Hormonal Control of Osmoregulatory Functions

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Int. J. Med. Sci. 2007, 4 131International Journal of Medical Sciences ISSN 1449-1907 www.medsci.org 2007 4(3):131-139 © Ivyspring International Publisher. All rights reserved Research Paper Thioglycosides as inhibitors of hSGLT1 and hSGLT2: Potential therapeutic agents for the control of hyperglycemia in diabetes Francisco Castaneda1, Antje Burse2, Wilhelm Boland2, Rolf K-H. Kinne1 1. Laboratory for Molecular Pathobiochemistry and Clinical Research, Max Planck Institute of Molecular Physiology, Dort-mund, Germany; 2. Max Planck Institute for Chemical Ecology, Dortmund, Germany Correspondence to: Francisco Castaneda, MD, Laboratory for Molecular Pathobiochemistry and Clinical Research, Max Planck Institute for Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany; Tel. 49-231-9742-6490, Fax. 49-231-133-2699, E-mail: francisco.castaneda@mpi-dortmund.mpg.de Received: 2007.04.14; Accepted: 2007.04.30; Published: 2007.05.05 The treatment of diabetes has been mainly focused on maintaining normal blood glucose concentrations. Insulin and hypoglycemic agents have been used as standard therapeutic strategies. However, these are characterized by limited efficacy and adverse side effects, making the development of new therapeutic alternatives mandatory. Inhibition of glucose reabsorption in the kidney, mediated by SGLT1 or SGLT2, represents a promising thera-peutic approach. Therefore, the aim of the present study was to evaluate the effect of thioglycosides on human SGLT1 and SGLT2. For this purpose, stably transfected Chinese hamster ovary (CHO) cells expressing human SGLT1 and SGLT2 were used. The inhibitory effect of thioglycosides was assessed in transport studies and membrane potential measurements, using α-methyl-glucoside uptake and fluorescence resonance energy trans-fer, respectively. We found that some thioglycosides inhibited hSGLT more strongly than phlorizin. Specifically, thioglycoside I (phenyl-1’-thio-β-D-glucopyranoside) inhibited hSGLT2 stronger than hSGLT1 and to a larger extent than phlorizin. Thioglycoside VII (2-hydroxymethyl-phenyl-1’-thio-β-D-galacto-pyranoside) had a pro-nounced inhibitory effect on hSGLT1 but not on hSGLT2. Kinetic studies confirmed the inhibitory effect of these thioglycosides on hSGLT1 or hSGLT2, demonstrating competitive inhibition as the mechanism of action. There-fore, these thioglycosides represent promising therapeutic agents for the control of hyperglycemia in patients with diabetes. Key words: Thioglycoside, sodium-dependent glucose transport, α-methyl-glucoside uptake, fluorescence resonance energy transfer, diabetes, hyperglycemia 1. Introduction Diabetes mellitus is characterized by reduced insulin secretion from pancreatic β-cells (type 1 diabe-tes) [1] or deficient insulin action (type 2 diabetes) [2], both causing an increase in blood glucose concentra-tion. High blood glucose (hyperglycemia) represents the main pathogenic factor for the development of diabetic complications including coronary heart dis-ease, retinopathy, nephropathy, and neuropathy [3, 4]. In addition, chronic hyperglycemia leads to progres-sive impairment of insulin secretion and to insulin resistance of peripheral tissues (referred to as glucose toxicity) [1, 2, 5, 6]. As a consequence, the treatment of diabetes has been mainly focused on maintaining normal blood glucose levels. For that purpose either insulin or Hormonal Control of Osmoregulatory Functions Hormonal Control of Osmoregulatory Functions Bởi: OpenStaxCollege While the kidneys operate to maintain osmotic balance and blood pressure in the body, they also act in concert with hormones Hormones are small molecules that act as messengers within the body Hormones are typically secreted from one cell and travel in the bloodstream to affect a target cell in another portion of the body Different regions of the nephron bear specialized cells that have receptors to respond to chemical messengers and hormones [link] summarizes the hormones that control the osmoregulatory functions Hormones That Affect Osmoregulation Hormone Where produced Function Epinephrine Can decrease kidney function temporarily by and Adrenal medulla vasoconstriction Norepinephrine Renin Kidney nephrons Increases blood pressure by acting on angiotensinogen Angiotensin Liver Angiotensin II affects multiple processes and increases blood pressure Aldosterone Adrenal cortex Prevents