{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T10:31:05Z","timestamp":1773916265070,"version":"3.50.1"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":3134,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2007,2]]},"abstract":"<jats:sec><jats:title\/><jats:p><jats:bold>Cholestasis is associated with changes in NO metabolism and thiol oxidation. Thioredoxin contributes to regulate vascular tone and intracellular redox status by cleaving nitrosothiols and maintaining \u2212SH groups. This study investigated the changes in circulating thioredoxin and nitrosothiols and the relationship with protein sulfhydryls (PSH), hepatic concentrations, hyaluronate, and histology in patients with primary biliary cirrhosis (PBC) and in rats with bile duct ligation (BDL). PSH in erythrocytes were significantly decreased in stage III and IV PBC and at day 10 after BDL. Compared with controls, erythrocyte thioredoxin levels were higher in stage I through III PBC and lower in stage IV patients. Serum thioredoxin levels were significantly higher in PBC stages I and II and lower in stages III and IV. Serum nitrosothiols were higher in all PBC patients and inversely related to thioredoxin and hyaluronate. In rats, serum, hepatic, and mitochondrial thioredoxin had initially increased after BDL (day 1-3) and then decreased. After day 7 BDL, nitrosothiols were 10-fold increased in serum and liver, and even higher in mitochondria. In the liver, thioredoxin was inversely related to both nitrosothiols and PSH. In rats, the difference in time average changes from baseline among serum, hepatic, and erythrocyte thioredoxin suggests that most of circulating thioredoxin originates from the liver.<\/jats:bold><\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion:<\/jats:title><jats:p><jats:bold>Our findings indicate that cholestasis is associated with significant mutual and interrelated changes between circulating and hepatic thioredoxin and nitrosothiols. The increase of hepatic, mitochondrial, and circulating nitrosothiols with ongoing cholestasis suggests an active participation of NO in both liver injury and extrahepatic changes.<\/jats:bold><\/jats:p><\/jats:sec>","DOI":"10.1002\/hep.21519","type":"journal-article","created":{"date-parts":[[2007,1,26]],"date-time":"2007-01-26T23:23:02Z","timestamp":1169853782000},"page":"331-339","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":22,"title":["Mutual changes of thioredoxin and nitrosothiols during biliary cirrhosis: Results from humans and cholestatic rats"],"prefix":"10.1097","volume":"45","author":[{"given":"Ignazio","family":"Grattagliano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piero","family":"Portincasa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo O.","family":"Palmieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Palasciano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"R1-11-20241201","first-page":"607","article-title":"Reduced antioxidative capacity in liver mitochondria from bile duct ligated rats.","volume":"22","author":"Krahenbuhl","year":"1995","journal-title":"Hepatology"},{"key":"R2-11-20241201","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/S0168-8278(02)00234-9","article-title":"Hepatic oxidative alterations in patients with extrahepatic cholestasis: effect of surgical drainage.","volume":"37","author":"Vendemiale","year":"2002","journal-title":"J Hepatol"},{"key":"R3-11-20241201","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/0024-3205(93)90456-D","article-title":"Erythrocyte alterations correlate with CCl4 and biliary obstructioninduced liver damage in the rat.","volume":"52","author":"Muriel","year":"1993","journal-title":"Life Sci"},{"key":"R4-11-20241201","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1046\/j.1365-2362.2003.01238.x","article-title":"Structural and oxidative modifications of erythrocyte ghosts in patients with primary biliary cirrhosis: relation with the disease stage and effect of bile acid treatment.","volume":"33","author":"Grattagliano","year":"2003","journal-title":"Eur J Clin Invest"},{"key":"R5-11-20241201","first-page":"1255","article-title":"Low membrane protein sulfhydrils but not G6PD deficiency predict ribavirininduced hemolysis in hepatitis C.","volume":"391248-","author":"Grattagliano","year":"2004","journal-title":"Hepatology"},{"key":"R6-11-20241201","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1067\/msy.2001.110427","article-title":"Expression of inducible nitric oxide synthase in the liver of bile