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  • 1.
    Elksnis, Andris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass2019In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 10, article id 107Article, review/survey (Refereed)
    Abstract [en]

    Type 2 diabetes (T2D) is a complex and heterogeneous disease which affects millions of people worldwide. The classification of diabetes is at an interesting turning point and there have been several recent reports on sub-classification of T2D based on phenotypical and metabolic characteristics. An important, and perhaps so far underestimated, factor in the pathophysiology of T2D is the role of oxidative stress and reactive oxygen species (ROS). There are multiple pathways for excessive ROS formation in T2D and in addition, beta-cells have an inherent deficit in the capacity to cope with oxidative stress. ROS formation could be causal, but also contribute to a large number of the metabolic defects in T2D, including beta-cell dysfunction and loss. Currently, our knowledge on beta-cell mass is limited to autopsy studies and based on comparisons with healthy controls. The combined evidence suggests that beta-cell mass is unaltered at onset of T2D but that it declines progressively. In order to better understand the pathophysiology of T2D, to identify and evaluate novel treatments, there is a need for in vivo techniques able to quantify beta-cell mass. Positron emission tomography holds great potential for this purpose and can in addition map metabolic defects, including ROS activity, in specific tissue compartments. In this review, we highlight the different phenotypical features of T2D and how metabolic defects impact oxidative stress and ROS formation. In addition, we review the literature on alterations of beta-cell mass in T2D and discuss potential techniques to assess beta-cell mass and metabolic defects in vivo.

  • 2.
    Jauhiainen, Suvi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Univ Eastern Finland, AI Virtanen Inst Mol Sci, Kuopio, Finland.
    Laakkonen, Johanna P.
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Kuopio, Finland.
    Ketola, Kirsi
    Univ Eastern Finland, Inst Biomed, Kuopio, Finland.
    Toivanen, Pyry, I
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Kuopio, Finland.
    Nieminen, Tina
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Kuopio, Finland.
    Ninchoji, Takeshi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Levonen, Anna-Liisa
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Kuopio, Finland.
    Kaikkonen, Minna U.
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Kuopio, Finland.
    Ylä-Herttuala, Seppo
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Kuopio, Finland;Kuopio Univ Hosp, Heart Ctr & Gene Therapy Unit, Kuopio, Finland.
    Axon Guidance-Related Factor FLRT3 Regulates VEGF-Signaling and Endothelial Cell Function2019In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 10, article id 224Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factors (VEGFs) are key mediators of endothelial cell (EC) function in angiogenesis. Emerging knowledge also supports the involvement of axon guidance-related factors in the regulation of angiogenesis and vascular patterning. In the current study, we demonstrate that fibronectin and leucine-rich transmembrane protein-3 (FLRT3), an axon guidance-related factor connected to the regulation of neuronal cell outgrowth and morphogenesis but not to VEGF-signaling, was upregulated in ECs after VEGF binding to VEGFR2. We found that FLRT3 exhibited a transcriptionally paused phenotype in non-stimulated human umbilical vein ECs. After VEGF-stimulation its nascent RNA and mRNA-levels were rapidly upregulated suggesting that the regulation of FLRT3 expression is mainly occurring at the level of transcriptional elongation. Blockage of FLRT3 by siRNA decreased survival of ECs and their arrangement into capillary-like structures but enhanced cell migration and wound closure in wound healing assay. Bifunctional role of FLRT3 in repulsive vs. adhesive cell signaling has been already detected during embryogenesis and neuronal growth, and depends on its interactions either with UNC5B or another FLRT3 expressed by adjacent cells. In conclusion, our findings demonstrate that besides regulating neuronal cell outgrowth and morphogenesis, FLRT3 has a novel role in ECs via regulating VEGF-stimulated EC-survival, migration, and tube formation. Thus, FLRT3 becomes a new member of the axon guidance-related factors which participate in the VEGF-signaling and regulation of the EC functions.

