endothelin-1 and Chemical-and-Drug-Induced-Liver-Injury

Tannic acid (TA) is the polyphenol that has beneficial health effects against oxidative stress. However, the hepatoprotective effects of TA are still relatively unknown. In the present study, we evaluated the effects of TA on an acetaminophen (APAP)-induced hepatotoxicity model, which was established by administration of 400mg/kg of APAP. The levels of alanine transferase (ALT), aspartate transferase (AST), dendothelin-1 (ET-1), nitric oxide (NO) and malondialdehyde (MDA) in the APAP-induced hepatotoxicity mice were significantly increased (up to ~200%), while their levels were reduced by pretreatment with TA (25 and 50mg/kg) (P<0.05). The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in the APAP-induced hepatotoxicity mice were significantly reduced (lower to ~65%), while their activities were increased by pretreatment with TA (25 and 50mg/kg) (P<0.05). In addition, pretreatment with oral TA (25 and 50mg/kg) for 3days before the APAP administration dose-dependently ameliorated changes in hepatic histopathology, suppressed overexpression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), c-fos, c-jun, NF-κB (p65) and caspase-3 (all P<0.05), downregulated bax and upregulated bcl-2, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) (all P<0.05) in the liver. These results indicate that TA exhibits significant hepatoprotective effects against APAP-induced hepatotoxicity and suggest that the hepatoprotective mechanisms of TA may be related to anti-oxidation, anti-inflammation and anti-apoptosis.

Topics: Acetaminophen; Alanine Transaminase; Animals; Anti-Inflammatory Agents; Apoptosis; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Endothelin-1; Heme Oxygenase-1; Humans; Inflammation Mediators; Malondialdehyde; Mice; Mice, Inbred Strains; Nitric Oxide; Oxidative Stress; Superoxide Dismutase; Tannins

Evidence indicates that Cadmium (Cd) can accumulate in liver, which results in acute or chronic cell damage with unclear complex mechanisms. Thus, we aimed to explore the possible molecules and pathways by using bioinformatics methods Consequently, two datasets (GSE8865 and GSE31286) were retrieved and the differentially expressed genes (DEGs) were screened out. The intersection of the DEGs included seven up-regulated and forty-three down-regulated genes, which were mainly enriched in biological cell proliferation items, and were enriched in several metabolism-related pathways. Among the DEGs, several hub genes such as EGR1, FOSL1, ITGA2, EDN1, and IER3 were screened out through protein-protein interaction analysis. Interestingly, BW-B70C was predicted to be a potential agent for attenuating Cd-induced liver cell damage. The present study gave a novel insight into the mechanisms of Cd-induced liver cell damage or malignant transformation and identified several small agents that might be critical for Cd toxicity prevention and treatment.

Topics: Apoptosis Regulatory Proteins; Cadmium; Chemical and Drug Induced Liver Injury; Computational Biology; Databases, Genetic; Early Growth Response Protein 1; Endothelin-1; Gene Expression Regulation; Gene Regulatory Networks; Humans; Hydroxyurea; Integrin alpha2; Membrane Proteins; Protein Interaction Maps; Proto-Oncogene Proteins c-fos; Signal Transduction; Small Molecule Libraries

This study was designed to investigate the protective effects of bosentan an orally active non-peptide mixed ETA/ETB receptor antagonist, on liver injury in streptozotocin-induced diabetic rats.. 24 Albino-Wistar rats were randomly divided into 4 groups: healthy (Group 1), diabetic (Group 2) (60 mg/kg of streptozotocin i.p.), diabetic treated with bosentan 50 mg/kg (Group 3) and diabetic treated with bosentan 100 mg/kg (Group 4). The treatment of bosentan was initiated after streptozocin injection and continued for 60 days.. Liver from diabetic rats showed significant increase in malondialdehyde (MDA) level and significant decrease in glutathione (GSH), and superoxide dismutase (SOD) activity. Endothelin (ET-1), tumor necrosis factor (TNF-α) and transforming growth factor beta (TGF-β) gene expression significantly increased in the diabetic groups in the rat liver tissue. Bosentan treatment showed a significant up-regulatory effect on ET-1, TNF-α and TGF-β mRNA expression. Results from histopathological evaluation of the liver were in accordance with our biochemical and molecular results.. These data provide clear evidence that bosentan treatment is associated with promising hepatoprotective effect against diabetes-induced liver damage via reduction of cell inflammation and oxidative damage. These data suggest that ET receptors may be an important actor in diabetes-related liver damage, and blockage of these receptors may become a target for preventing diabetic complications in the future.

