Arginase Isoforms Expression of Nitric Oxide Synthase and Populations Of
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Nitric Oxide in Health and Disease of the Nervous System H-Y Yun1,2, VL Dawson1,3,4 and TM Dawson1,3
Molecular Psychiatry (1997) 2, 300–310 1997 Stockton Press All rights reserved 1359–4184/97 $12.00 PROGRESS Nitric oxide in health and disease of the nervous system H-Y Yun1,2, VL Dawson1,3,4 and TM Dawson1,3 Departments of 1Neurology; 3Neuroscience; 4Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Nitric oxide (NO) is a widespread and multifunctional biological messenger molecule. It mediates vasodilation of blood vessels, host defence against infectious agents and tumors, and neurotransmission of the central and peripheral nervous systems. In the nervous system, NO is generated by three nitric oxide synthase (NOS) isoforms (neuronal, endothelial and immunologic NOS). Endothelial NOS and neuronal NOS are constitutively expressed and acti- vated by elevated intracellular calcium, whereas immunologic NOS is inducible with new RNA and protein synthesis upon immune stimulation. Neuronal NOS can be transcriptionally induced under conditions such as neuronal development and injury. NO may play a role not only in physiologic neuronal functions such as neurotransmitter release, neural development, regeneration, synaptic plasticity and regulation of gene expression but also in a variety of neurological disorders in which excessive production of NO leads to neural injury. Keywords: nitric oxide synthase; endothelium-derived relaxing factor; neurotransmission; neurotoxic- ity; neurological diseases Nitric oxide is probably the smallest and most versatile NO synthases isoforms and regulation of NO bioactive molecule identified. Convergence of multi- generation disciplinary efforts in the field of immunology, cardio- vascular pharmacology, chemistry, toxicology and neu- NO is formed by the enzymatic conversion of the guan- robiology led to the revolutionary novel concept of NO idino nitrogen of l-arginine by NO synthase (NOS). -
Dietary Supplementation with L-Arginine, Single Nucleotide
The Journal of Nutrition Commentary Dietary Supplementation with L-Arginine, Single Nucleotide Polymorphisms of Arginase Downloaded from https://academic.oup.com/jn/advance-article/doi/10.1093/jn/nxaa431/6131937 by University of Memphis - Library user on 10 February 2021 1 and 2, and Plasma L-Arginine Keith R Martin Center for Nutraceutical and Dietary Supplement Research, College of Health Sciences, University of Memphis, Memphis, TN, USA There are ∼3 million single nucleotide polymorphisms (SNPs) Arginine-dependent NO impacts the immune, neuronal, and between 2 unrelated individuals, with each SNP representing cardiovascular systems and is a potent vasodilator critical for a single modification in the genomic code and cumulatively vascular tone, blood pressure modulation, vascular permeabil- representing 0.1% human genetic diversity. Although many of ity, and angiogenesis (7–9). SNPs in the ARG1 gene are clinically these differences are silent, relatively recent data suggest that associated with cardiovascular diseases such as hypertension, around half of the various responses to dietary agents could cardiomyopathy, myocardial infarction, and carotid intima be related to genetic variation, a field coined as nutrigenetics. media thickness, and upregulation of arginase is implicated in These variations are of considerable interest in improving the vascular dysfunction (10, 11). Thus, dietary supplementation health of individuals and collectively mitigating the risk of with l-arginine could be warranted. chronic disease. In this issue of the Journal, Hannemann et The study by Hannemann et al. is the first to describe al. (1) describe a possible functional relation between arginase an association between genotypes of ARG1 and ARG2 with isoforms, important in the urea cycle and nitric oxide (NO) consequent circulating plasma concentrations of l-arginine. -
Mesenchymal Stem Cells Prevent the Progression of Diabetic