  • 3.
    Lewandowska, Marta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Bogatikov, Evgenii
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hierlemann, Andreas R.
    Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Basel, Switzerland.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Long-Term High-Density Extracellular Recordings Enable Studies of Muscle Cell Physiology2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 1424Article in journal (Refereed)
    Abstract [en]

    Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important biomedical research subject. Studies of neuromuscular transmission, including disorders of ion channels or receptors in autoimmune or genetic neuromuscular disorders, require high-spatial-resolution measurement techniques and an ability to acquire repeated recordings over time in order to track pharmacological interventions. Preclinical techniques for studying diseases of neuromuscular transmission can be enhanced by physiologic ex vivo models of tissue-tissue and cell-cell interactions. Here, we present a method, which allows tracking the development of primary skeletal muscle cells from myoblasts into mature contracting myotubes over more than 2 months. In contrast to most previous studies, the myotubes did not detach from the surface but instead formed functional networks between the myotubes, whose electrical signals were observed over the entire culturing period. Primary cultures of mouse myoblasts differentiated into contracting myotubes on a chip that contained an array of 26,400 platinum electrodes at a density of 3,265 electrodes per mm(2). Our ability to track extracellular action potentials at subcellular resolution enabled study of skeletal muscle development and kinetics, modes of spiking and spatio-temporal relationships between muscles. The developed system in turn enables creation of a novel electrophysiological platform for establishing ex vivo disease models.

  • 4.
    Lundqvist, Martin H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Almby, Kristina E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Abrahamsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Is the Brain a Key Player in Glucose Regulation and Development of Type 2 Diabetes?2019In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 10, article id 457Article, review/survey (Refereed)
    Abstract [en]

    Ever since Claude Bernards discovery in the mid 19th-century that a lesion in the floor of the third ventricle in dogs led to altered systemic glucose levels, a role of the CNS in whole-body glucose regulation has been acknowledged. However, this finding was later overshadowed by the isolation of pancreatic hormones in the 20th century. Since then, the understanding of glucose homeostasis and pathology has primarily evolved around peripheral mechanism. Due to scientific advances over these last few decades, however, increasing attention has been given to the possibility of the brain as a key player in glucose regulation and the pathogenesis of metabolic disorders such as type 2 diabetes. Studies of animals have enabled detailed neuroanatomical mapping of CNS structures involved in glucose regulation and key neuronal circuits and intracellular pathways have been identified. Furthermore, the development of neuroimaging techniques has provided methods to measure changes of activity in specific CNS regions upon diverse metabolic challenges in humans. In this narrative review, we discuss the available evidence on the topic. We conclude that there is much evidence in favor of active CNS involvement in glucose homeostasis but the relative importance of central vs. peripheral mechanisms remains to be elucidated. An increased understanding of this field may lead to new CNS-focusing pharmacologic strategies in the treatment of type 2 diabetes.

  • 5.
    McKeever, Steve
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Informatics and Media.
    Johnson, David
    The role of markup for enabling interoperability in health informatics2015In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 6, article id 152Article, review/survey (Refereed)
    Abstract [en]

    lnteroperability is the faculty of making information systems work together. In this paper we will distinguish a number of different forms that interoperability can take and show how they are realized on a variety of physiological and health care use cases. The last 15 years has seen the rise of very cheap digital storage both on and off site. With the advent of the Internet of Things people's expectations are for greater interconnectivity and seamless interoperability. The potential impact these technologies have on healthcare are dramatic: from improved diagnoses through immediate access to a patient's electronic health record, to in silico modeling of organs and early stage drug trials, to predictive medicine based on top-down modeling of disease progression and treatment. We will begin by looking at the underlying technology, classify the various kinds of interoperability that exist in the field, and discuss how they are realized. We conclude with a discussion on future possibilities that big data and further standardizations will enable.

  • 6.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Koeners, Maarten P.
    Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England.;Univ Bristol, Sch Physiol Pharmacol & Neurosci, Biomed Sci, Bristol, Avon, England..
    Editorial: Hypoxia in Kidney Disease2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 485Article in journal (Other academic)
  • 7.
    Peleli, Maria
    et al.
    Karolinska institutet.
    Hezel, Michael
    Karolinska institutet.
    Zollbrecht, Christa
    Karolinska institutet.
    Persson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lundberg, Jon O.
    Karolinska institutet.
    Weitzberg, Eddie
    Karolinska institutet.
    Fredholm, Bertil B.
    Karolinska institutet.
    Carlstrom, Mattias
    Karolinska institutet.
    In adenosine A(2B) knockouts acute treatment with inorganic nitrate improves glucose disposal, oxidative stress, and AMPK signaling in the liver2015In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 6, article id 222Article in journal (Refereed)
    Abstract [en]