loss of sodium and water Anti-diuretic hormone (vasopressin) Hypothalamus (stored in the posterior pituitary) Prevents water loss 1/5 Hormonal Control of Osmoregulatory Functions Hormones That Affect Osmoregulation Hormone Atrial natriuretic peptide Where produced Function Heart atrium Decreases blood pressure by acting as a vasodilator and increasing glomerular filtration rate; decreases sodium reabsorption in kidneys Epinephrine and Norepinephrine Epinephrine and norepinephrine are released by the adrenal medulla and nervous system respectively They are the flight/fight hormones that are released when the body is under extreme stress During stress, much of the body’s energy is used to combat imminent danger Kidney function is halted temporarily by epinephrine and norepinephrine These hormones function by acting directly on the smooth muscles of blood vessels to constrict them Once the afferent arterioles are constricted, blood flow into the nephrons stops These hormones go one step further and trigger the renin-angiotensin-aldosterone system Renin-Angiotensin-Aldosterone The renin-angiotensin-aldosterone system, illustrated in [link] proceeds through several steps to produce angiotensin II, which acts to stabilize blood pressure and volume Renin (secreted by a part of the juxtaglomerular complex) is produced by the granular cells of the afferent and efferent arterioles Thus, the kidneys control blood pressure and volume directly Renin acts on angiotensinogen, which is made in the liver and converts it to angiotensin I Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II Angiotensin II raises blood pressure by constricting blood vessels It also triggers the release of the mineralocorticoid aldosterone from the adrenal cortex, which in turn stimulates the renal tubules to reabsorb more sodium Angiotensin II also triggers the release of anti-diuretic hormone (ADH) from the hypothalamus, leading to water retention in the kidneys It acts directly on the nephrons and decreases glomerular filtration rate Medically, blood pressure can be controlled by drugs that inhibit ACE (called ACE inhibitors) 2/5 Hormonal Control of Osmoregulatory Functions The renin-angiotensin-aldosterone system increases blood pressure and volume The hormone ANP has antagonistic effects (credit: modification of work by Mikael Häggström) Mineralocorticoids Mineralocorticoids are hormones synthesized by the adrenal cortex that affect osmotic balance Aldosterone is a mineralocorticoid that regulates sodium levels in the blood Almost all of the sodium in the blood is reclaimed by the renal tubules under the influence of aldosterone Because sodium is always reabsorbed by active transport and water follows sodium to maintain osmotic balance, aldosterone manages not only sodium levels but also the water levels in body fluids In contrast, the aldosterone also stimulates potassium secretion concurrently with sodium reabsorption In contrast, absence of aldosterone means that no sodium gets reabsorbed in the renal tubules and all of it gets excreted in the urine In addition, the daily dietary potassium load is not secreted and the retention of K+ can cause a dangerous increase in plasma K+ concentration Patients who have Addison's disease have a failing adrenal cortex and cannot produce aldosterone They lose sodium in their urine constantly, and if the supply is not replenished, the consequences can be fatal Antidiurectic Hormone As previously discussed, antidiuretic hormone or ADH (also called vasopressin), as the name suggests, helps the body conserve water when body fluid volume, especially that of blood, is low It is formed by the hypothalamus and is stored and released from the posterior pituitary It acts by inserting aquaporins in the collecting ducts and promotes reabsorption of water ADH also acts as a vasoconstrictor and increases blood pressure during hemorrhaging 3/5 Hormonal Control of Osmoregulatory Functions Atrial ...Int. J. Med. Sci. 2005 2 91International Journal of Medical Sciences ISSN 1449-1907 www.medsci.org 2005 2(3):91-92 ©2005 Ivyspring International Publisher. All rights reserved Editorial Birth Defects Are Preventable Andrew E. Czeizel Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary Corresponding address: Andrew E. Czeizel Foundation for the Community Control of Hereditary Diseases, 1148 Budapest, Bolgárkerék utca 3. Hungary Received: 2005.05.01; Accepted: 2005.05.25; Published: 2005.07.01 Editorial Birth defects – or by according to the World Health Organization’s (WHO) term: congenital anomalies – are structural, functional and/or biochemical-molecular defects present at birth whether detected at that time or not (Figure 1). Among different categories of birth defects, congenital abnormalities, i.e. structural-morphological defects represent the largest one. Congenital abnormalities can be divided into three groups: 1. Lethal if the defects (such as anencephaly or hypoplastic left heart syndrome) cause stillbirth (late fetal death) or infant death or pregnancies are terminated after the prenatal diagnosis of fetal defects in more than 50% of cases. 