Lee et al. Experimental & Molecular Medicine (2019) 51:77 https://doi.org/10.1038/s12276-019-0268-5 Experimental & Molecular Medicine ARTICLE Open Access Mesenchymal stem cells prevent the progression of diabetic nephropathy by improving mitochondrial function in tubular epithelial cells Seung Eun Lee1,2,7,JungEunJang1,2,8,HyunSikKim2,MinKyoJung2,MyoungSeokKo2,Mi-OkKim2, Hye Sun Park2, Wonil Oh3, Soo Jin Choi3,HyeJinJin3, Sang-Yeob Kim4,YunJaeKim2,SeongWhoKim5, Min Kyung Kim5, Chang Ohk Sung6, Chan-Gi Pack 2,Ki-UpLee1,2 and Eun Hee Koh1,2 Abstract The administration of mesenchymal stem cells (MSCs) was shown to attenuate overt as well as early diabetic nephropathy in rodents, but the underlying mechanism of this beneficial effect is largely unknown. Inflammation and mitochondrial dysfunction are major pathogenic factors in diabetic nephropathy. In this study, we found that the repeated administration of MSCs prevents albuminuria and injury to tubular epithelial cells (TECs), an important element in the progression of diabetic nephropathy, by improving mitochondrial function. The expression of M1 macrophage markers was significantly increased in diabetic kidneys compared with that in control kidneys. Interestingly, the expression of arginase-1 (Arg1), an important M2 macrophage marker, was reduced in diabetic kidneys and increased by MSC treatment. In cultured TECs, conditioned media from lipopolysaccharide-activated 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; macrophages reduced peroxisomal proliferator-activated receptor gamma coactivator 1α (Pgc1a) expression and impaired mitochondrial function. The coculture of macrophages with MSCs increased and decreased the expression of Arg1 and M1 markers, respectively. Treatment with conditioned media from cocultured macrophages prevented activated macrophage-induced mitochondrial dysfunction in TECs. -
Nitric Oxide Produced by Ultraviolet-Irradiated Keratinocytes Stimulates Melanogenesis
Nitric oxide produced by ultraviolet-irradiated keratinocytes stimulates melanogenesis. C Roméro-Graillet, … , J P Ortonne, R Ballotti J Clin Invest. 1997;99(4):635-642. https://doi.org/10.1172/JCI119206. Research Article Ultraviolet (UV) radiation is the main physiological stimulus for human skin pigmentation. Within the epidermal-melanin unit, melanocytes synthesize and transfer melanin to the surrounding keratinocytes. Keratinocytes produce paracrine factors that affect melanocyte proliferation, dendricity, and melanin synthesis. In this report, we show that normal human keratinocytes secrete nitric oxide (NO) in response to UVA and UVB radiation, and we demonstrate that the constitutive isoform of keratinocyte NO synthase is involved in this process. Next, we investigate the melanogenic effect of NO produced by keratinocytes in response to UV radiation using melanocyte and keratinocyte cocultures. Conditioned media from UV-exposed keratinocytes stimulate tyrosinase activity of melanocytes. This effect is reversed by NO scavengers, suggesting an important role for NO in UV-induced melanogenesis. Moreover, melanocytes respond to NO-donors by decreased growth, enhanced dendricity, and melanogenesis. The rise in melanogenesis induced by NO-generating compounds is associated with an increased amount of both tyrosinase and tyrosinase-related protein 1. These observations suggest that NO plays an important role in the paracrine mediation of UV-induced melanogenesis. Find the latest version: https://jci.me/119206/pdf Nitric Oxide Produced by Ultraviolet-irradiated Keratinocytes Stimulates Melanogenesis Christine Roméro-Graillet, Edith Aberdam, Monique Clément, Jean-Paul Ortonne, and Robert Ballotti Institut National de la Santé et de la Recherche Médicale U385, Faculté de Médecine, 06107 Nice cedex 02, France Abstract lin-1 (ET-1),1 and GM-CSF by keratinocytes is upregulated after UV light exposure, and these peptides stimulate melanocyte Ultraviolet (UV) radiation is the main physiological stimu- growth (16–19). -
Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury’S Biological Network Based on Systematic Pharmacology