ductligated Wistar rats with modulation by lymphomononuclear cells.","volume":"129","author":"Arriero","year":"2001","journal-title":"Surgery"},{"key":"R7-11-20241201","doi-asserted-by":"crossref","first-page":"17161","DOI":"10.1073\/pnas.0134112100","article-title":"Distribution of nitric oxide synthase in normal and cirrhotic human liver.","volume":"99","author":"McNaughton","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R8-11-20241201","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1046\/j.1440-1746.2002.02689.x","article-title":"Detection of serum nitrite and nitrate in primary biliary cirrhosis: possible role of nitric oxide in bile duct injury.","volume":"17","author":"Hokari","year":"2002","journal-title":"J Gastroenterol Hepatol"},{"key":"R9-11-20241201","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/S0891-5849(01)00647-5","article-title":"Increased formation of Snitrothiols and nitrotyrosine in cirrhotic rats during endotoxemia.","volume":"31","author":"Ottesen","year":"2001","journal-title":"Free Radic Biol Med"},{"key":"R10-11-20241201","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/S0168-8278(02)00266-0","article-title":"Enhanced intrahepatic inducible nitric oxide synthase expression and nitrotyrosine accumulation in primary biliary cirrhosis and autoimmune hepatitis.","volume":"37","author":"SanzCameno","year":"2002","journal-title":"J Hepatol"},{"key":"R11-11-20241201","first-page":"1018","article-title":"Myeloperoxidasepositive inflammatory cells participate in bile duct damage in primary biliary cirrhosis through nitric oxidemediated reactions.","volume":"38","author":"Wu","year":"2003","journal-title":"Hepatology"},{"key":"R12-11-20241201","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/S0891-5849(01)00724-9","article-title":"Reactive oxygen species, antioxidants, and the mammalian thioredoxin system.","volume":"31","author":"Nordberg","year":"2001","journal-title":"Free Radic Biol Med"},{"key":"R13-11-20241201","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0076-6879(02)47030-9","article-title":"Mitochondrial thioredoxin reductase and thiol status.","volume":"347","author":"Bindoli","year":"2002","journal-title":"Methods Enzymol"},{"key":"R14-11-20241201","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1146\/annurev.immunol.15.1.351","article-title":"Redox regulation of cellular activation.","volume":"15","author":"Nakamura","year":"1997","journal-title":"Annu Rev Immunol"},{"key":"R15-11-20241201","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/S0891-5849(97)00216-5","article-title":"Purification of mitochondrial thioredoxin reductase and its involvement in the redox regulation of membrane permeability.","volume":"24","author":"Rigobello","year":"1998","journal-title":"Free Radic Biol Med"},{"key":"R16-11-20241201","doi-asserted-by":"crossref","first-page":"351","DOI":"10.4049\/jimmunol.163.1.351","article-title":"Involvement of thioredoxin in rheumatoid arthritis: its costimulatory roles in the TNFalphainduced production of IL6 and IL8 from cultured synovial fibroblasts.","volume":"163","author":"Yoshida","year":"1999","journal-title":"J Immunol"},{"key":"R17-11-20241201","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1084\/jem.189.11.1783","article-title":"Thioredoxin, a redox enzyme released in infection and inflammation, is a unique chemoattractant for neutrophils, monocytes, and T cells.","volume":"189","author":"Bertini","year":"1999","journal-title":"J Exp Med"},{"key":"R18-11-20241201","doi-asserted-by":"crossref","first-page":"19180","DOI":"10.1074\/jbc.271.32.19180","article-title":"Snitrosoglutathione is cleaved by the thioredoxin system with liberation of glutathione and redox regulating nitric oxide.","volume":"271","author":"Nikitovic","year":"1996","journal-title":"J Biol Chem"},{"key":"R19-11-20241201","doi-asserted-by":"crossref","first-page":"15815","DOI":"10.1021\/ja0529135","article-title":"Thioredoxin and lipoic acid catalyze the denitrosation of low molecular weight and protein Snitrosothiols.","volume":"127","author":"Stoyanovsky","year":"2005","journal-title":"J Am Chem Soc"},{"key":"R20-11-20241201","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/j.exger.2004.06.001","article-title":"Effect of dietary restriction and Nacetylcysteine supplementation on intestinal mucosa and liver mitochondrial redox status and function in aged rats.","volume":"39","author":"Grattagliano","year":"2004","journal-title":"Exp