2. Severe if the defects (such as cleft lip or congenital pyloric stenosis) without medical intervention cause handicap or death. 3. Mild if defects (such as congenital dislocation of the hip or undescended testis) require medical intervention but life expectancy is good. Lethal and severe defects together constitute major congenital abnormalities. Minor anomalies or morphological variants (such as epicanthal folds, ocular hypotelorism, preauricular tags and pits, low-set ears, simian crease, clino- and camptodactyly, partial syndactyly between toes 2 and 3, hydrocele, umbilical hernia, sacral dimple, etc) without serious medical or cosmetic consequences are excluded from the category of congenital abnormalities. In general we cannot measure the incidence of congenital abnormalities due to the prenatal loss of fetuses such as blighted ova, miscarriages and ectopic pregnancies. Thus we used the term birth (live- and stillbirths) prevalence in the past. However, recently the different methods of prenatal diagnoses have been used widely for the detection of fetal defects and pregnancies are frequently terminated if the fetus is severely affected. Thus, the rate of defects is calculated for informative offspring including (i) live born infants, (ii) stillborn fetuses, and (iii) prenatal diagnosed and terminated affected fetuses and the term total (birth and fetal) prevalence of congenital abnormalities is used. Of course, the total prevalence of congenital abnormalities depends on the spectrum of congenital abnormalities evaluated, the period of study (only at birth or in early neonatal period or prenatal or the whole infant period are included), the completeness of ascertainment, the diagnostic skill of experts, demographic and genetic characteristics of the study population, etc. In Hungary the total prevalence of congenital abnormalities was 66.83 per 1000 informative offspring in the 1980s and within this, the total rate of major congenital abnormalities was 27.01 per 1000 informative offspring [1,2]. The causes of congenital abnormalities can be classified into three main groups: 1. Genetic which includes chromosomal aberrations (e.g. Down syndrome) and Mendelian single-gene defects (e.g. achondroplasia or Holt-Oram syndrome). The proportion of genetic origin is Journal of Water and Environment Technology, Vol. 8, No.3, 2010 Address correspondence to Jun Nakajima, Department of Environmental Systems Engineering, Faculty of Science and Engineering, Ritsumeikan University, Email: jnt07778@se.ritsumei.ac.jp Received May 7, 2010, Accepted July 7, 2010. - 203 - Control of Membrane Fouling by Coagulant and Coagulant Aid Addition in Membrane Bioreactor Systems Tuyet T. TRAN*, Md. SHAFIQUZZAMAN*, Jun NAKAJIMA* * Department of Environmental Systems Engineering, Faculty of Science and Engineering, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu 525-8577, Japan. ABSTRACT The mixture of polysilicate and Fe(III), and commercial polysilicato-iron (PSI) were employed to control membrane fouling risk. Batch experiments and long-term membrane bioreactor (MBR) experiments were conducted with the addition of 1) polysilicate, 2) mixtures of polysilicate and Fe(III) with various ratios, and 3) sole Fe(III) and commercial PSI with two available molar ratios, Fe/Si = 1:1 (PSI-100) and Fe/Si = 1:0.25 (PSI-025). Sole polysilicate addition in MBR showed no effect on controlling membrane fouling risk, while the mixture of polysilicate and Fe(III) could yield some advantages at a specific combination, 90 mg/L Fe(III) with 5 mg/L Si for batch experiment, and 45 mg/L Fe(III) with 20 mg/L Si for long-term MBR experiment. On the other hand, the higher efficiency of biopolymer removal was attained by the addition of PSI in batch experiments. Furthermore, the membrane fouling frequencies were reduced and the