ORIGINAL RESEARCH published: 25 June 2021 doi: 10.3389/fphar.2021.601846 Exploring the Regulatory Mechanism of Hedysarum Multijugum Maxim.-Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury’s Biological Network Based on Systematic Pharmacology Kailin Yang 1†, Liuting Zeng 1†, Anqi Ge 2†, Yi Chen 1†, Shanshan Wang 1†, Xiaofei Zhu 1,3† and Jinwen Ge 1,4* Edited by: 1 Takashi Sato, Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of 2 Tokyo University of Pharmacy and Life Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China, Galactophore Department, The First 3 Sciences, Japan Hospital of Hunan University of Chinese Medicine, Changsha, China, School of Graduate, Central South University, Changsha, China, 4Shaoyang University, Shaoyang, China Reviewed by: Hui Zhao, Capital Medical University, China Background: Clinical research found that Hedysarum Multijugum Maxim.-Chuanxiong Maria Luisa Del Moral, fi University of Jaén, Spain Rhizoma Compound (HCC) has de nite curative effect on cerebral ischemic diseases, *Correspondence: such as ischemic stroke and cerebral ischemia-reperfusion injury (CIR). However, its Jinwen Ge mechanism for treating cerebral ischemia is still not fully explained. [email protected] †These authors share first authorship Methods: The traditional Chinese medicine related database were utilized to obtain the components of HCC. The Pharmmapper were used to predict HCC’s potential targets. Specialty section: The CIR genes were obtained from Genecards and OMIM and the protein-protein This article was submitted to interaction (PPI) data of HCC’s targets and IS genes were obtained from String Ethnopharmacology, a section of the journal database. -
Investigation of COVID-19 Comorbidities Reveals Genes and Pathways Coincident with the SARS-Cov-2 Viral Disease
bioRxiv preprint doi: https://doi.org/10.1101/2020.09.21.306720; this version posted September 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Title: Investigation of COVID-19 comorbidities reveals genes and pathways coincident with the SARS-CoV-2 viral disease. Authors: Mary E. Dolan1*,2, David P. Hill1,2, Gaurab Mukherjee2, Monica S. McAndrews2, Elissa J. Chesler2, Judith A. Blake2 1 These authors contributed equally and should be considered co-first authors * Corresponding author [email protected] 2 The Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609, USA Abstract: The emergence of the SARS-CoV-2 virus and subsequent COVID-19 pandemic initiated intense research into the mechanisms of action for this virus. It was quickly noted that COVID-19 presents more seriously in conjunction with other human disease conditions such as hypertension, diabetes, and lung diseases. We conducted a bioinformatics analysis of COVID-19 comorbidity-associated gene sets, identifying genes and pathways shared among the comorbidities, and evaluated current knowledge about these genes and pathways as related to current information about SARS-CoV-2 infection. We performed our analysis using GeneWeaver (GW), Reactome, and several biomedical ontologies to represent and compare common COVID- 19 comorbidities. Phenotypic analysis of shared genes revealed significant enrichment for immune system phenotypes and for cardiovascular-related phenotypes, which might point to alleles and phenotypes in mouse models that could be evaluated for clues to COVID-19 severity. -
Potential Roles of Nitrate and Nitrite in Nitric Oxide Metabolism in the Eye Ji Won Park1, Barbora Piknova1, Audrey Jenkins2, David Hellinga2, Leonard M
www.nature.com/scientificreports OPEN Potential roles of nitrate and nitrite in nitric oxide metabolism in the eye Ji Won Park1, Barbora Piknova1, Audrey Jenkins2, David Hellinga2, Leonard M. Parver3 & Alan N. Schechter1* Nitric oxide (NO) signaling has been studied in the eye, including in the pathophysiology of some eye diseases. While NO production by nitric oxide synthase (NOS) enzymes in the eye has been − characterized, the more recently described pathways of NO generation by nitrate ( NO3 ) and nitrite − (NO2 ) ions reduction has received much less attention. To elucidate the potential roles of these pathways, we analyzed nitrate and nitrite levels in components of the eye and lacrimal glands, primarily in porcine samples. Nitrate and nitrite levels were higher in cornea than in other eye parts, while lens contained the least amounts. Lacrimal glands exhibited much higher levels of both ions compared to other organs, such as