    Rationale: Accumulating studies suggest that nitric oxide (NO) deficiency and oxidative stress are central pathological mechanisms in type 2 diabetes (T2D). Recent findings demonstrate therapeutic effects by boosting the nitrate-nitrite-NO pathway, which is an alternative pathway for NO formation. This study aimed at investigating the acute effects of inorganic nitrate on glucose and insulin signaling in adenosine A2B receptor knockout mice (A(2B)(-/-), a genetic mouse model of impaired metabolic regulation. Methods: Acute effects of nitrate treatment were investigated in aged wild-type (WT) and A(2B)(-/-) mice. One hour after injection with nitrate (0.1 mmol/kg, i.p.) or placebo, metabolic regulation was evaluated by intraperitoneal glucose and insulin tolerance tests. NADPH oxidase-mediated superoxide production and AMPK phosphorylation were measured in livers obtained from non-treated or glucose-treated mice, with or without prior nitrate injection. Plasma was used to determine insulin resistance (HOMA-IR) and NO signaling. Results: A(2B)(-/-) displayed increased body weight, reduced glucose clearance, and attenuated overall insulin responses compared with age-matched WT mice. Nitrate treatment increased circulating levels of nitrate, nitrite and cGMP in the A(2B)(-/-), and improved glucose clearance. In WT mice, however, nitrate treatment did not influence glucose clearance. HOMA-IR increased following glucose injection in the A(2B)(-/-), but remained at basal levels in mice pretreated with nitrate. NADPH oxidase activity in livers from A(2B)(-/-), but not WT mice, was reduced by nitrate treatment. Livers from A(2B)(-/-) displayed reduced AMPK phosphorylation compared with WT mice, and this was increased by nitrate treatment. Finally, injection with the anti-diabetic agent metformin induced similar therapeutic effects in the A(2B)(-/-) as observed with nitrate. Conclusion: The A(2B)(-/-) mouse is a genetic mouse model of metabolic syndrome. Acute treatment with nitrate improved the metabolic profile in it, at least partly via reduction in oxidative stress and improved AMPK signaling in the liver.

  • 8.
    Scaramuzzo, Gaetano
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Univ Ferrara, Dept Morphol Surg & Expt Med, Ferrara, Italy.
    Broche, Ludovic
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. European Synchrotron Radiat Facil, Grenoble, France;Grenoble Alpes Univ, Synchrotron Radiat Biomed STROBE Lab, INSERM UA7, Amiens, France.
    Pellegrini, Mariangela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Porra, Liisa
    Univ Helsinki, Fac Math & Nat Sci, Dept Phys, Helsinki, Finland;Univ Helsinki, Cent Hosp, Helsinki, Finland.
    Derosa, Savino
    Univ Bari Aldo Moro, Dept Emergency & Organ Transplant, Bari, Italy.
    Tannoia, Angela Principia
    Univ Bari Aldo Moro, Dept Emergency & Organ Transplant, Bari, Italy.
    Marzullo, Andrea
    Univ Bari Aldo Moro, Dept Emergency & Organ Transplant, Bari, Italy.
    Batista Borges, João
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Kings Coll London, Fac Sci & Med, Ctr Human & Appl Physiol Sci, London, England.
    Bayat, Sam
    Grenoble Alpes Univ, Synchrotron Radiat Biomed STROBE Lab, INSERM UA7, Amiens, France.
    Bravin, Alberto
    European Synchrotron Radiat Facil, Grenoble, France.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Perchiazzi, Gaetano
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Regional Behavior of Airspaces During Positive Pressure Reduction Assessed by Synchrotron Radiation Computed Tomography2019In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 10, article id 719Article in journal (Refereed)
    Abstract [en]

    Introduction: The mechanisms of lung inflation and deflation are only partially known. Ventilatory strategies to support lung function rely upon the idea that lung alveoli are isotropic balloons that progressively inflate or deflate and that lung pressure/volume curves derive only by the interplay of critical opening pressures, critical closing pressures, lung history, and position of alveoli inside the lung. This notion has been recently challenged by subpleural microscopy, magnetic resonance, and computed tomography (CT). Phase-contrast synchrotron radiation CT (PC-SRCT) can yield in vivo images at resolutions higher than conventional CT.