concentrations of protein and carbohydrate in soluble microbial products (SMP less than 1m) were largely diminished by the addition of PSI in long-term MBR experiments. These results suggested that PSI would be useful to control membrane fouling problem and enhance the performance of membrane filtration. Keywords: coagulants, fouling, MBR, mixture of polysilicate and Fe(III), polysilicato – iron (PSI). INTRODUCTION Membrane bioreactor (MBR) technology combines the biological degradation process by activated sludge with a direct solid-liquid separation by membrane filtration. Through micro or ultrafiltration membrane technology (with pore sizes ranging from 0.05 to 0.4 m), MBR system allows the complete physical retention of bacterial flocs and virtually all suspended solids within the bioreactor (Le-Clech et al., 2006; Tran et al., 2006; Mishima and Nakajima, 2009). The MBR has brought several advantages for conventional wastewater treatment process, including stable and high effluent quality, good disinfection capability, and less excess sludge production (Mishima and Nakajima, 2003; Le-Clech et al., 2006; Meng et al., 2009). However, membrane fouling, which results in the reduction of permeate flux or an increase of transmembrane pressure (TMP), is still the most serious problem in this process (Jarusutthirak and Amy, 2006; Arabi and Nakhal, 2008; Wu et al., 2006; Yu et al., 2006). According to Zhang et al. (2008), several factors have been found to affect membrane fouling, including floc size, viscosity of mixed liquor, and especially soluble microbial products (SMP). SMP are compounds of microbial origin which are derived during biological processes of wastewater treatment (Drews et al., 2007; Ichihashi et al., 2006). They exhibit the characteristics           DISSECTING THE HORMONAL CONTROL OF THE SALT STRESS RESPONSE IN ARABIDOPSIS ROOTS YU GENG A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF BIOLOGICAL SCIENCES NATIONAL UNIVERSITY OF SINGAPORE 2013               ACKNOWLEDGEMENT   ACKNOWLEDGEMENT First I would like to thank my supervisor José R. Dinneny. He is the one who gave me the opportunity to start this amazing journey. He is also the one giving me lots of help and support in the past four years. He makes me became a better scientist. I appreciate Department of Biological Science in National University of Singapore for allowing me to be a part of the top university in Asia. I appreciate Temasek Life Sciences Laboratory and Carnegie Institution for Science for their generous financial support. There is no way I can finish my Ph D training without them. I would like to thank all the members in Dinneny’s lab for the discussions and help. I am very lucky to work with these people. I would like to thank people from Yu Hao’s lab in TLL, people from Wang Zhiyong’s lab in Carnegie, David Ehrhardt and Heather Cartwright for their valuable advice and help. Finally, I would like to thank my family and friends for them to understand me, stand by me no matter what decision I made. Aug 2013 Geng Yu i   TABLE OF CONTENTS   TABLE OF CONTENTS ACKNOWLEGEMENT i TABLE OF CONTENTS ii SUMMARY . vii LIST OF TABLES . ix LIST OF FIGURES x LIST OF ABBREVIATIONS AND SYMBOLS . xiii Chapter LITERATURE REVIEW . 1.1 Introduction . 1.2 Salt stress in plants . 1.2.1 Early effects . 1.2.2 Long term effects . 1.3 Salt stress signaling in plants . 1.3.1 CBL-CIPK signaling network .7 1.3.1.1 Salt Overly Sensitive (SOS) pathway 1.3.1.2 CBL1/CBL9-CIPK23-AKT1 network and K+ transportation .9 1.3.2 Osmotic stress signaling .10 1.3.3 The transcriptional programs and phyto-hormones in salt stress response .11 1.3.3.1 ABA biosynthesis and signaling pathways, and its function in salt stress…………………………………………………………………………… .11 ii   TABLE OF CONTENTS   1.3.3.2 Jasmonates ( JAs) biosynthesis and signaling pathway and its function in salt stress 16 1.3.3.3 Ethylene (ET) biosynthesis and signaling pathway and its function in salt stress .18 1.3.3.4 Gibberellic acid (GA) and Brassinosteriod (BR), two positive growth regulators and their functions in salt stress 20 1.4 Arabidopsis root development .23 1.5 Cell type specific studies in Arabidopsis roots 25 1.6 Objective and significance of this study 28 Chapter MATERIAL AND METHODS .31 2.1 Plant materials .32 2.2 Plant growth conditions 32 2.3 Live-imaging and data analysis .33 2.4 Sample preparation, RNA isolation, microarray hybridization and data analysis: Agilent array 33 2.4.1 Protoplasting of roots and