liver and skeletal muscle, and even to salivary glands which are known to concentrate these ions. Western blotting showed expression of sialin, a known nitrate transporter, in the lacrimal glands and other eye components, and also xanthine oxidoreductase, a nitrate and nitrite reductase, in cornea and sclera. Cornea and sclera homogenates possessed a measurable amount of nitrate reduction activity. These results suggest that nitrate ions are concentrated in the lacrimal glands by sialin and can be secreted into eye components via tears and then reduced to nitrite and NO, thereby being an important source of NO in the eye. Te NO generation pathway from L-arginine by endogenous NOS enzymes under normoxic conditions has been central in identifying the physiological roles of NO in numerous biological processes1. -
Nitric Oxide Signaling in Plants
plants Editorial Nitric Oxide Signaling in Plants John T. Hancock Department of Applied Sciences, University of the West of England, Bristol BS16 1QY, UK; [email protected]; Tel.: +44-(0)117-328-2475 Received: 3 November 2020; Accepted: 10 November 2020; Published: 12 November 2020 Abstract: Nitric oxide (NO) is an integral part of cell signaling mechanisms in animals and plants. In plants, its enzymatic generation is still controversial. Evidence points to nitrate reductase being important, but the presence of a nitric oxide synthase-like enzyme is still contested. Regardless, NO has been shown to mediate many developmental stages in plants, and to be involved in a range of physiological responses, from stress management to stomatal aperture closure. Downstream from its generation are alterations of the actions of many cell signaling components, with post-translational modifications of proteins often being key. Here, a collection of papers embraces the differing aspects of NO metabolism in plants. Keywords: nitrate reductase; nitration; nitric oxide; reactive oxygen species; stress responses; S-nitrosation; S-nitrosylation; SNO-reductase; thiol modification 1. Introduction Nitric oxide (NO) is now well acknowledged as an instrumental signaling molecule in both plants and animals [1]. First recognized as important as a signal in the control of vascular tone [2], its role in plants came to prominence in the late 1990s [3–5]. The forty years of research into NO in plants has just been highlighted by a review by Kolbert et al. [6]. In plants, NO has been found to be involved in a wide range of developmental stages and physiological responses. -
The Urea Cycle Is Transcriptionally Controlled by Hypoxia
bioRxiv preprint doi: https://doi.org/10.1101/2021.01.25.428152; this version posted January 27, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The urea cycle is transcriptionally controlled by hypoxia-inducible factors Charandeep Singh1, Andrew Benos1, Allison Grenell1,2, Vincent Tran1, Demiana Hanna1, Bela Anand-Apte1,3, Henri Brunengraber4, Jonathan E. Sears1,5 1Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195, USA. 2Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. 3Department of Ophthalmology and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH 44195, USA. 4Department of Nutrition, Case Western Reserve School of Medicine Cleveland, Cleveland, OH, 44106, USA. 5Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195, USA. Keywords Transcriptional regulation, stable-isotope, carbamoyl phosphate synthetase 1, arginase 1, FG-4592, urea cycle, HIF Abbreviations HIF PHi, hypoxia inducible factor-prolyl hydroxylase inhibition; OIR, oxygen induced retinopathy; CPS1, Carbamoyl phosphate synthetase I; ARG1, Arginase 1; ARG2, Arginase 2; OTC, Ornithine transcarbamylase; HNF3-β, Hepatocyte nuclear factors; bioRxiv preprint doi: https://doi.org/10.1101/2021.01.25.428152; this version posted January 27, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Here, we demonstrate transcriptional regulation of urea cycle genes CPS1 and ARG1 by hypoxia-inducible factors (HIFs) and demonstrate a hepatic HIF dependent increase in urea cycle activity. -
Synthase from Rat Liver
