for ROR1 as a potential target for the treatment of ischemic heart injury.
  • Heliste, Juho; Jokilammi, Anne; Paatero, Ilkka; Chakroborty, Deepankar; Stark, Christoffer; Savunen, Timo; Laaksonen, Maria; Elenius, Klaus (2018)
    BackgroundReceptor tyrosine kinases (RTK) are potential targets for the treatment of ischemic heart disease. The human RTK family consists of 55 members, most of which have not yet been characterized for expression or activity in the ischemic heart.MethodsRTK gene expression was analyzed from human heart samples representing healthy tissue, acute myocardial infarction or ischemic cardiomyopathy. As an experimental model, pig heart with ischemia-reperfusion injury, caused by cardiopulmonary bypass,was used, from which phosphorylation status of RTKs was assessed with a phospho-RTK array. Expression and function of one RTK, ROR1, was further validated in pig tissue samples, and in HL-1 cardiomyocytes and H9c2 cardiomyoblasts, exposed to hypoxia and reoxygenation. ROR1 protein level was analyzed by Western blotting. Cell viability after ROR1 siRNA knockdown or activation with Wnt-5a ligand was assessed by MTT assays.ResultsIn addition to previously characterized RTKs, a group of novel active and regulated RTKs was detected in the ischemic heart. ROR1 was the most significantly upregulated RTK in human ischemic cardiomyopathy. However, ROR1 phosphorylation was suppressed in the pig model of ischemia-reperfusion and ROR1 phosphorylation and expression were down-regulated in HL-1 cardiomyocytes subjected to short-term hypoxia in vitro. ROR1 expression in the pig heart was confirmed on protein and mRNA level. Functionally, ROR1 activity was associated with reduced viability of HL-1 cardiomyocytes in both normoxia and during hypoxia-reoxygenation.ConclusionsSeveral novel RTKs were found to be regulated in expression or activity in ischemic heart. ROR1 was one of the most significantly regulated RTKs. The in vitro findings suggest a role for ROR1 as a potential target for the treatment of ischemic heart injury.
  • Ruuhijärvi, Jukka; Malinen, Tommi; Kuoppamäki, Kirsi; Ala-Opas, Pasi; Vinni, Mika (2020)
    We studied the responses of a food web, especially fish and zooplankton, to summertime aeration, pumping of oxygen-rich epilimnetic water to the hypolimnion in Lake Vesijärvi, southern Finland. The aim of hypolimnetic aeration was to reduce internal loading of phosphorus from sediment. The population of smelt (Osmerus eperlanus L.), the main planktivore of the pelagial area, collapsed during the two 1st years of aeration due to increased temperature and low oxygen concentrations in the hypolimnion. The population recovered after the 4th year of hypolimnetic aeration, when oxygen conditions were improved. Despite elevated hypolimnetic temperature, smelt reached exceptionally high abundance, which led to a significant reduction in cladoceran body size. The density of perch (Perca fluviatilis L.) increased at first, but then decreased when the proportion of smelt and cyprinids increased. Biomasses of Daphnia decreased probably as a result of the disappearance of dark, low-oxygen deep-water refuge against fish predation and low availability of nutritionally high-quality algae. Occasionally filamentous cyanobacteria, such as turbulence tolerant Planktothrix agardhii (Gomont), were abundant, suggesting deteriorated food resources for zooplankton. The responses of food web were controversial with respect to the aim of the management, which was to prevent the occurrence of harmful algal blooms.
  • Esposito, Pasquale; Mereu, Roberto; De Barbieri, Giacomo; Rampino, Teresa; Di Toro, Alessandro; Groop, Per-Henrik; Dal Canton, Antonio; Bernardi, Luciano (2016)
    Cardiovascular autonomic dysfunction, evaluated as baroreflex sensitivity (BRS), could be acutely corrected by slow breathing or oxygen administration in patients with type 1 diabetes, thus suggesting a functional component of the disorder. We tested this hypothesis in patients with the type 2 diabetes with or without renal impairment. Twenty-six patients with type 2 diabetes (aged 61.0 +/- A 0.8 years, mean +/- A SEM; duration of diabetes 10.5 +/- A 2 years, BMI 29.9 +/- A 0.7 kg/m(2), GFR 68.1 +/- A 5.6 ml/min) and 24 healthy controls (aged 58.5 +/- A 1.0 years) were studied. BRS was obtained from recordings of RR interval and systolic blood pressure fluctuations during spontaneous and during slow, deep (6 breaths/min) controlled breathing in conditions of normoxia or hyperoxia (5 l/min oxygen). During spontaneous breathing, diabetic patients had lower RR interval and lower BRS compared with the control subjects (7.1 +/- A 1.2 vs. 12.6 +/- A 2.0 ms/mmHg, p <0.025). Deep breathing and oxygen administration significantly increased arterial saturation, reduced RR interval and increased BRS in both groups (to 9.6 +/- A 1.8 and 15.4 +/- A 2.4 ms/mmHg, respectively, p <0.05, hyperoxia vs. normoxia). Twelve diabetic patients affected by chronic diabetic kidney disease (DKD) presented a significant improvement in the BRS during slow breathing and hyperoxia (p <0.025 vs. spontaneous breathing during normoxia). Autonomic dysfunction present in patients with type 2 diabetes can be partially reversed by slow breathing, suggesting a functional role of hypoxia, also in patients with DKD. Interventions known to relieve tissue hypoxia and improve autonomic function, like physical activity, may be useful in the prevention and management of complications in patients with diabetes.