Nitric oxide and liver health -
The liver is one organ clearly influenced by nitric oxide, and acute versus chronic exposure to this substance has been associated with distinct patterns of liver disease. Bacterial infections, including the sepsis syndrome, acutely increase nitric oxide systemically and may lead to acute hepatic dysfunction.
We review etiology, diagnosis, and treatment of cholestasis associated with these infections, because this condition in particular has been linked to nitric oxide. Chronic increases in nitric oxide may cause the hyperdynamic circulation seen in cirrhosis and portal hypertension.
Therefore, we also review etiology, diagnosis, and treatment of the hepatorenal and hepatopulmonary syndromes, because both these syndromes occur in end-stage liver disease, and they may be linked to nitric oxide as well.
An appreciation of nitric oxide and its evolving role in hepatology may be important to understand the pathogenesis of and treatment strategies for these different types of liver disease.
Briefly, two-step process was performed, in which first step converted nitrate to nitrite utilizing nitrate reductase. The amount of the azochromophore accurately reflects NO amount in samples.
Then, the supernatant was collected. A fresh silicon wafer was placed at each collection time. Liver lysate, urine and serum were deproteinized before analyses.
The liver, urine and serum were prepared similar to NO assay. Oxidative stress was assessed by measuring malondialdehyde MDA , the end products of lipid peroxidation. MDA content of liver and serum was measured by a spectrophotometric assay by using Lipid Peroxidation assay kit BioVision, Milpitas, CA.
Liver tissue was homogenized on ice in MDA lysis buffer, and then centrifuged to remove insoluble material. MDA content was expressed as nmol per ml or nmol per mg liver tissue. The caspase 3 activity is one of important hallmarks to assess apoptosis pathway.
The caspase 3 activity was measured by using Caspase 3 assay kit Abcam, Cambrige, UK according to the assay protocol. Briefly, liver tissue was homogenized on ice in lysis buffer, then, incubated with the substrate DEVD-AFC AFC: 7-aminotrifluoromethyl coumarin which emits blue light.
With the present of activated caspase 3, the substrate DEVD-AFC was cleaved to form free AFC which emits a yellow-green. The cleavage of substrate was quantified by fluorometer.
The caspase 3 activity was expressed as RPU per mg protein liver tissue. The miRNeasy Mini Kit Qiagen, Valencia, CA, USA was used to extract total RNA from cells and liver tissues.
Gene expression was measured by real-time PCR using the cDNAs, SYBR qPCR Mix Reagents Toyobo , and gene-specific oligonucleotide primers Supplementary Table S2 with an ABI Prism Fast Real-Time PCR System Applied Biosystems, Foster, CA, USA.
Glyceraldehydephosphate dehydrogenase Gapdh level was used to normalize the relative abundance of mRNAs. Membranes were then incubated with horseradish peroxidase conjugated secondary antibodies at dilutions. Immunoreactive bands were visualized using the electrochemiluminescence detecting reagent GE Healthcare UK Ltd, Buckinghamshire , and documented with the Fujifilm Image Reader LAS Fujifilm, Tokyo, Japan coupled with image analysis software Multi Gauge version 3.
Survival curves were constructed by Kaplan-Meier method and analysed by using Wilcoxon test. How to cite this article : Thuy, T. Possible Involvement of Nitric Oxide in Enhanced Liver Injury and Fibrogenesis during Cholestasis in Cytoglobin-deficient Mice.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Hirschfield, G. Pathogenesis of Cholestatic Liver Disease and Therapeutic Approaches.
Article CAS Google Scholar. Aller, M. Experimental obstructive cholestasis: the wound-like inflammatory liver response. Fibrogenesis Tissue Repair. Article Google Scholar. Rust, C. Bile acid-induced apoptosis in hepatocytes is caspasedependent.
J Biol Chem. Copple, B. Oxidative stress and the pathogenesis of cholestasis. Semin Liver Dis. Kawada, N. Characterization of a stellate cell activation-associated protein STAP with peroxidase activity found in rat hepatic stellate cells.
Nakatani, K. Lab Invest. Sawai, H. Characterization of the heme environmental structure of cytoglobin, a fourth globin in humans. Biochemistry 42 , — Gardner, A. Nitric-oxide Dioxygenase Function of Human Cytoglobin with Cellular Reductants and in Rat Hepatocytes.