Proc. Nati. Acad. Sci. USA Vol. 89, pp. 5361-5365, June 1992 Biochemistry Purification of a distinctive form of endotoxin-induced nitric oxide synthase from rat liver (endothelium-derived relaxing factor/L-arginine/calmodulin) TOM EVANS, ADAM CARPENTER, AND JONATHAN COHEN* Department of Infectious Diseases, Royal Postgraduate Medical School, Du Cane Road, London W12 ONN, United Kingdom Communicated by Robert F. Furchgott, March 6, 1992 (received for review November 18, 1991) ABSTRACT An endotoxin-induced form of nitric oxide We are interested in the hepatic form of the NO synthase, synthase (EC 1.14.23) was purified to homogeneity from rat which is induced by the administration of endotoxin (8). liver by sequential anion-exchange chromatography and afflin- Livers from untreated animals show minimal NO synthase ity chromatography using 2',5'-ADP-Sepharose. The enzyme activity. NO production in the liver seems to suppress protein has a subunit molecular mass of 135 kDa as determined by synthesis and protects the liver against damage (18). We have SDS/PAGE, a maximum specific activity of 462 nmol of purified this enzyme to homogeneity and show that it is citrulline formed from arginine per min per mg, and a K. for strongly stimulated by calmodulin, whereas its activity is arginine of 11 jIM. The enzyme was strongly stimulated by the only affected to a small degree by free calcium concentra- addition of calmodulin with an EC50 of 2 nM, but removal of tions-even in the presence ofcalmodulin. Thus, this hepatic free calcium from the assay medium only reduced activity by endotoxin-induced NO synthase is distinct from that de- 15%. -
Nitro-L-Arginine Methyl Ester (L-NAME) Causes Limb Defects in Mouse Fetuses: Protective Effect of Acute Hyperoxia
0031-3998/03/5401-0069 PEDIATRIC RESEARCH Vol. 54, No. 1, 2003 Copyright © 2003 International Pediatric Research Foundation, Inc. Printed in U.S.A. The Nitric Oxide Synthesis Inhibitor N -Nitro-L-Arginine Methyl Ester (L-NAME) Causes Limb Defects in Mouse Fetuses: Protective Effect of Acute Hyperoxia GIAN MARIO TIBONI, FRANCA GIAMPIETRO, AND CAMILLO DI GIULIO Sezione di Ostetricia e Ginecologia, Dipartimento di Medicina e Scienze dell’Invecchiamento [G.M.T., F.G.], and Sezione di Fisiologia, Dipartimento di Scienze Biomediche [C.d.G.], Facoltà di Medicina e Chirurgia, Università “G. d’Annunzio”, Chieti, Italy. ABSTRACT In the present study the relationship between exposure to the teratogenesis was investigated. To this aim, a group of L-NAME– nitric oxide synthesis inhibitor N -nitro-L-arginine methyl ester treated animals (90 mg/kg s.c. on gestation d 14) were exposed (L-NAME) and the induction of limb defects, with respect to to 98 to 100% O2 for 12 h. L-NAME–treated mice breathing stage specificity and dose dependency, was investigated in the room air served as positive controls. In response to hyperoxia, a mouse. ICR (CD-1) mice were dosed s.c with L-NAME at 50 or significant decrement of L-NAME–induced limb defects was 90 mg/kg on gestation d 12, 13, 14, 15, or 16. A group of animals found. This study characterizes for the first time the teratogenic treated with vehicle on gestation d 14 served as control. Uterine capacity of L-NAME in the mouse. Results obtained with hyper- contents were evaluated for teratogenesis on gestation d 18. -
Effect of Arginase Inhibition on Ischemia-Reperfusion Injury in Patients with Coronary Artery Disease with and Without Diabetes Mellitus
Effect of Arginase Inhibition on Ischemia-Reperfusion Injury in Patients with Coronary Artery Disease with and without Diabetes Mellitus Oskar Ko¨ vamees*, Alexey Shemyakin, John Pernow Department of Medicine, Karolinska Institutet, Stockholm, Sweden Abstract Background: Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD) and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes (Clinical trial registration number: NCT02009527). Methods: Male patients with CAD (n = 12) or CAD + type 2 diabetes (n = 12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (Nv-hydroxy-nor- L-arginine, 0.1 mg/min) or saline. Results: The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.765.2% to 7.964.0% during saline administration (P,0.05). Nv-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.364.3% at baseline vs. 11.563.6% at reperfusion). Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P,0.01).