isolation of GFP-enriched cell populations by FACS   Chapter RESULTS AND DISCUSSION 87       4.1 Abstract   High salinity is an important agricultural contaminant that causes damage to the plant. However, the distinctive roles of different cell types in the transition process from normal growth to stress acclimation are largely unknown. Here, we show that ethylene promotes radial expansion of cortex cells through the canonical ethylene signaling pathway, while its precursor ACC may have an ethylene-independent function of inhibiting cell elongation during salt stress. By using mutants that have radial patterning defects, we show that salt-mediated induction of ethylene biosynthetic pathway members at the transcriptional level depends on the endodermis. In order to find the components that work downstream of ethylene in regulating salt-mediated cell swelling, we performed microarray experiments with ethylene signaling mutants at early stages of salt stress. Bioinformatic analysis revealed cell-type specificity in the expression pattern of the downstream targets of ethylene during salt stress, indicating the cell-type specific function of ethylene in regulating the salt response. Further, we demonstrated that local synthesis of auxin in the early elongation zone serves as a downstream component of ethylene signaling during salt stress. Based on these observations, we that ethylene promotes salt-mediated cortical cell swelling through auxin signaling in an endodermisdependent manner.           88       4.2 Introduction   Plants, through intricate compositions of cell and tissue types, are good planners. In favorable habitats, they plan their lives in a simple and effective way. However, when they are facing stressful environments, they need to quickly coordinate their different tissue layers, conduct complex regulation to change their developmental and physiological plane to adapt to such environments. Salt stress is one of the most common environmental stresses. It creates both osmotic and ionic stress to affect plant growth. Decades of research into the effects of salinity on plant physiology and development have generated a wealth of information. However, the distinctive roles of different cell types in the transition process from normal growth to stress adaptation are largely unknown. In this study, we used a particular salt-sensitive plant, Arabidopsis thaliana, focusing on one environmental stress, high salinity, in order to understand how plants make this transition and how different cell types contribute to this process.     High salinity has complex effects on root physiology. These effects are mainly caused by both osmotic stress and ionic stress. When the rhizosphere soil is contaminated with toxic soluble molecules, like NaCl, the water potential of the soil become lower, making it more difficult for plants to take up water from the environment. When the cells are suffering from dehydration, the turgor pressure of the cells against their cell walls is reduced, which can reduce the rigidity of plants and make them more vulnerable to wounding. Along with water deprivation becoming more and more severe, many biological processes, such as photosynthesis, are disrupted (Allen et al., 2001). 89       Furthermore, due to their similar chemical properties, the high amount of Na+ will break the K+/Na+ balance, leading to K+ deprivation by engrossing ion channels, which are normally used to transport K+ into the cell (Rubio et al., 1995). It has been shown that K+ is crucial for the activity of many enzymes; lack of K+ will largely affect plant development and growth (Shabala et al., 2008).     When exposed to salt stress, the Arabidopsis root undergoes dramatic morphological changes, which include the inhibition of primary root elongation, reduction of meristem size, and inhibition of lateral root formation in a dosage-dependent manner (Burssens et al., 2000; West et al., 2004; Wang et al., 2009). Besides ... filtration rate Medically, blood pressure can be controlled by drugs that inhibit ACE (called ACE inhibitors) 2/5 Hormonal Control of Osmoregulatory Functions The renin-angiotensin-aldosterone system.. .Hormonal Control of Osmoregulatory Functions Hormones That Affect Osmoregulation Hormone Atrial natriuretic peptide... acts as a vasoconstrictor and increases blood pressure during hemorrhaging 3/5 Hormonal Control of Osmoregulatory Functions Atrial Natriuretic Peptide Hormone The atrial natriuretic peptide (ANP)