Gerontol"},{"key":"R21-11-20241201","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1006\/abbi.1995.1231","article-title":"NO, NO, and NO donation by Snitrosothiols: implications for regulation of physiological functions by Snitrosylation and acceleration of disulfide formation.","volume":"318","author":"Arnelle","year":"1995","journal-title":"Arch Biochem Biophys"},{"key":"R22-11-20241201","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/0092-8674(94)90269-0","article-title":"Redox signaling: nitrosylation and related target interactions of nitric oxide.","volume":"78","author":"Stamler","year":"1994","journal-title":"Cell"},{"key":"R23-11-20241201","doi-asserted-by":"crossref","first-page":"7674","DOI":"10.1073\/pnas.89.16.7674","article-title":"Nitric oxide circulates in mammalian plasma primarily as an Snitroso adduct of serum albumin.","volume":"89","author":"Stamler","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R24-11-20241201","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/S0168-8278(02)00331-8","article-title":"Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease.","volume":"38","author":"Sumida","year":"2003","journal-title":"J Hepatol"},{"key":"R25-11-20241201","first-page":"G459","article-title":"Enhanced endotheliumdependent vasodilation in patients with cirrhosis.","volume":"268","author":"Albillos","year":"1995","journal-title":"Am J Physiol"},{"key":"R26-11-20241201","first-page":"1257","article-title":"Primary biliary cirrhosis.","volume":"60","author":"Scheuer","year":"1967","journal-title":"Proc R Soc Med"},{"key":"R27-11-20241201","doi-asserted-by":"crossref","first-page":"4164","DOI":"10.1016\/S0021-9258(18)50710-9","article-title":"Riboflavin and rat hepatic cell structure and function. Mitochondrial oxidative metabolism in deficiency states.","volume":"254","author":"Hoppel","year":"1979","journal-title":"J Biol Chem"},{"key":"R28-11-20241201","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/0076-6879(95)52023-6","article-title":"Thioredoxin and thioredoxin reductase.","volume":"252","author":"Holmgren","year":"1995","journal-title":"Methods Enzymol"},{"key":"R29-11-20241201","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1006\/abio.1996.0268","article-title":"Convenient colorimetric and fluorometric assays for Snitrosothiols.","volume":"238","author":"Cook","year":"1996","journal-title":"Anal Biochem"},{"key":"R30-11-20241201","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/S0168-8278(96)80324-2","article-title":"Oxidation of circulating proteins in alcoholics: role of acetaldehyde and xanthine oxidase.","volume":"25","author":"Grattagliano","year":"1996","journal-title":"J Hepatol"},{"key":"R31-11-20241201","first-page":"615","article-title":"Regulation and subcellular location of nitrogen oxide synthases in RAW264.7 macrophages.","volume":"41","author":"Schmidt","year":"1992","journal-title":"Mol Pharmacol"},{"key":"R32-11-20241201","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1016\/j.freeradbiomed.2006.01.004","article-title":"Metalloproteindependent decomposition of Snitrosothiols: studies on the stabilization and measurement of Snitrosothiols in tissues.","volume":"40","author":"Mani","year":"2006","journal-title":"Free Radic Biol Med"},{"key":"R33-11-20241201","first-page":"1529","article-title":"Biological activity of Snitrosothiols: the role of nitric oxide.","volume":"267","author":"Mathews","year":"1993","journal-title":"J Pharmacol Exp Ther"},{"key":"R34-11-20241201","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1053\/jhep.2002.31432","article-title":"The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough.","volume":"35","author":"Wiest","year":"2002","journal-title":"Hepatology"},{"key":"R35-11-20241201","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/S0022-3565(24)29200-4","article-title":"Arginine reverses ethanolinduced inflammatory and fibrotic changes in liver despite continued ethanol administration.","volume":"299","author":"Nanji","year":"2001","journal-title":"J Pharmacol Exp Ther"},{"key":"R36-11-20241201","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.jhep.2004.09.020","article-title":"Overexpression of thioredoxin prevents thioacetamideinduced hepatic fibrosis in mice.","volume":"42","author":"Okuyama","year":"2005","journal-title":"J Hepatol"},{"key":"R37-11-20241201","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1034\/j.1600-0676.2002.01653.x","article-title":"Endothelial, but not the inducible, nitric oxide synthase is detectable in normal and portal hypertensive