Topics: Animals; Bosentan; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Experimental; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Glutathione; Liver; Male; Malondialdehyde; Rats; Streptozocin; Sulfonamides; Superoxide Dismutase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Hepatic stellate cells (HSCs) that express glial fibrillary acidic protein (GFAP) are located between the sinusoidal endothelial cells and hepatocytes. HSCs are activated during liver injury and cause hepatic fibrosis by producing excessive extracellular matrix. HSCs also produce many growth factors, chemokines and cytokines, and thus may play an important role in acute liver injury. However, this function has not been clarified due to unavailability of a model, in which HSCs are depleted from the normal liver.. We treated mice expressing HSV-thymidine kinase under the GFAP promoter (GFAP-Tg) with 3 consecutive (3 days apart) CCl4 (0.16 μl/g; ip) injections to stimulate HSCs to enter the cell cycle and proliferate. This was followed by 10-day ganciclovir (40 μg/g/day; ip) treatment, which is expected to eliminate actively proliferating HSCs. Mice were then subjected to hepatic ischemia/reperfusion (I/R) or endotoxin treatment.. CCl4/ganciclovir treatment caused depletion of the majority of HSCs (about 64-72%), while the liver recovered from the initial CCl4-induced injury (confirmed by histology, serum ALT and neutrophil infiltration). The magnitude of hepatic injury due to I/R or endotoxemia (determined by histopathology and serum ALT) was lower in HSC-depleted mice. Their hepatic expression of TNF-α, neutrophil chemoattractant CXCL1 and endothelin-A receptor also was significantly lower than the control mice.. HSCs play an important role both in I/R- and endotoxin-induced acute hepatocyte injury, with TNF-α and endothelin-1 as important mediators of these effects.

Topics: Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Chemokine CXCL1; Disease Models, Animal; Endothelin-1; Ganciclovir; Gene Expression; Glial Fibrillary Acidic Protein; Hepatic Stellate Cells; Interleukin-6; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Reperfusion Injury; Thymidine Kinase; Tumor Necrosis Factor-alpha

Paracetamol is one of the first rank drugs which cause hepatic damage during drug intoxications. Endothelin (ET) which is known as one of the most potent vasoactive agent has been shown to contribute in the pathophysiology of various diseases. We hypothesized that bosentan, which is a non-selective ET-1 receptor antagonist, can prevent liver damage. This study included 49 female rats. Groups; I: Healthy group, II: Paracetamol (2 g/kg orally). Groups 3, 4 and 5 received NAC 140 mg/kg (2 doses), BOS 45 mg/kg and BOS 90 mg/kg orally, respectively. 1 h after administration of pretreatment drugs, Groups 3, 4, 5 were given paracetamol. VI: received BOS 90 mg/kg. VII: received 140 mg/kg NAC (2 doses). According to biochemical results, TNF-α, ALT and AST levels were statistically increased in the paracetamol group, these parameters were improved in the bosentan groups. Paracetamol administration decreased SOD activity, GSH level and increased level of MDA in the liver, while bosentan administration significantly improved these parameters. In immunohistochemical staining ET-1 receptor expression was excessively increased in paracetamol group, but not in bosentan groups when compared to healthy control. All these results suggest that bosentan exerted protective effects against experimentally induced paracetamol toxicity in liver.

Topics: Acetaminophen; Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Bosentan; Chemical and Drug Induced Liver Injury; Cytoprotection; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Female; Liver; Oxidative Stress; Rats; Receptors, Endothelin; Sulfonamides; Tumor Necrosis Factor-alpha