    Objectives: We aimed to assess the numerosity (ASden) and the extension of the surface of airspaces (ASext) in healthy conditions at different volumes, during stepwise lung deflation, in concentric regions of the lung. Methods: The study was conducted in seven anesthetized New Zealand rabbits. They underwent PC-SRCT scans (resolution of 47.7 mu m) of the lung at five decreasing positive end expiratory pressure (PEEP) levels of 12, 9, 6, 3, and 0 cmH(2)O during end-expiratory holds. Three concentric regions of interest (ROIs) of the lung were studied: subpleural, mantellar, and core. The images were enhanced by phase contrast algorithms. ASden and ASext were computed by using the Image Processing Toolbox for MatLab. Statistical tests were used to assess any significant difference determined by PEEP or ROI on ASden and ASext.

    Results: When reducing PEEP, in each ROI the ASden significantly decreased. Conversely, ASext variation was not significant except for the core ROI. In the latter, the angular coefficient of the regression line was significantly low.

    Conclusion: The main mechanism behind the decrease in lung volume at PEEP reduction is derecruitment. In our study involving lung regions laying on isogravitational planes and thus equally influenced by gravitational forces, airspace numerosity and extension of surface depend on the local mechanical properties of the lung.

  • 9.
    Schiffer, Tomas A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Friederich-Persson, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mitochondrial Reactive Oxygen Species and Kidney Hypoxia in the Development of Diabetic Nephropathy2017In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, article id 211Article, review/survey (Refereed)
    Abstract [en]

    The underlying mechanisms in the development of diabetic nephropathy are currently unclear and likely consist of a series of dynamic events from the early to late stages of the disease. Diabetic nephropathy is currently without curative treatments and it is acknowledged that even the earliest clinical manifestation of nephropathy is preceded by an established morphological renal injury that is in turn preceded by functional and metabolic alterations. An early manifestation of the diabetic kidney is the development of kidney hypoxia that has been acknowledged as a common pathway to nephropathy. There have been reports of altered mitochondrial function in the diabetic kidney such as altered mitophagy, mitochondrial dynamics, uncoupling, and cellular signaling through hypoxia inducible factors and AMP-kinase. These factors are also likely to be intertwined in a complex manner. In this review, we discuss how these pathways are connected to mitochondrial production of reactive oxygen species (ROS) and how they may relate to the development of kidney hypoxia in diabetic nephropathy. From available literature, it is evident that early correction and/or prevention of mitochondrial dysfunction may be pivotal in the prevention and treatment of diabetic nephropathy.

  • 10.
    Zanchi, Davide
    et al.
    Univ Basel Hosp, Dept Psychiat, Basel, Switzerland.
    Viallon, Magalie
    Univ Jean Monnet St Etienne, Univ Lyon, INSA Lyon, CNRS,UMR 5220,INSERM,U1206,CREATIS, St Etienne, France.; CHU St Etienne, Dept Radiol, St Etienne, France.
    Le Goff, Caroline
    Univ Liege, Dept Clin Chem, Liege, Belgium.
    Millet, Grégoire P
    Univ Lausanne, Inst Sports Sci, Lausanne, Switzerland.
    Giardini, Guido
    Department of Neurology and Stroke Unit, Mountain Medicine and Neurology Center Valle d'Aosta Regional Hospital, Aosta, Italy.
    Croisille, Pierre
    Univ Jean Monnet St Etienne, Univ Lyon, INSA Lyon, CNRS,UMR 5220,INSERM,U1206,CREATIS, St Etienne, France.; CHU St Etienne, Dept Radiol, St Etienne, France.
    Haller, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Affidea Ctr Diagnost Radiol Carouge CDRC, Geneva, Switzerland.; Univ Geneva, Fac Med, Geneva, Switzerland.; Univ Hosp Freiburg, Dept Neuroradiol, Freiburg, Germany.
    Extreme Mountain Ultra-Marathon Leads to Acute but Transient Increase in Cerebral Water Diffusivity and Plasma Biomarkers Levels Changes2017In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, article id 664Article in journal (Refereed)
    Abstract [en]

    Background: Pioneer studies demonstrate the impact of extreme sport load on the human brain, leading to threatening conditions for athlete's health such as cerebral edema. The investigation of brain water diffusivity, allowing the measurement of the intercellular water and the assessment of cerebral edema, can give a great contribution to the investigation of the effects of extreme sports on the brain. We therefore assessed the effect of supra-physiological effort (extreme distance and elevation changes) in mountain ultra-marathons (MUMs) athletes combining for the first time brain magnetic resonance imaging (MRI) and blood parameters.