rats.","volume":"22","author":"Stumm","year":"2002","journal-title":"Liver"},{"key":"R38-11-20241201","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/S0168-8278(96)80218-2","article-title":"Decreased constitutive hepatic nitric oxide synthase expression in secondary biliary fibrosis and its changes after RouxenY choledochojejunostomy in the rat.","volume":"25","author":"Zimmermann","year":"1996","journal-title":"J Hepatol"},{"key":"R39-11-20241201","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.3748\/wjg.v11.i13.1951","article-title":"Protective effect of low dose of melatonin against cholestatic oxidative stress after common bile duct ligation in rats.","volume":"11","author":"Esrefoglu","year":"2005","journal-title":"World J Gastroenterol"},{"key":"R40-11-20241201","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.freeradbiomed.2004.12.016","article-title":"SNitrosothiols: cellular formation and transport.","volume":"38","author":"Zhang","year":"2005","journal-title":"Free Radic Biol Med"},{"key":"R41-11-20241201","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/S0891-5849(02)00901-2","article-title":"Mitochondria: regulators of signal transduction by reactive oxygen and nitrogen species.","volume":"33","author":"Brookes","year":"2002","journal-title":"Free Radic Biol Med"},{"key":"R42-11-20241201","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.abb.2004.11.015","article-title":"The extracellular microenvironment plays a key role in regulating the redox status of cell surface proteins in HIVinfected subjects.","volume":"434","author":"Sahaf","year":"2005","journal-title":"Arch Biochem Biophys"},{"key":"R43-11-20241201","doi-asserted-by":"crossref","first-page":"7631","DOI":"10.1073\/pnas.95.13.7631","article-title":"Persistent inhibition of cell respiration by nitric oxide: crucial role of Snitrosylation of mitochondrial complex I and protective action of glutathione.","volume":"95","author":"Clementi","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R44-11-20241201","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/S0014-5793(97)01397-5","article-title":"Nitric oxide synthase activity in mitochondria.","volume":"418","author":"Ghafourifar","year":"1997","journal-title":"FEBS Lett"},{"key":"R45-11-20241201","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1042\/bj3560395","article-title":"Metabolism of Snitrosoglutathione in intact mitochondria.","volume":"356","author":"Steffen","year":"2001","journal-title":"Biochem J"},{"key":"R46-11-20241201","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/hep.20255","article-title":"Mitochondrial nitric oxide synthase drives redox signals for proliferation and quiescence in rat liver development.","volume":"40","author":"Carreras","year":"2004","journal-title":"Hepatology"},{"key":"R47-11-20241201","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1126\/science.1079368","article-title":"Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide.","volume":"299","author":"Nisoli","year":"2003","journal-title":"Science"},{"key":"R48-11-20241201","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0163-7258(93)90020-E","article-title":"Alterations in mitochondrial function and morphology in chronic liver disease: pathogenesis and potential for therapeutic intervention.","volume":"60","author":"Krahenbuhl","year":"1993","journal-title":"Pharmacol Ther"},{"key":"R49-11-20241201","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1002\/hep.20813","article-title":"Glutathione depletion renders rat hepatocytes sensitive to nitric oxide donormediated toxicity.","volume":"42","author":"Chen","year":"2005","journal-title":"Hepatology"},{"key":"R50-11-20241201","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1006\/jsre.2002.6436","article-title":"Increased nitric oxide production in hepatocytes is involved in liver dysfunction following obstructive jaundice.","volume":"106","author":"Tu","year":"2002","journal-title":"J Surg Res"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.21519","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200702000-00011","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T06:32:59Z","timestamp":1736749979000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200702000-00011"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,2]]},"references-count":50,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2007]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.21519","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2007,2]]}}}