Liver fibrosis is mediated by hepatic stellate cells (HSCs), which respond to a variety of cytokine and growth factors to moderate the response to injury and create extracellular matrix at the site of injury. G-protein coupled receptor (GPCR)-mediated signaling, via endothelin-1 (ET-1) and angiotensin II (AngII), increases HSC contraction, migration and fibrogenesis. Regulator of G-protein signaling-5 (RGS5), an inhibitor of vasoactive GPCR agonists, functions to control GPCR-mediated contraction and hypertrophy in pericytes and smooth muscle cells (SMCs). Therefore we hypothesized that RGS5 controls GPCR signaling in activated HSCs in the context of liver injury. In this study, we localize RGS5 to the HSCs and demonstrate that Rgs5 expression is regulated during carbon tetrachloride (CCl4)-induced acute and chronic liver injury in Rgs5LacZ/LacZ reporter mice. Furthermore, CCl4 treated RGS5-null mice develop increased hepatocyte damage and fibrosis in response to CCl4 and have increased expression of markers of HSC activation. Knockdown of Rgs5 enhances ET-1-mediated signaling in HSCs in vitro. Taken together, we demonstrate that RGS5 is a critical regulator of GPCR signaling in HSCs and regulates HSC activation and fibrogenesis in liver injury.

Topics: Animals; Cell Line; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Endothelin-1; Gene Expression; Gene Expression Regulation; Hematopoietic Stem Cells; Hepatic Stellate Cells; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Male; Mice; Mice, Knockout; Mice, Transgenic; RGS Proteins; RNA, Small Interfering; Signal Transduction

The effects of endothelin 1 (ET-1) on hemodynamics and acute liver damage were studied using perfused livers of rats treated with D-galactosamine. In control liver perfused in situ with constant pressure, infusion of ET-1 into the portal vein at a concentration of 0.1 nmol/L decreased the flow rate without a significant leakage of lactate dehydrogenase (LDH) or aspartate transaminase (AST) into the effluent. In contrast, in similarly perfused liver 24 hours after treatment with D-galactosamine (800 mg/kg intraperitoneally), ET-1 caused rapid and remarkable increases in the leakage of LDH and AST from the liver accompanied by the reduction of perfusion flow to the extent similar to that observed in control livers. In addition, ET-1 decreased oxygen uptake and bile secretion in galactosamine-treated livers. The potentiating effects of ET-1 on enzyme leakage were also observed under constant flow conditions. Moreover, infusion of the thromboxane A2 analogue at a concentration of 10 nmol/L decreased the flow rate markedly, yet the rapid increases in enzyme leakage were not observed. Infusion of ET-3 induced the responses of flow reduction and the potentiation of rapid enzyme leakage similar to those obtained with ET-1. Neither the endothelin A-receptor antagonist BQ485 nor the endothelin B-receptor antagonist BQ788 could inhibit the acute liver damage caused by ET-1; instead they exaggerated its effects. The combination of both antagonists together, however, almost completely suppressed the flow reduction and the potentiation of enzyme leakage caused by ET-1. These results indicate that ET-1 is capable of aggravating acute liver damage not merely through reduction of the flow rate but through direct action on liver cells. They also suggest that both the endothelin A and endothelin B receptors are involved in this action of ET-1.

Topics: Acute Disease; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Galactosamine; Hemodynamics; L-Lactate Dehydrogenase; Liver; Liver Circulation; Liver Diseases; Male; Perfusion; Rats; Rats, Sprague-Dawley; Thromboxane A2

The major objective of the present study was to evaluate mechanisms by which teprenone, a gastric mucosal protecting agent, increases hepatic mucosal blood flow using male Sprague-Dawley rats. Hepatic and gastric blood flow was measured using a laser blood flow meter after administration of teprenone, dissolved in Tween 80, into the inferior vena cava. Teprenone itself increased hepatic and gastric blood flow. It also increased hepatic and gastric blood flow in rats with acute hepatic disorders due to carbon tetrachloride (CCL4) and improved histological changes, such as inflammatory cell infiltration and fatty changes in the liver. The fact that blood endothelin (ET) concentrations increased after administration of teprenone suggest that teprenone has great affinity for ET beta receptors and shows ET beta-receptor antagonist-like effects. Hepatic blood flow decreased after administration of N-nitro-L-arginine methyl ester, a nitric oxide (NO) synthetase inhibitor, suggesting that teprenone increase NO activity. Teprenone was thought to increase hepatic and gastric blood flow by different mechanisms, because it increased gastric mucosal prostaglandin E2 concentrations.

Topics: Animals; Anti-Ulcer Agents; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Diterpenes; Endothelin-1; Gastric Mucosa; Liver; Liver Circulation; Male; Nitric Oxide; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Stimulation, Chemical