    Methods:This longitudinal study included 19 volunteers (44.2 ± 9.5 years) finishing a MUM (330 km, elevation + 24000 m). Quantitative measurements of brain diffusion-weighted images (DWI) were performed at 3 time-points: Before the race, upon arrival and after 48 h. Multiple blood biomarkers were simultaneously investigated. Data analyses included brain apparent diffusion coefficient (ADC) and physiological data comparisons between three time-points.

    Results:The whole brain ADC significantly increased from baseline to arrival (p = 0.005) and then significantly decreased at recovery (p = 0.005) to lower values than at baseline (p = 0.005). While sodium, potassium, calcium, and chloride as well as hematocrit (HCT) changed over time, the serum osmolality remained constant. Significant correlations were found between whole brain ADC changes and osmolality (p = 0.01), cholesterol (p = 0.009), c-reactive protein (p = 0.04), sodium (p = 0.01), and chloride (p = 0.002) plasma level variations.

    Conclusions:These results suggest the relative increase of the inter-cellular volume upon arrival, and subsequently its reduction to lower values than at baseline, indicating that even after 48 h the brain has not fully recovered to its equilibrium state. Even though serum electrolytes may only indirectly indicate modifications at the brain level due to the blood brain barrier, the results concerning osmolality suggest that body water might directly influence the change in cerebral ADC. These findings establish therefore a direct link between general brain inter-cellular water content and physiological biomarkers modifications produced by extreme sport.

  • 11.
    Zhang, Suping
    et al.
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Huang, Qian
    Quanzhou Med Coll, Dept Physiol, Quanzhou, Peoples R China.
    Cai, Xiaoxia
    Honghe Hlth Vocat Coll, Dept Basic Med Sci, Mengzi, Peoples R China.
    Jiang, Shan
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Xu, Nan
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Zhou, Qin
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Cao, Xiaoyun
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tian, Jiong
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Lai, En Yin
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Osthole Ameliorates Renal Fibrosis in Mice by Suppressing Fibroblast Activation and Epithelial-Mesenchymal Transition2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 1650Article in journal (Refereed)
    Abstract [en]

    Renal fibrosis is a common pathway of virtually all progressive kidney diseases. Osthole (OST, 7-Methoxy-8-(3-methylbut-2-enyl)-2-chromenone), a derivative of coumarin mainly found in plants of the Apiaceae family, has shown inhibitory effects on inflammation, oxidative stress, fibrosis and tumor progression. The present study investigated whether OST mediates its effect via suppressing fibroblast activation and epithelial-mesenchymal transition (EMT) in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Herein, we found that OST inhibited fibroblast activation in a dose-dependent manner by inhibiting the transforming growth factor-beta 1 (TGF beta 1)-Smad pathway. OST also blocked fibroblast proliferation by reducing DNA synthesis and downregulating the expressions of proliferation- and cell cycle-related proteins including proliferating cell nuclear antigen (PCNA), CyclinD1 and p21 Waf1/Cip1. Meanwhile, in the murine model of renal interstitial fibrosis induced by UUO, myofibroblast activation with increased expression of alpha-smooth muscle actin (alpha-SMA) and proliferation were attenuated by OST treatment. Additionally, we provided in vivo evidence suggesting that OST repressed EMT with preserved E-cadherin and reduced Vimentin expression in obstructed kidney. UUO injury-induced upregulation of EMT-related transcription factors, Snail family transcriptional repressor-1(Snail 1) and Twist family basic helix-loop-helix (BHLH) transcription factor (Twist) as well as elevated G2/M arrest of tubular epithelial cell, were rescued by OST treatment. Further, OST treatment reversed aberrant expression of TGF beta 1-Smad signaling pathway, increased level of proinflammatory cytokines and NF-kappaB (NF-kappa B) activation in kidneys with obstructive nephropathy. Taken together, these findings suggest that OST hinder renal fibrosis in UUO mouse mainly through inhibition of fibroblast activation and EMT.

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