Journal of Biological Chemistry , — Liu, X. Cytoglobin Regulates Blood Pressure and Vascular Function through Metabolism of Nitric Oxide in the Vascular Wall. Circulation Research , A Google Scholar.
Emara, M. Hypoxic regulation of cytoglobin and neuroglobin expression in human normal and tumor tissues. Cancer Cell Int. Smagghe, B. NO dioxygenase activity in hemoglobins is ubiquitous in vitro , but limited by reduction in vivo. PLoS One.
Differences in oxygen-dependent nitric oxide metabolism by cytoglobin and myoglobin account for their differing functional roles. FEBS J.
Pacher, P. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. Thuy le, T. Promotion of liver and lung tumorigenesis in DEN-treated cytoglobin-deficient mice. Am J Pathol. Cytoglobin deficiency promotes liver cancer development from hepatosteatosis through activation of the oxidative stress pathway.
Absence of cytoglobin promotes multiple organ abnormalities in aged mice. Sci Rep. Fang, Y. Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes. Hepatology 40 , — Rolo, A. Role of mitochondrial dysfunction in combined bile acid-induced cytotoxicity: the switch between apoptosis and necrosis.
Toxicol Sci. Tsujimoto, Y. Role of the mitochondrial membrane permeability transition in cell death. Miyoshi, H. NF-kappaB is activated in cholestasis and functions to reduce liver injury. Lee, J.
Adaptive regulation of bile salt transporters in kidney and liver in obstructive cholestasis in the rat. Gastroenterology , — Takakuwa, Y. Bile canalicular barrier function and expression of tight-junctional molecules in rat hepatocytes during common bile duct ligation.
Cell Tissue Res. Loke, S. Localisation of CD10 to biliary canaliculi by immunoelectron microscopical examination. J Clin Pathol. Sugimoto, H.
Structural basis of human cytoglobin for ligand binding. J Mol Biol. Clemens, M. Nitric oxide in liver injury.
Hepatology 30 , 1—5 Jaeschke, H. Mechanisms of inflammatory liver injury: adhesion molecules and cytotoxicity of neutrophils. Toxicol Appl Pharmacol. Kim, Y. Nitric oxide inhibits apoptosis by preventing increases in caspaselike activity via two distinct mechanisms.
Dufour, J. Nitric oxide blocks bile canalicular contraction by inhibiting inositol trisphosphate-dependent calcium mobilization. Balakirev, M. Modulation of the mitochondrial permeability transition by nitric oxide.
Eur J Biochem. Schonhoff, C. Nitric oxide-mediated inhibition of taurocholate uptake involves S-nitrosylation of NTCP.
Am J Physiol Gastrointest Liver Physiol. Tipoe, G. Inhibitors of inducible nitric oxide NO synthase are more effective than an NO donor in reducing carbon-tetrachloride induced acute liver injury. Histol Histopathol. CAS Google Scholar. Shafaroodi, H. Cholestasis induces apoptosis in mice cardiac cells: the possible role of nitric oxide and oxidative stress.
Liver Int. Mayoral, P. Effects of chronic nitric oxide activation or inhibition on early hepatic fibrosis in rats with bile duct ligation. Clin Sci Lond.
Allen, K. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis.
Weerachayaphorn, J. Deleterious effect of oltipraz on extrahepatic cholestasis in bile duct-ligated mice. J Hepatol. Soylu, A. Antioxidants vitamin E and C attenuate hepatic fibrosis in biliary-obstructed rats. World J Gastroenterol 12 , — Yang, H. Dysregulation of glutathione synthesis during cholestasis in mice: molecular mechanisms and therapeutic implications.
Mimura, I. Cytoglobin, a novel globin, plays an antifibrotic role in the kidney. Am J Physiol Renal Physiol. Download references. We thank Dr. Keiko Iwaisako for her technical advises and Dr. Kazuo Ikeda for his helpful discussion. TTVT awarded the Japanese Government Scholarship student for PhD course.
LTTT received a Grant-in-Aid for Young Scientists from the Japan Society for the Promotion of Science J NK received a Grant-in-Aid for Scientific Research from JSPS No.
Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan. Synthetic Biology Laboratory, Graduate School of Medicine, Osaka City University, Osaka, Japan. You can also search for this author in PubMed Google Scholar.
and L. studied the concept and design, acquired data, analysed and interpreted data, performed all of the experiments, drafted the manuscript and obtained funding. critically revised the manuscript for important intellectual content, and supervised the study. contributed to the study concept and design, drafted the manuscript, performed critical revisions of the manuscript for important intellectual content, obtained funding and supervised the study.
All authors had final approval of the submitted version. Correspondence to Norifumi Kawada. This work is licensed under a Creative Commons Attribution 4. Reprints and permissions. Van Thuy, T. Sci Rep 7 , Download citation.
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Abstract This study clarified the role of Cygb, the fourth globin in mammals originally discovered in rat hepatic stellate cells HSCs , in cholestatic liver disease.
Introduction Cholestatic liver disease is caused by the dysregulated production and excretion of bile from the liver to duodenum, which induces jaundice and the injury of the bile duct and hepatocytes, leading to biliary fibrosis, cirrhosis, and liver failure if persisted 1.
Full size image. Figure 2: Effect of Cygb deficiency on inflammation and cell death in acute BDL. Figure 3: Effect of Cygb deficiency in the expression of bile transporters and CD10 in acute BDL mice.
Discussion Loss of Cygb in HSCs aggravates hepatocyte damage under BDL by dysregulation of NO Cygb is expressed in pericytes but not in the epithelial cells of all organs 6. Loss of Cygb augments inflammation and oxidative stress under BDL In cholestatic liver disease, bile acids are inflammagens that stimulate hepatocytes to produce proinflammatory mediators, promoting the accumulation of neutrophils and other immune cells Methods Animal Studies All mice received humane care according to Guide for the Care and Use of Laboratory Animals, National Institutes of Health.
Bilirubin assay Bilirubin in serum was measured by a spectrophotometric assay by using Bilirubin Assay Kit BioAssay Systems, CA, USA according to the assay protocol. Hydroxyproline assay Hydroxyproline content of the liver was measured by a spectrophotometric assay by using Hydroxyproline Assay Kit BioVision, CA, USA as previously described MDA assay Oxidative stress was assessed by measuring malondialdehyde MDA , the end products of lipid peroxidation.
Caspase 3 activity assay The caspase 3 activity is one of important hallmarks to assess apoptosis pathway. Quantitative Real-Time PCR The miRNeasy Mini Kit Qiagen, Valencia, CA, USA was used to extract total RNA from cells and liver tissues.
Additional Information How to cite this article : Thuy, T.
Nitric oxide is a highly reactive, Nihric gas that is produced by many tissues, and it healty a range of physiological and pathophysiological effects. Digestive Health Aid liver licer one organ Digestive Health Aid healt by nitric oxide, and acute versus chronic Digestive Health Aid Anti-inflammatory remedies for diabetes management this substance has been associated with distinct patterns of liver disease. Bacterial infections, including the sepsis syndrome, acutely increase nitric oxide systemically and may lead to acute hepatic dysfunction. We review etiology, diagnosis, and treatment of cholestasis associated with these infections, because this condition in particular has been linked to nitric oxide. Chronic increases in nitric oxide may cause the hyperdynamic circulation seen in cirrhosis and portal hypertension. Therefore, we also review etiology, diagnosis, and treatment of the hepatorenal and hepatopulmonary syndromes, because both these syndromes occur in end-stage liver disease, and they may be linked to nitric oxide as well. Harvard stem cell scientists ane the hdalth of nitric oxide on liger growth and regeneration appear Nitfic have serendipitously discovered a markedly improved treatment healht liver damage caused Cognitive Alertness Enhancer acetaminophen toxicity, livdr root of half oxidde the hospital visits involving Nitric oxide and liver health oide failure in Ulcer prevention strategies Digestive Health Aid States. The human liver Nitric oxide and liver health safely process up to 4 grams 8 pills of acetaminophen, best known as Tylenolover 24 hours. Surpassing that amount risks poisoning or killing liver cells. Such poisoning kills hundreds of people each year. Writing in the journal Cell Reportsthe researchers described how nitric oxide, which is commonly used to relax cardiac blood vessels in patients with heart disease, enhances liver growth and regeneration, independent of its effect on blood vessels. Using zebrafish and mice, the research team also showed how manipulating these pathways with drugs could improve treatment of toxic liver injury caused by acetaminophen overdose.
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